Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)[CH:10]=1)=[O:5])C.[OH-].[Li+]>C1COCC1.C(O)C>[N:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[N:9]1[CH:10]=[C:6]([C:4]([OH:5])=[O:3])[CH:7]=[N:8]1
Reactant: CCOC(=O)c1cnn(-c2ccccn2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: O=C(O)c1cnn(-c2ccccn2)c1
Temperature: 0 °C
Reaction time: 7 h
Yield: 96.4 %

Procedure:
Pyridin-2-yl-1H-pyrazol-4-carboxylic acid ethyl ester (0.81 g, 3.73 mmol) was dissolved in a THF/ethanol (50 ml/10 ml) mixture, cooled to 0° C. and treated with lithium hydroxide (11.2 ml, 1N aqueous solution). The reaction mixture was allowed to warm-up to ambient temperature and subsequently stirred at that temperature for 7 h. The reaction mixture was extracted with dichloromethane (4×100 ml) and the combined organic phases were dried and evaporated to yield the product as white solid (0.68 g, 96%) which was used without any further purification.
Reaction SMILES: [CH:1]([O:4][C:5]1[N:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[CH:7]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:8]([C:16]([O:18][CH3:19])=[O:17])=[C:9]([CH3:15])[NH:10]2)([CH3:3])[CH3:2].N1C=CC=CC=1.C1C=C[NH+]=CC=1.Br[Br-]Br.[CH3:41][N:42]1[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]1>C(O)C.C(Cl)(Cl)Cl>[CH:1]([O:4][C:5]1[N:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[CH:7]([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[C:8]([C:16]([O:18][CH3:19])=[O:17])=[C:9]([CH2:15][N:45]1[CH2:46][CH2:47][N:42]([CH3:41])[CH2:43][CH2:44]1)[NH:10]2)([CH3:3])[CH3:2]
Reactant: CN1CCNCC1
Reactant: COC(=O)C1=C(C)Nc2ccnc(OC(C)C)c2C1c1ccccc1
Agent: c1cc[nH+]cc1
Solvent: CCO
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: COC(=O)C1=C(CN2CCN(C)CC2)Nc2ccnc(OC(C)C)c2C1c1ccccc1
Temperature: -10 °C
Reaction time: 0.5 h

Procedure:
1.0 g (3.0 mMole) methyl (±)-1,4-dihydro-5-isopropoxy-2-methyl-4-phenyl-1,6-naphthyridine-3-carboxylate (for the preparation cf. Federal Republic of Germany Patent Specification No. 34 31 303) in ethanol-free chloroform is cooled to -10° C., mixed with 0.26 ml (3.2 mMole) pyridine and subsequently portionwise with 1.1 g (3.1 mMole) pyridinium bromide perbromide (90%). After 30 minutes at -10° C., 0.62 g (6.2 mMole) N-methylpiperazine is added dropwise thereto and the reaction mixture is stirred for 15 minutes at -10° C. and then warmed to 20° C. within the course of one hour. The reaction mixture is diluted with chloroform, washed with water and the organic phase is dried over anhydrous sodium sulphate. The residue obtained after distilling off the solvent is chromatographed on silica gel with dichloromethane/methanol (9:1 v/v). The fraction with the Rf of 0.3 is recrystallized from n-hexane. There is obtained methyl (±)-1,4-dihydro-5 -isopropoxy-2-[(4-methyl-piperazin-l-yl)-methyl]-4-phenyl-1,6-naphthyridine-3-carboxylate in the form of colorless crystals; mp 149°-151° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([CH2:13][NH:14][CH:15]([CH3:17])[CH3:16])[C@H:10]([C:18]([CH3:26])([CH3:25])[O:19][SiH2:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:27][O:28][CH2:29][CH2:30][CH2:31][N:32]1[C:40]2[C:35](=[CH:36][CH:37]=[C:38]([C:41](O)=[O:42])[CH:39]=2)[C:34]([CH3:44])=[CH:33]1.O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1.C(N(CC)CC)C>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([CH2:13][N:14]([CH:15]([CH3:16])[CH3:17])[C:41]([C:38]2[CH:39]=[C:40]3[C:35]([C:34]([CH3:44])=[CH:33][N:32]3[CH2:31][CH2:30][CH2:29][O:28][CH3:27])=[CH:36][CH:37]=2)=[O:42])[C@H:10]([C:18]([CH3:26])([CH3:25])[O:19][SiH2:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COCCCn1cc(C)c2ccc(C(=O)O)cc21
Reactant: CC(C)NC[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]1C(C)(C)O[SiH2]C(C)(C)C
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COCCCn1cc(C)c2ccc(C(=O)N(C[C@@H]3CN(C(=O)OC(C)(C)C)C[C@H]3C(C)(C)O[SiH2]C(C)(C)C)C(C)C)cc21
Reaction time: 3 h

