Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]([CH2:50][CH3:51])[C:4]([C:6]1[CH:11]=[C:10]([C:12]2[CH:13]=[N:14][N:15]([CH2:17][CH2:18][CH2:19][OH:20])[CH:16]=2)[CH:9]=[CH:8][C:7]=1[NH:21][C:22]1[C:27]([C:28]([F:31])([F:30])[F:29])=[CH:26][N:25]=[C:24]([NH:32][C:33]2[CH:47]=[CH:46][C:36]([CH2:37][P:38](=[O:45])([O:42]CC)[O:39][CH2:40][CH3:41])=[CH:35][C:34]=2[O:48][CH3:49])[N:23]=1)=[O:5])[CH3:2].[I-].[Na+]>N1C=CC=CC=1>[CH2:50]([N:3]([CH2:1][CH3:2])[C:4]([C:6]1[CH:11]=[C:10]([C:12]2[CH:13]=[N:14][N:15]([CH2:17][CH2:18][CH2:19][OH:20])[CH:16]=2)[CH:9]=[CH:8][C:7]=1[NH:21][C:22]1[C:27]([C:28]([F:29])([F:30])[F:31])=[CH:26][N:25]=[C:24]([NH:32][C:33]2[CH:47]=[CH:46][C:36]([CH2:37][P:38](=[O:42])([OH:45])[O:39][CH2:40][CH3:41])=[CH:35][C:34]=2[O:48][CH3:49])[N:23]=1)=[O:5])[CH3:51]
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(-c4cnn(CCCO)c4)cc3C(=O)N(CC)CC)n2)c(OC)c1)OCC
Agent: [I-]
Agent: [Na+]
Solvent: c1ccncc1
Product: CCOP(=O)(O)Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(-c4cnn(CCCO)c4)cc3C(=O)N(CC)CC)n2)c(OC)c1
Yield: 76.1 %

Procedure:
A mixture of diethyl (4-{[4-({2-(diethylcarbamoyl)-4-[1-(3-hydroxypropyl)-1H-pyrazol-4-yl]phenyl}amino)-5-(trifluoromethyl)pyrimidin-2-yl]amino}-3-methoxybenzyl)phosphonate (Compound 3B, 228 mg, 311 μmol), sodium iodide (158 mg, 1.06 mmol) in pyridine (3.52 ml) was stirred at reflux for 16 hrs then concentrated in vacuo to a solid which was purified by a Teledyne ISCO Combiflash® Rf system [elution gradient: 5%→95% MeOH in water over 25 CV using a C-18 RP column] to yield the desired product (167 mg, 76%). 1H NMR (400 MHz, CD3OD) δ 8.25 (s, 1H), 8.18 (s, 1H), 7.93 (s, 1H), 7.74 (d, J=1.01 Hz, 2H), 7.69 (d, J=7.07 Hz, 1H), 7.55 (s, 1H), 6.99 (br. s., 1H), 6.52 (br. s., 1H), 4.32 (t, J=6.69 Hz, 2H), 3.88 (s, 3H), 3.71-3.80 (m, 2H), 3.59 (t, J=6.06 Hz, 2H), 3.47 (d, J=6.32 Hz, 2H), 3.14-3.23 (m, 2H), 2.85 (d, J=19.96 Hz, 2H), 2.07-2.16 (m, 2H), 1.11 (t, J=6.82 Hz, 6H), 0.90 (br. s., 3H). MS (ESI): m/z 706.80 [M+H]+. UPLC: tR=1.07 min (UPLC-SQD: analytical—2 min).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:27])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][C:16]=2[CH:25]=O)[CH:7]=1)[CH3:2].[CH2:28]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[C@@H:30]([NH2:37])[C@H:29]1[OH:38]>>[CH2:1]([O:3][C:4](=[O:27])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:23])([F:22])[F:24])=[CH:17][C:16]=2[CH2:25][NH:37][C@@H:30]2[C:31]3[C:36](=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH2:28][C@@H:29]2[OH:38])[CH:7]=1)[CH3:2]
Reactant: N[C@@H]1c2ccccc2C[C@@H]1O
Reactant: CCOC(=O)Cc1ccc(OC)c(Oc2ccc(C(F)(F)F)cc2C=O)c1
Product: CCOC(=O)Cc1ccc(OC)c(Oc2ccc(C(F)(F)F)cc2CN[C@@H]2c3ccccc3C[C@@H]2O)c1

Procedure:
Prepared according to the procedure described in Example 45, Step 3, using the following starting materials: [3-(2-Formyl-4-trifluoromethyl-phenoxy)-4-methoxy-phenyl]-acetic acid ethyl ester and (1R,2S)-(+)-cis-1-amino-2-indanol.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[CH2:4][CH2:5][NH2:6].C(N(C(C)C)CC)(C)C.[Cl:21][CH:22]([CH3:26])[C:23](Cl)=[O:24]>ClCCl>[Cl:21][CH:22]([CH3:26])[C:23]([NH:6][CH2:5][CH2:4][C:3]1[CH:7]=[CH:8][C:9]([Cl:11])=[CH:10][C:2]=1[Cl:1])=[O:24]
Reactant: CC(Cl)C(=O)Cl
Reactant: NCCc1ccc(Cl)cc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(Cl)C(=O)NCCc1ccc(Cl)cc1Cl
Temperature: 20 °C
Reaction time: 4 h
Yield: 100.9 %

Procedure:
A solution of 2,4-dichlorophenethylamine (1.0 g, 5.3 mmol) in dichloromethane (20 mL) was treated with diisopropylethylamine (0.82 g, 6.3 mmol) and 2-chloropropionylchloride (0.67 mL, 5.3 mmol) sequentially, and stirred at 20° C. for 4 hours. The mixture was diluted with dichloromethane (50 mL), washed with 10% aqueous HCl, brine (20 mL), dried with Na2SO4 and concentrated, resulting in 1.5 g of the desired product as a brown oil. MS calculated for C11H12Cl3NO+H: 280, observed: 280.
Reaction SMILES: Br[C:2]1[CH:8]=[C:7]([Cl:9])[C:5]([NH2:6])=[C:4]([Cl:10])[CH:3]=1.[Cl:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1B(O)O>>[Cl:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:2]1[CH:8]=[C:7]([Cl:9])[C:5]([NH2:6])=[C:4]([Cl:10])[CH:3]=1
Reactant: OB(O)c1ccccc1Cl
Reactant: Nc1c(Cl)cc(Br)cc1Cl
Product: Nc1c(Cl)cc(-c2ccccc2Cl)cc1Cl
Yield: 69.9 %

Procedure:
The title compound (0.4 g) was prepared from 4-bromo-2,6-dichloroaniline (0.5 g, 2.1 mmol) and 2-chlorophenylboronic acid (0.421 g, 2.7 mmol) as a white solid. 1H-NMR (δ ppm, DMSO-d6, 400 MHz): 7.55-7.50 (m, 1H), 7.40-7.32 (m, 3H), 7.29 (s, 2H), 5.72 (s, 2H).
Reaction SMILES: [Br:1][C:2]1[C:3]([F:20])=[C:4]([F:19])[C:5]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:18])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[CH2:21]1COCC1.C[Si](C=[N+]=[N-])(C)C>CO>[CH3:21][O:8][C:7](=[O:9])[C:6]1[CH:10]=[C:2]([Br:1])[C:3]([F:20])=[C:4]([F:19])[C:5]=1[NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[Cl:18]
Reactant: C1CCOC1
Reactant: O=C(O)c1cc(Br)c(F)c(F)c1Nc1ccccc1Cl
Agent: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Product: COC(=O)c1cc(Br)c(F)c(F)c1Nc1ccccc1Cl
Reaction time: 2 h
Yield: 93 %