Procedure:
A mixture of (3S,4R)-3-(tert-butyl-dimethyl-silanyloxymethyl)-4-(isopropylamino-methyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (8.5 g, 22 mmol), 1-(3-methoxy-propyl)-3-methyl-1H-indole-6-carboxylic acid (7.6 g, 30.8 mmol), bis(2-oxo-3-oxazolidinyl)phosphinic chloride (7.84 g, 30.8 mmol) and triethylamine (12.3 mL, 88 mmol) in CH2Cl2 (425 mL) is refluxed overnight under a nitrogen atmosphere and then quenched by the addition of an aqueous saturated solution of NaHCO3. The organic layer is separated, and the aqueous phase is extracted 3 times with AcOEt. The combined organic extracts are concentrated in vacuo. The residual oil is taken up in a mixture of THF and MeOH, NaOH 1N is added to cleave the anhydride side product and the mixture stirred for 3 h. The solvents are concentrated, CH2Cl2 is added and the layers are separated. The aqueous one is then back extracted twice with CH2Cl2 and the combined organic extracts are washed with brine, dried over Na2SO4, filtered and concentrated. The crude product is used in the next step without further purification. TLC, Rf (AcOEt)=0.6. MS (LC-MS): 516.3 [M-Boc+H]+; tR (HPLC, Macherey-Nagel Nucleosil C18 column, 10-100% CH3CN/H2O/5 min, 100% CH3CN/3 min, CH3CN an H2O containing 0.1% TFA, flow: 1.5 mL/min): 8.60 min.
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[CH2:13][CH2:12][CH2:11][C@@H:10]1[NH2:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:15]1[CH2:21][S:18](=[O:20])(=[O:19])[O:17][CH2:16]1>O1CCCC1>[CH2:1]([O:8][C@H:9]1[CH2:13][CH2:12][CH2:11][C@@H:10]1[NH:14][CH2:16][CH2:15][CH2:21][S:18]([OH:20])(=[O:19])=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N[C@H]1CCC[C@@H]1OCc1ccccc1
Reactant: O=S1(=O)CCCO1
Solvent: C1CCOC1
Product: O=S(=O)(O)CCCN[C@H]1CCC[C@@H]1OCc1ccccc1
Temperature: 25 °C
Yield: 86.8 %

Procedure:
To a solution of (1S,2S)-2-benzyloxycyclopentylamine (1.0 g, 5.2 mmol) in tetrahydrofuran (12 mL) was slowly added 1,3-propanesultone (601 mg, 5.0 mmol). The solution was stirred at reflux for 2 hours. The reaction was cooled to room temperature. The solid was collected by filtration, washed with acetone (2×25 mL) and dried in vacuo, affording the title compound (1.36 g, 87%). 1H NMR (D2O, 500 MHz) δ ppm 7.32 (m, 5H), 4.53 (d, 1H, J=11.2 Hz), 4.41 (d, 1H, J=11.2 Hz), 4.01 (m, 1H), 3.36 (m, 1H), 3.00 (t, 2H, J=7.8 Hz), 2.80 (t, 2H, J=7.8 Hz), 2.00 (m, 4H), 1.64 (m, 3H), 1.49 (m, 1H). 13C NMR (D2O, 125 MHz) δ ppm 136.99, 129.06, 129.01, 128.77, 81.78, 71.81, 63.88, 48.01, 45.33, 29.91, 27.43, 21.60, 20.93. [α]D=+31.1° (c=0.0064 in water). ES-MS 314 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@@H:9]2[CH2:18][CH2:17][C:12]3([CH2:16][CH2:15][CH2:14][CH2:13]3)[C:11](=[O:19])[NH:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1.N[C:21]1[CH:22]=C2C(=C[CH:38]=1)C[C@]1(C3C(=NC=CC=3)NC1=O)C2>>[CH2:22]([N:10]1[C@H:9]([C:4]2[CH:3]=[C:2]([F:1])[CH:7]=[C:6]([F:8])[CH:5]=2)[CH2:18][CH2:17][C:12]2([CH2:16][CH2:15][CH2:14][CH2:13]2)[C:11]1=[O:19])[CH:21]=[CH2:38]
Reactant: Nc1ccc2c(c1)C[C@@]1(C2)C(=O)Nc2ncccc21
Reactant: O=C1N[C@H](c2cc(F)cc(F)c2)CCC12CCCC2
Product: C=CCN1C(=O)C2(CCCC2)CC[C@H]1c1cc(F)cc(F)c1