Procedure:
To a solution of 5-bromo-2-(2-chlorophenylamino)-3,4-difluorobenzoic acid (3) (4.50 g, 12.4 mmol) in a 3:1 mixture of THF:MeOH (32 mL) was added (trimethylsilyl)-diazomethane (8.10 ml of a 2 M solution in hexanes) at room temperature. After stirring for 2 hours, the reaction mixture was quenched with acetic acid, diluted with EtOAc, and washed with water. The organic layer was dried (MgSO4) and concentrated under reduced pressure to give 4.35 g (93%) of the desired methyl ester (4).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([N:13]1[CH2:18][CH2:17][CH:16]([C:19]3[C:24]([O:25][CH3:26])=[CH:23][CH:22]=[CH:21][C:20]=3[O:27][CH3:28])[CH2:15][CH2:14]1)=[O:12])=[CH:5]2.[H-].[Na+].Cl[CH2:32][C:33]([N:35]([CH3:37])[CH3:36])=[O:34]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:32][C:33]([N:35]([CH3:37])[CH3:36])=[O:34])[C:6]([C:11]([N:13]1[CH2:14][CH2:15][CH:16]([C:19]3[C:24]([O:25][CH3:26])=[CH:23][CH:22]=[CH:21][C:20]=3[O:27][CH3:28])[CH2:17][CH2:18]1)=[O:12])=[CH:5]2
Reactant: CN(C)C(=O)CCl
Reactant: COc1cccc(OC)c1C1CCN(C(=O)c2cc3cc(Cl)ccc3[nH]2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cccc(OC)c1C1CCN(C(=O)c2cc3cc(Cl)ccc3n2CC(=O)N(C)C)CC1
Reaction time: 0.33 h
Yield: 72.3 %

Procedure:
To a stirred solution of 40 mg (0.10 mmol) of (5-chloro-1H-indol-2-yl)-[4-(2,6-dimethoxy-phenyl)-piperidin-1-yl]-methanone in DMF (3 ml) at RT was added 5 mg (0.11 mmol) of NaH (in oil, 55%). After 20 minutes, 12 mg (0.10 mmol) of 2-chloro-N,N-dimethyl-acetamide was added and stirring was continued over night. The reaction mixture was concentrated in vacuo and purification by preparative HPLC (30% CH3CN/H2O) afforded 35 mg (72%) of 2-{5-chloro-2-[4-(2,6-dimethoxy-phenyl)-piperidine-1-carbonyl]-indol-1-yl}-N,N-dimethyl-acetamide as a white solid.
Reaction SMILES: C([O:3][C:4](=[O:34])[C@@H:5]([O:32][CH3:33])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][CH2:16][O:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]([F:31])([F:30])[CH:27]([F:29])[F:28])=[CH:20][CH:19]=2)=[CH:9][CH:8]=1)C.[OH-].[Na+]>>[CH3:33][O:32][C@@H:5]([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][CH2:14][CH2:15][CH2:16][O:17][C:18]2[CH:19]=[CH:20][C:21]([O:24][CH2:25][C:26]([F:30])([F:31])[CH:27]([F:29])[F:28])=[CH:22][CH:23]=2)=[CH:11][CH:12]=1)[C:4]([OH:34])=[O:3]
Reactant: CCOC(=O)[C@H](Cc1ccc(OCCCOc2ccc(OCC(F)(F)C(F)F)cc2)cc1)OC
Agent: [Na+]
Agent: [OH-]
Product: CO[C@@H](Cc1ccc(OCCCOc2ccc(OCC(F)(F)C(F)F)cc2)cc1)C(=O)O

Procedure:
The title compound was prepared from (2S)-2-methoxy-3-(4-{3-[4-(2,2,3,3-tetrafluoro-propoxy)-phenoxy]-propoxy}-phenyl)-propionic acid ethyl ester (Step C) by standard hydrolysis procedure C (NaOH). 1H-NMR (CDCl3, 200.15 MHz): δ 7.14 (d, 2H, J=8.6), 6.84–6.79 (m, 6H), 6.04 (tt, 1H, J=53.0, 4.8), 4.27 (t, 2H, J=12.0), 4.09 (t, 4H, J=5.9), 3.97–3.91 (m, 1H), 3.34 (s, 3H), 3.11–2.87 (m, 2H), 2.20 (qn, 2H, J=5.9).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O.Br[CH:22]1[CH2:24][CH2:23]1>[I-].[K+].O>[CH:22]1([O:1][C:2]2[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=2)[CH2:24][CH2:23]1
Reactant: O=Cc1ccc(O)cc1
Reactant: BrC1CC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=Cc1ccc(OC2CC2)cc1
Temperature: 200 °C
Reaction time: 3 h

Procedure:
To a mixture of 4-hydroxybenzaldehyde (1.20 g), potassium carbonate (2.04 g), potassium iodide (49.0 mg) and N,N-dimethylformamide (9.80 mL), bromocyclopropane (1.02 mL) was added and the mixture was stirred at 200° C. for 3 hours under irradiation with microwaves. After being cooled to room temperature, the reaction mixture was poured into water and extracted with diethyl ether three times. The combined organic layers were washed with saturated brine and thereafter passed through a phase separator to be concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=100:0-50:50) to give the titled compound as a colorless oil (510 mg).
Reaction SMILES: [H-].[Na+].[CH2:3]([O:10][CH:11]([CH2:14][OH:15])[CH2:12][OH:13])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.O.[CH2:17]1[CH2:21][O:20][CH2:19][CH2:18]1>>[CH2:3]([O:10][CH:11]1[CH2:12][O:13][CH2:17][CH2:21][O:20][CH2:19][CH2:18][O:15][CH2:14]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: C1CCOC1
Reactant: OCC(CO)OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: c1ccc(COC2COCCOCCOC2)cc1
Temperature: 23 °C
Yield: 19 %

Procedure:
To a refluxing suspension of sodium hydride (60% in mineral oil, pre-washed with hexane, 84 mg, 2.1 mmol) in dry THF (5 mL), a solution of 17 (182 mg, 1.0 mmol) and di(ethyleneglycol)dimethanesulfonate (260 mg, 1.0 mmol) in dry THF (5 mL) was added dropwise. The resulting mixture was heated under reflux for 20 h, afterward was cooled to 23° C. and H2O (2 mL) was added. The solvent was removed and the aqueous phase was extracted with CHCl3. The organic extracts were washed several times with water, dried (Na2SO4) and evaporated. The residue was purified by flash-chromatography (2:3 CH2Cl2/EtOAc) to afford 49 mg (19%) of 18 as a colourless oil: 1H NMR (CDCl3) δ 7.36-7.26 (m, 5H), 4.66 (s, 2H), 3.75-3.57 (m, 13H); MS (ESI) m/z 275 [M+Na]+.
Reaction SMILES: [F:1][C:2]1[C:3]([O:13][CH3:14])=[C:4](I)[C:5]2[O:9][CH2:8][C:7](=[O:10])[C:6]=2[CH:11]=1.[C:15]([CH:17]1[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]1)#[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>[F:1][C:2]1[C:3]([O:13][CH3:14])=[C:4]([C:16]#[C:15][CH:17]2[CH2:18][CH2:19][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:21][CH2:22]2)[C:5]2[O:9][CH2:8][C:7](=[O:10])[C:6]=2[CH:11]=1
Reactant: C#CC1CCN(C(=O)OC(C)(C)C)CC1
Reactant: COc1c(F)cc2c(c1I)OCC2=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: COc1c(F)cc2c(c1C#CC1CCN(C(=O)OC(C)(C)C)CC1)OCC2=O
Temperature: 50 °C
Reaction time: 4 h
Yield: 70.1 %

Procedure:
A solution of 5-fluoro-7-iodo-6-methoxybenzofuran-3(2H)-one (0.0582 g, 0.184 mmol) in triethylamine (3 mL) was added with tert-butyl 4-ethynylpiperidine-1-carboxylate (0.0389 g, 0.184 mmol), dichlorobis(triphenylphosphine)palladium(II) (0.0129 g, 0.0184 mmol) and copper(I) iodide (0.00350 g, 0.0184 mmol), and the mixture was stirred at 50° C. for 4 hours. The reaction mixture was concentrated, and the resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain tert-butyl 4-[(5-fluoro-6-methoxy-3-oxo-2,3-dihydrobenzofuran-7-yl)ethynyl]piperidine-1-carboxylate (0.0502 g, 70%).
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH:8]=[C:7]([C:10]2[C:15]3[CH:16]=[CH:17][O:18][C:14]=3[CH:13]=[CH:12][N:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].C([O-])=O.[NH4+]>CO.[Pd]>[C:1]([N:4]1[CH2:9][CH2:8][CH:7]([C:10]2[C:15]3[CH:16]=[CH:17][O:18][C:14]=3[CH:13]=[CH:12][N:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CC=C(c2nccc3occc23)CC1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: CC(=O)N1CCC(c2nccc3occc23)CC1