Procedure:
Prepared from (8S)-8-(3,5-difluorophenyl)-7-azaspiro[4.5]decan-6-one (Intermediate 16) by a procedure identical to that described in Intermediate 3 Step B. MS: m/z=306 (M+1).
Reaction SMILES: [CH3:1][CH2:2][C@H:3]1[O:18][C:16](=[O:17])[C@H:15]([CH3:19])[C@@H:14]([O:20][C@@H:21]2[O:26][C@@H:25]([CH3:27])[C@H:24]([OH:28])[C@@:23]([O:30][CH3:31])([CH3:29])[CH2:22]2)[C@H:13]([CH3:32])[C@@H:12]([O:33][C@@H:34]2[O:39][C@H:38]([CH3:40])[CH2:37][C@H:36]([N:41](C)[CH3:42])[C@H:35]2[OH:44])[C@@:11]([OH:46])([CH3:45])[CH2:10][C@@H:9]([CH3:47])[C:7](=[O:8])[C@H:6]([CH3:48])[C@@H:5]([OH:49])[C@@:4]1([OH:51])[CH3:50].C([O-])(=O)C.[Na+].II.N>CO.O.O>[CH3:1][CH2:2][C@H:3]1[O:18][C:16](=[O:17])[C@H:15]([CH3:19])[C@@H:14]([O:20][C@@H:21]2[O:26][C@@H:25]([CH3:27])[C@H:24]([OH:28])[C@@:23]([O:30][CH3:31])([CH3:29])[CH2:22]2)[C@H:13]([CH3:32])[C@@H:12]([O:33][C@@H:34]2[O:39][C@H:38]([CH3:40])[CH2:37][C@H:36]([NH:41][CH3:42])[C@H:35]2[OH:44])[C@@:11]([OH:46])([CH3:45])[CH2:10][C@@H:9]([CH3:47])[C:7](=[O:8])[C@H:6]([CH3:48])[C@@H:5]([OH:49])[C@@:4]1([OH:51])[CH3:50]
Reactant: CC[C@H]1OC(=O)[C@H](C)[C@@H](O[C@H]2C[C@@](C)(OC)[C@@H](O)[C@H](C)O2)[C@H](C)[C@@H](O[C@@H]2O[C@H](C)C[C@H](N(C)C)[C@H]2O)[C@](C)(O)C[C@@H](C)C(=O)[C@H](C)[C@@H](O)[C@]1(C)O
Agent: CC(=O)[O-]
Agent: II
Agent: N
Solvent: CO
Solvent: O
Product: CC[C@H]1OC(=O)[C@H](C)[C@@H](O[C@H]2C[C@@](C)(OC)[C@@H](O)[C@H](C)O2)[C@H](C)[C@@H](O[C@@H]2O[C@H](C)C[C@H](NC)[C@H]2O)[C@](C)(O)C[C@@H](C)C(=O)[C@H](C)[C@@H](O)[C@]1(C)O
Yield: 40.8 %

Procedure:
5 g of erythromycin A and 4.7 g of sodium acetate (×3 H2O) were dissolved in 200 ml of an 8:2 methanol/water mixture. 1.75 g of iodine were added to the solution, and the reaction mixture was then irradiated with a quartz lamp at room temperature for 20 minutes. Subsequently, half the solvent was evaporated, and the remaining reaction mixture was poured into a mixture of 140 ml of water and 10 ml of ammonia. The reaction mixture was extracted three times with 20 ml portions of methyl t-butyl ether. The ether extract was separated and some of the ether was evaporated. The reaction product was then left to crystallize out and was recrystallized from acetone. 2 g of N-demethylerythromycin A were obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:18]=[CH:19][CH:20]=1)[CH:6]([Cl:17])[C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)C=[CH:9][CH:8]=1.COC1C=C(C=CC=1)C(O)C1C2C(=CC=CC=2)[N:30]=CC=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:18]=[CH:19][CH:20]=1)[CH:6]([Cl:17])[C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:30]=[CH:9][CH:8]=1
Reactant: COc1cccc(C(O)c2ccnc3ccccc23)c1
Reactant: COc1cccc(C(Cl)c2cccc3ccccc23)c1
Product: COc1cccc(C(Cl)c2ccnc3ccccc23)c1