Procedure:
0.7 g of Pd/C (10%) is added to a solution of 3.4 g of the product obtained in Step C and 4.4 g of ammonium formate in 150 ml of anhydrous methanol under a stream of argon. After refluxing for 45 minutes, the reaction mixture is cooled, 4.4 g of ammonium formate and 0.2 g of Pd/C (10%) are added, and the reaction mixture is then heated at reflux for 30 minutes. After returning to ambient temperature, filtration over Celite and concentration under reduced pressure, the residue is taken up in water and then extracted with dichloromethane. The expected product is isolated by extraction, drying, filtration and concentration under reduced pressure.
Reaction SMILES: [CH2:1]([O:4][C:5](=[O:15])[NH:6][C:7]1[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][C:8]=1[CH3:14])[CH2:2][CH3:3].[CH3:16][N:17]([CH3:30])[C:18]1[CH:29]=[CH:28][C:21]2[S:22][C:23]([CH:26]=O)=[C:24]([CH3:25])[C:20]=2[CH:19]=1.C([BH3-])#N.[Na+].C(O)(=O)C>C(#N)C.CO>[CH2:1]([O:4][C:5](=[O:15])[NH:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][CH2:26][C:23]2[S:22][C:21]3[CH:28]=[CH:29][C:18]([N:17]([CH3:16])[CH3:30])=[CH:19][C:20]=3[C:24]=2[CH3:25])=[CH:9][C:8]=1[CH3:14])[CH2:2][CH3:3]
Reactant: CCCOC(=O)Nc1ccc(N)cc1C
Reactant: Cc1c(C=O)sc2ccc(N(C)C)cc12
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Solvent: CC#N
Product: CCCOC(=O)Nc1ccc(NCc2sc3ccc(N(C)C)cc3c2C)cc1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 77.8 %

Procedure:
A solution of (4-amino-2-methylphenyl)-carbamic acid propyl ester (21 mg, 0.10 mmol) and 5-dimethylamino-3-methyl-benzo[b]thiophene-2-carbaldehyde (26 mg, 0.12 mmol) in acetonitrile (0.5 mL) was heated at 170° C. for 2 minutes using a Personal Chemistry Smith Synthesizer microwave device. After cooling to room temperature, a solution of sodium cyanoborohydride (25 mg, 0.40 mmol) in methanol (0.1 mL) was added followed by acetic acid (50 μL), and the mixture was stirred for 30 minutes. It was partitioned between saturated aqueous sodium bicarbonate (10 mL) and ethyl acetate (10 mL), and the organic layer was dried over sodium sulfate and evaporated. Preparative LC-MS afforded the title compound (32 mg, 77% yield).
Reaction SMILES: C[O:2][C:3](=O)/[C:4](/[CH2:25][CH2:26][CH2:27][C@H:28]([CH3:38])[CH2:29][O:30][Si:31]([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32])=[CH:5]/[CH2:6][C@H:7]([O:17][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19])/[C:8](/[CH3:16])=[CH:9]/[C:10]1[N:11]=[C:12]([CH3:15])[S:13][CH:14]=1.CC(C[AlH]CC(C)C)C>C1COCC1>[C:21]([Si:18]([CH3:20])([CH3:19])[O:17][C@H:7](/[C:8](/[CH3:16])=[CH:9]/[C:10]1[N:11]=[C:12]([CH3:15])[S:13][CH:14]=1)[CH2:6]/[CH:5]=[C:4](\[CH2:25][CH2:26][CH2:27][C@H:28]([CH3:38])[CH2:29][O:30][Si:31]([C:34]([CH3:35])([CH3:36])[CH3:37])([CH3:32])[CH3:33])/[CH2:3][OH:2])([CH3:22])([CH3:23])[CH3:24]
Reactant: COC(=O)/C(=C/C[C@H](O[Si](C)(C)C(C)(C)C)/C(C)=C/c1csc(C)n1)CCC[C@H](C)CO[Si](C)(C)C(C)(C)C
Agent: CC(C)C[AlH]CC(C)C
Solvent: C1CCOC1
Product: C/C(=C\c1csc(C)n1)[C@H](C/C=C(/CO)CCC[C@H](C)CO[Si](C)(C)C(C)(C)C)O[Si](C)(C)C(C)(C)C
Temperature: -78 °C
Reaction time: 3 h
Yield: 76.5 %

Procedure:
To 13.9 g (23 mmol) of allylic ester XIII in 500 ml of THF at −78° C. was added over 10 min 47 ml (70 mmol) of DIBALH (1.5 M in toluene). The reaction mixture was successively stirred at −78° C. for 3 h, allowed to warm to 0° C. within 30 min. and further stirred at 0° C. for 30 min. before being quenched by the addition of 50 ml of aqueous 0.1N HCl. The layers were separated and the aqueous layer was washed with TBME (2×50 ml). The combined organic extracts were washed with aqueous saturated NaHCO3 (2×50 ml) and brine (50 ml), dried over MgSO4 and concentrated in vacuo. The crude product was purified by flash-chromatography (SiO2, 5:1 heptane/EtOAc) to afford 10.0 g (76%) of allylic alcohol XIV as a pale yellowish oil. Rf=0.16 (SiO2, 3:1 heptane-AcOEt).
Reaction SMILES: [C:1]1([CH2:7][C:8]([C:10]2[CH:15]=[CH:14][C:13]([C:16]3([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[CH2:18][CH2:17]3)=[CH:12][CH:11]=2)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:27][C:28]1[C:33]([CH:34]=O)=[C:32]([NH:36]C(=O)OC(C)(C)C)[CH:31]=[CH:30][N:29]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[Cl:27][C:28]1[N:29]=[CH:30][CH:31]=[C:32]2[C:33]=1[CH:34]=[C:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:8]([C:10]1[CH:11]=[CH:12][C:13]([C:16]3([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:24])([CH3:23])[CH3:25])[CH2:17][CH2:18]3)=[CH:14][CH:15]=1)=[N:36]2
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(C(=O)Cc3ccccc3)cc2)CC1
Reactant: CC(C)(C)OC(=O)Nc1ccnc(Cl)c1C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4ccnc(Cl)c4cc3-c3ccccc3)cc2)CC1
Temperature: 25 °C

Procedure:
A solution of 33-2 (0.64 g, 2.5 mmol), 3-1 (0.88 g, 2.5 mmol) and potassium carbonate (2.1 g, 15 mmol) in DMF (14 mL) was heated to 120° C. for 4.5 hours. The reaction was cooled to room temperature, diluted with ethyl acetate, washed with water, brine, dried over sodium sulfate, filtered and concentrated. Purification by silica gel chromatography (1% ethyl acetate/hexane→70% ethyl acetate/hexane) gave the title compound as a foam. MS (M+H+): calculated=471.98, observed=472.1.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-])=O)=[C:14]([C:21](=[O:25])[N:22]([CH3:24])[CH3:23])[CH:13]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]>O1CCCC1.C(O)C.[H][H].[C].[Pd]>[CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:17]=[CH:16][C:15]([NH2:18])=[C:14]([C:21](=[O:25])[N:22]([CH3:24])[CH3:23])[CH:13]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: [H][H]
Reactant: CCOC(=O)C1CCN(c2ccc([N+](=O)[O-])c(C(=O)N(C)C)c2)CC1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: CCOC(=O)C1CCN(c2ccc(N)c(C(=O)N(C)C)c2)CC1