Procedure:
The compound 27 was prepared by following the synthesis procedure as described for compound 2, but substituting compound 1 for compound 26.
Reaction SMILES: [CH2:1]([C:7]1[CH:15]=[CH:14][C:10]([C:11](Cl)=[O:12])=[CH:9][CH:8]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[NH2:16][C:17]([CH3:31])([CH2:20][N:21]1[CH:30]=[C:24]2[N:25]=[CH:26][C:27]([Br:29])=[CH:28][C:23]2=[N:22]1)[C:18]#[N:19]>C1COCC1>[Br:29][C:27]1[CH:26]=[N:25][C:24]2=[CH:30][N:21]([CH2:20][C:17]([NH:16][C:11](=[O:12])[C:10]3[CH:14]=[CH:15][C:7]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])=[CH:8][CH:9]=3)([C:18]#[N:19])[CH3:31])[N:22]=[C:23]2[CH:28]=1
Reactant: CC(N)(C#N)Cn1cc2ncc(Br)cc2n1
Reactant: CCCCCCc1ccc(C(=O)Cl)cc1
Solvent: C1CCOC1
Product: CCCCCCc1ccc(C(=O)NC(C)(C#N)Cn2cc3ncc(Br)cc3n2)cc1

Procedure:
Using a procedure similar to that described in Example 60, except using a solution of 4-hexylbenzoyl chloride (0.16 mmole) in THF and a solution of 2-amino-3-(6-bromo-2H-pyrazolo[4,3-b]pyridin-2-yl)-2-methylpropionitrile (0.075 mmole, described in Example 182) in THF mixed with TEA (3% v./v.), the title compound was isolated as solid residue (13.9 mg). It was dissolved in DMSO for further biological evaluation and analyzed by LCMS. MS (ES): M/Z [M+H]=468, RT=0.76 min.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Si:8]([CH3:11])([CH3:10])[CH3:9])=[CH:4][CH:3]=1.COCCOC.[F:18][C:19]1[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=1B(O)O.C([O-])([O-])=O.[Na+].[Na+]>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.CCOCC.O>[CH3:9][Si:8]([CH3:11])([CH3:10])[C:5]1[CH:6]=[CH:7][C:2]([C:23]2[CH:22]=[CH:21][CH:20]=[C:19]([F:18])[C:24]=2[F:25])=[CH:3][CH:4]=1
Reactant: OB(O)c1cccc(F)c1F
Reactant: C[Si](C)(C)c1ccc(Br)cc1
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: [Na+]
Solvent: O
Solvent: COCCOC
Solvent: CCOCC
Product: C[Si](C)(C)c1ccc(-c2cccc(F)c2F)cc1
Temperature: 100 °C
Yield: 91 %

Procedure:
First, 7.9 g of 1-bromo-4-trimethylsilylbenzene was dissolved into 86 ml of DME, and 6.5 g of 2,3-difluorophenylboronic acid, 1.2 g of tetrakis(triphenylphosphine)palladium (0) and 86 ml of 2.0M Na2CO3 was added thereto. Next, the reaction mixture was heated to 100° C. to perform a reaction for about 10 hours. After being cooled to room temperature, the reaction mixture was worked up with water and ether, and then purified by silica gel column chromatography to obtain the 4′-trimethylsilyl-2,3-difluorobiphenyl compound with a yield of 91%. Then, 3.0 g of the biphenyl compound was dissolved into 20 ml of dry THF under nitrogen atmosphere, and 5.0 ml of 2.5M n-BuLi was added thereto at −78° C. to form an anion over about 3 hours. Then, 2.0 ml of 4-n-propylcyclohexanone was added to the anion, and the reaction mixture was warmed gradually to room temperature. After stirring at room temperature for 2 hours, the reaction mixture was worked up with water and ether, and evaporated under reduced pressure, and then dissolved into CH2Cl2 solvent. Next, 1.0 g of TsOH was added thereto, and the reaction mixture was allowed to react at 60° C. for 10 hours. After the completion of the reaction, the reaction mixture was purified by silica gel column chromatography to obtain the silicon-containing compound (yield: 80%). 400 MHz 1H-NMR, CDCl3, δ (ppm): 0.38 (s, 9H), 0.97 (m, 3H), 1.34˜1.46 (m, 5H), 1.63˜1.76 (br, 1H), 1.84˜1.98 (m, 2H), 2.33˜2.59 (m, 3H), 6.06 (br, 1H), 7.05˜7.12 (m, 1H), 7.12˜7.18 (m, 1H), 7.56 (d, 2H), 7.63 (d, 2H).
Reaction SMILES: [N:1]1OC([O-])=[C:4]2[CH2:9][CH2:8][CH2:7][CH2:6][N+:5]=12.[F:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]#[C:19][C:20]2[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=2)=[CH:14][CH:13]=1>C1(C)C=C(C)C=C(C)C=1>[F:11][C:12]1[CH:13]=[CH:14][C:15]([C:18]2[C:19]([C:20]3[CH:21]=[CH:22][N:23]=[CH:24][CH:25]=3)=[C:4]3[CH2:9][CH2:8][CH2:7][CH2:6][N:5]3[N:1]=2)=[CH:16][CH:17]=1
Reactant: Fc1ccc(C#Cc2ccncc2)cc1
Reactant: [O-]c1on[n+]2c1CCCC2
Solvent: Cc1cc(C)cc(C)c1
Product: Fc1ccc(-c2nn3c(c2-c2ccncc2)CCCC3)cc1
Temperature: 165 °C
Reaction time: 16 h
Yield: 27.3 %

Procedure:
A mixture of 1.64 g (11.1 mmol) of 4,5,6,7-tetrahydro[1,2,3]oxadiazolo[3,4-a]pyridin-8-ium 3-olate and 2.19 g (11.1 mmol) of 4-{[4-fluorophenyl]ethynyl}pyridine in 40 ml of mesitylene is stirred under argon at 165° C. for 16 h. After cooling, the reaction mixture is concentrated under reduced pressure. Purification by column chromatography on silica gel (cyclohexane/ethyl acetate) gives 888 mg (27%) of the desired product; log P(HCOOH): 1.03; 1H-NMR (CDCl3-d1): 8.52 (d, 2H), 7.38 (dd, 2H), 7.08 (d, 2H), 7.00 (dd, 2H), 4.25 (dd, 2H), 2.85 (dd, 2H), 2.12 (m, 2H), 1.92 (m, 2H).
Reaction SMILES: [H-].[Na+].[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4]1.I[CH2:13][CH3:14]>O1CCCC1>[CH2:13]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4]1)[CH3:14]
Reactant: CCI
Reactant: c1ccc2c(c1)CCN2
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCN1CCc2ccccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 78.1 %

Procedure:
NaH (10 g) was added to a chilled (0° C.) solution of indoline (30 g, 252.10 mmol) in tetrahydrofuran (300 mL). The resulting solution was then stirred at room temperature for 30 minutes. Iodoethane (50 g, 322.58 mmol) was then added dropwise and the resulting solution was maintained at room temperature for an additional 3 hours. The reaction mixture was then quenched by adding ethanol (100 mL). The resulting solution was extracted with dichloromethane (3×500 mL), and the organic layers were combined and concentrated. The residue was purified by column chromatography using a 100:1 ethyl acetate/petroleum ether solvent system to give 29 g (78%) of 1-ethylindoline as yellow oil.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([S:7](Cl)(=[O:9])=[O:8])[CH:2]=1.[C:11]([O:15][C:16](=[O:34])[CH2:17][N:18]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([CH2:32][NH2:33])[N:27]=1)[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])([CH3:14])([CH3:13])[CH3:12].C(N(CC)CC)C.S([O-])(O)(=O)=O.[K+]>C(Cl)Cl>[C:11]([O:15][C:16](=[O:34])[CH2:17][N:18]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([CH2:32][NH:33][S:7]([C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)(=[O:9])=[O:8])[N:27]=1)([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)OC(=O)CN(C(=O)OC(C)(C)C)c1cccc(CN)n1
Reactant: O=S(=O)(Cl)c1cccnc1
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)CN(C(=O)OC(C)(C)C)c1cccc(CNS(=O)(=O)c2cccnc2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.1 %

Procedure:
To a solution of 3-pyridylsulfonyl chloride (640 mg, 3.60 mmol) in methylene chloride (14 ml) were added tert-butyl[(6-aminomethylpyridin-2-yl)tert-butoxycarbonylamino]acetate (1.20 g, 3.56 mmol) obtained in Reference Example 12-(c) and triethylamine (2.24 ml, 16.2 mmol), followed by stirring at room temperature for 1 hour. After completion of the reaction, a 5% aqueous potassium hydrogensulfate solution was added to the reaction solution, followed by extraction with chloroform. The separated organic layer was washed sequentially with a saturated aqueous sodium hydrogencarbonate solution and a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography (eluent; hexane:ethyl acetate=1:1→1:2 (V/V)), and fractions containing the desired compound were concentrated under reduced pressure to afford the title compound (1.45 g) as a colorless oil. (Yield: 85%)
Reaction SMILES: [Br:1][C:2]1[S:3][C:4]([CH:7]=[O:8])=[CH:5][N:6]=1.[F-].[Cs+].[C:11]([Si](C)(C)C)([F:14])([F:13])[F:12]>COCCOC>[Br:1][C:2]1[S:3][C:4]([CH:7]([OH:8])[C:11]([F:14])([F:13])[F:12])=[CH:5][N:6]=1
Reactant: O=Cc1cnc(Br)s1
Reactant: C[Si](C)(C)C(F)(F)F
Agent: [Cs+]
Agent: [F-]
Solvent: COCCOC
Product: OC(c1cnc(Br)s1)C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution (0.52 M) of 2-bromo-5-formylthiazole (1.0 eq.) and CsF (0.2 eq.) in DME was treated with CF3SiMe3 (2.0 eq.) and then stirred for 2 h at RT. The reaction mixture was quenched by adding water and stirred for 15 min. Then, it was diluted with EtOAc and the organic phase was separated. The aqueous phase was extracted twice with EtOAc. The combined organic phase was dried (Na2SO4) and solvents were removed under reduced pressure. The residue was purified by flash chromatography on silica gel eluting with 5-25% EtOAc/petroleum ether to afford the title compound as a yellow solid. 1H NMR (300 MHz, CDCl3, 300K) δ 4.04 (1H, d, J=5.9 Hz), 5.32 (1H, dq, J=5.9 Hz, J=5.9 Hz), 7.59 (1H, s). MS (ES+) C5H3BrF3NOS requires: 261/263, found: 262/264 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7](CC1C=CC(OC)=CC=1)[N:6]=[CH:5]2.[NH2:20][C@@H:21]1[CH2:26][CH2:25][CH2:24][N:23](C(OC(C)(C)C)=O)[CH2:22]1>>[NH:23]1[CH2:24][CH2:25][CH2:26][C@@H:21]([NH:20][C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[NH:7][N:6]=[CH:5]3)[CH2:22]1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](N)C1
Reactant: COc1ccc(Cn2ncc3cc(Br)ccc32)cc1
Product: c1cc2[nH]ncc2cc1N[C@@H]1CCCNC1

Procedure:
Reaction of 5-bromo-1-(4-methoxybenzyl)-1H-indazole and (R)-tert-butyl 3-aminopiperidine-1-carboxylate using the method of Example 13 followed by deprotection using the method of Example 14 afforded the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[C:11]([O:13][CH3:14])[CH:12]=1)[N:9]=[CH:8][CH:7]=[C:6]2O.P(Cl)(Cl)([Cl:18])=O.CN(C)C=O>O>[Cl:18][C:6]1[C:5]2[C:10](=[C:11]([O:13][CH3:14])[CH:12]=[C:3]([O:2][CH3:1])[CH:4]=2)[N:9]=[CH:8][CH:7]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1cc(OC)c2nccc(O)c2c1
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(OC)c2nccc(Cl)c2c1

Procedure:
A solution of 6.5 g (31.6 mmol) of 6,8-dimethoxyquinolin-4-ol, 29 mL (316 mmol) of phosphorous oxychloride and 2.6 mL of N,N-dimethylformamide was stirred at room temperature for seven hours. The reaction solution was poured into a stirred mixture of ice and water. The aqueous mixture was washed three times with 300 mL portions of ethyl acetate, and then adjusted to pH 6 by the addition of solid sodium carbonate. 4-Chloro-6,8-dimethoxyquinoline was thus obtained as a colorless solid: yield 5.73 g (81%). The product was recrystallized from hot water for analysis: m.p. 115°-116° C.
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=1)[CH2:11]O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.S(Cl)([Cl:24])=O>C(Cl)(Cl)Cl>[O:1]([C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=1)[CH2:11][Cl:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCc1cccc(Oc2ccccc2)c1
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: ClCc1cccc(Oc2ccccc2)c1
Temperature: 25 °C
Yield: 96 %

Procedure:
To a solution of 200 g. of m-phenoxy-benzyl alcohol in 1 liter of dry chloroform 2 ml. of pyridine are added and a solution of 142.8 g. thionyl-chloride in 150 ml. of chloroform is added dropwise under cooling with ice water. When the addition is completed the cooling is terminated and the solution is allowed to warm up to room temperature under stirring and the temperature is maintained under stirring until the vigorous gas evolution ceases. The mixture is then boiled under stirring until the gas evolution ceases completely. The solution is then poured into 2 liters of cold water, the chloroform layer is separated and the aqueous layer is shaken out in 400 ml. of chloroform. The combined chloroform solutions are washed once with water and dried above sodium sulphate. The drying agent is filtered off and chloroform is distilled off; thus 210 g. (96%) of m-phenoxy-benzyl chloride are obtained, which can be distilled at 128° to 130° C. at a pressure of 0.3 mmHg. Substantially no forerun and residue are obtained.
Reaction SMILES: [C:1]([CH:5]1[CH2:10][CH2:9][CH:8](O)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].OS([O-])(=O)=O.[K+].C(OC(=O)C)C.OS([O-])(=O)=O.[K+]>>[C:1]([CH:5]1[CH2:10][CH2:9][CH:8]=[CH:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)C1CCC(O)CC1
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: CCOC(C)=O
Product: CC(C)(C)C1CC=CCC1
Temperature: 95 °C

Procedure:
20 g 4-t-butyl-1-cyclohexanol are mixed with 17 g KHSO4 and stirred for one week at 95° C. After the addition of ethylacetate KHSO4 is filtered off. Ethylacetate is evaporated and the product obtained by fractional distillation.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][CH:11]=[C:10]([CH2:16][C:17]3[CH:22]=[CH:21][C:20]([NH2:23])=[CH:19][CH:18]=3)[C:9]=2[F:24])[CH:5]=[CH:6][CH:7]=1.[O-:25][C:26]#[N:27].[Na+].CC(C)=O.CCCCCC>CC(O)=O.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][CH:11]=[C:10]([CH2:16][C:17]3[CH:18]=[CH:19][C:20]([NH:23][C:26]([NH2:27])=[O:25])=[CH:21][CH:22]=3)[C:9]=2[F:24])[CH:5]=[CH:6][CH:7]=1
Reactant: N#C[O-]
Reactant: COc1ccc(Cc2ccc(N)cc2)c(F)c1-c1cccc(Cl)c1
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(C)=O
Solvent: CCCCCC
Product: COc1ccc(Cc2ccc(NC(N)=O)cc2)c(F)c1-c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 56 %

Procedure:
A mixture of 4-(3′-chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-phenylamine (I-35) (100 mg, 0.26 mmol, 1 eq.), sodium cyanate (74 mg, 0.52 mmol, 2 eq.) in HOAc (1 ml) and water (1 ml) was sonicated at rt for 20 min. then was shaken at rt overnight. The mixture was diluted with water. The precipitate was collected by filtration and washed with water. After dried, 71 mg of crude product containing a less polar by product (presumably the corresponding acetamide) was obtained. Trituration of the crude product with acetone/hexane gave 56 mg of [4-(3′-chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-phenyl]-urea (P-243) as white solid in 56% yield. 1H NMR (DMSO-d6, 400 MHz): 8.42 (s, 1H), 7.40-7.47 (m, 2H), 7.36 (m, 1H), 7.23-7.32 (m, 4H), 7.07 (m, 2H), 6.92 (m, 1H), 5.76 (s, 2H), 3.83 (s, 2H), 3.72 (s, 3H) ppm.