Procedure:
1-(3-Dimethylcarbamoyl-4-nitrophenyl)-piperidine-4-carboxylic acid ethyl ester (1.578 g) was dissolved in tetrahydrofuran (5 mL) and ethanol (5 mL). After addition of 7.5% (w/w) palladium-carbon (0.316 g) to the solution, the mixture was stirred for 5 hours at normal pressure in hydrogen atmosphere. The reaction solution was filtered through a Celite pad and concentrated to give the title compound, which was used without isolation in the subsequent reaction.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1)#[N:2].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O.Cl[CH2:22][C:23]#[N:24]>O>[C:1]([C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][CH:8]=1)[O:9][CH2:22][C:23]#[N:24])#[N:2]
Reactant: N#CCCl
Reactant: N#Cc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: N#CCOc1cccc(C#N)c1
Temperature: 70 °C
Reaction time: 3 h

Procedure:
The compound 3-cyanophenoxyacetonitrile was prepared by heating 20.0 g of 3-cyanophenol, 30.1 g of anhydrous potassium carbonate and 30 ml of dimethylformamide with stirring in a 250 ml round-bottomed three-necked flask to 70° C. and then 12.7 g of chloroacetonitrile was added dropwise over a 15 minute period with cooling. The temperature of the mixture was held at 70°-80° C. for three hours, after which time the reaction mixture was poured into approximately 700 ml of ice and water which resulted in crystal formation. The crystals were separated by filtering and then washed thoroughly with water. After drying in a vacuum oven, a tan solid 3-cyanophenoxyacetonitrile was obtained.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[OH:11].ClC[CH2:14][CH2:15][O:16][CH3:17]>>[CH3:10][O:9][C:5]1[C:4]([O:11][CH2:14][CH2:15][O:16][CH3:17])=[C:3]([CH2:2][OH:1])[CH:8]=[CH:7][CH:6]=1
Reactant: COc1cccc(CO)c1O
Reactant: COCCCCl
Product: COCCOc1c(CO)cccc1OC

Procedure:
Analogously to Method F, 2.67 g of 2-hydroxymethyl-6-methoxyphenol and 2.19 g of 1-chloro-3-methoxypropane are reacted. The title compound is obtained as a colourless oil. Rf=0.23 (1:1 EtOAc-heptane); Rt=3.08.
Reaction SMILES: [NH2:1][C:2]1[C:7]2[C:8]([C:12]3[CH:17]=[CH:16][C:15]([NH:18][C:19]([NH:21][C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([CH3:28])[CH:23]=4)=[O:20])=[CH:14][CH:13]=3)=[C:9]([CH3:11])[S:10][C:6]=2[C:5]([N+:29]([O-])=O)=[CH:4][N:3]=1.[NH4+].[Cl-]>C(O)C.O.[Fe]>[NH2:1][C:2]1[C:7]2[C:8]([C:12]3[CH:17]=[CH:16][C:15]([NH:18][C:19]([NH:21][C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([CH3:28])[CH:23]=4)=[O:20])=[CH:14][CH:13]=3)=[C:9]([CH3:11])[S:10][C:6]=2[C:5]([NH2:29])=[CH:4][N:3]=1
Reactant: Cc1cccc(NC(=O)Nc2ccc(-c3c(C)sc4c([N+](=O)[O-])cnc(N)c34)cc2)c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: Cc1cccc(NC(=O)Nc2ccc(-c3c(C)sc4c(N)cnc(N)c34)cc2)c1
Temperature: 25 °C
Yield: 36.8 %

Procedure:
A suspension of Example 66E (0.44 g, 1.01 mmol), NH4Cl (0.054 g, 1.01 mmol), and iron powder (0.45 g, 8.1 mmol) in ethanol (16 mL) and water (4 mL) was heated at 80° C. for 3 hours, cooled to room temperature, and filtered through diatomaceous earth (Celite®). The pad was washed with ethyl acetate and ethanol and the filtrate was extracted three times with ethyl acetate. The combined extracts were washed with brine, dried (Na2SO4), flitered, and concentrated. The residue was purified by flash column chromatography on silica gel with 5% methanol/dichloromethane to provide 0.15 g of the desired product. 1H NMR (300 MHz, DMSO-d6) δ 2.27 (s, 3H), 2.29 (s, 3H), 4.48 (s, 2H), 4.59 (s, 2H), 6.80 (d, J=7.46 Hz, 1H), 7.17 (t, J=7.80 Hz, 1H), 7.25–7.29 (m, 3H), 7.30 (s, 1H), 7.31 (s, 1H), 7.60 (d, J=8.81 Hz, 2H), 8.67 (s, 1H), 8.86 (s, 1H); MS (ESI(+)) m/e 404 (M+H)+.
Reaction SMILES: F[C:2]1[N:7]=[C:6]([C:8]2[C:16]3[C:11](=[CH:12][N:13]=[C:14]([C:17]4[CH:18]=[N:19][N:20]([CH3:22])[CH:21]=4)[CH:15]=3)[N:10](C3CCCCO3)[N:9]=2)[CH:5]=[CH:4][CH:3]=1.[NH:29]1[CH2:34][CH2:33][CH2:32][CH:31]([OH:35])[CH2:30]1>>[CH3:22][N:20]1[CH:21]=[C:17]([C:14]2[CH:15]=[C:16]3[C:8]([C:6]4[N:7]=[C:2]([N:29]5[CH2:34][CH2:33][CH2:32][CH:31]([OH:35])[CH2:30]5)[CH:3]=[CH:4][CH:5]=4)=[N:9][NH:10][C:11]3=[CH:12][N:13]=2)[CH:18]=[N:19]1
Reactant: OC1CCCNC1
Reactant: Cn1cc(-c2cc3c(-c4cccc(F)n4)nn(C4CCCCO4)c3cn2)cn1
Product: Cn1cc(-c2cc3c(-c4cccc(N5CCCC(O)C5)n4)n[nH]c3cn2)cn1
Yield: 62.8 %

Procedure:
Following the procedures as described in Example 189, 3-(6-fluoropyridin-2-yl)-5-(1-methyl-1H-pyrazol-4-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridine and piperidin-3-ol were reacted. The product was deprotected and purified to give 262 as a white solid (62.8% over two steps). 1H NMR δ 13.68 (broad s, 1H), 9.03 (s, 1H), 8.60 (s, 1H), 8.24 (s, 1H), 7.96 (s, 1H), 7.67-7.58 (m, 1H), 7.42 (d, J=7.4 Hz, 1H), 6.83 (d, J=8.5 Hz, 1H), 5.04 (d, J=5.1 Hz, 1H), 4.59-4.49 (m, 1H), 4.08 (d, J=13.1 Hz, 1H), 3.89 (s, 3H), 3.65 (dt, J=14.0, 4.8 Hz, 1H), 3.05 (dd, J=17.1, 6.8 Hz, 1H), 2.91 (dd, J=12.4, 9.4 Hz, 1H), 2.07-1.97 (m, 1H), 1.91-1.78 (m, 1H), 1.65-1.42 (m, 2H). LC/MS: m/z 376.1 [M+1]
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].CN(C)C=O.[I:17]N1C(=O)CCC1=O>O>[NH2:1][C:2]1[C:10]([I:17])=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: Nc1ccc(Cl)cc1C(=O)O
Reactant: O=C1CCC(=O)N1I
Solvent: CN(C)C=O
Solvent: O
Product: Nc1c(I)cc(Cl)cc1C(=O)O
Temperature: 25 °C
Reaction time: 24 h
Yield: 46.1 %

Procedure:
To a mixture of 1.5 g of 2-amino-5-chlorobenzoic acid and 100 ml of N,N-dimethylformamide was added 2.7 g of N-iodosuccinimide at room temperature, and the mixture was stirred at room temperature for 24 hours. After 30 ml of water was poured into the reaction mixture, the mixture was extracted with ethyl acetate three times. The organic layers were combined, washed with an aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain 1.2 g of 2-amino-5-chloro-3-iodobenzoic acid of the formula: