Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[C:16](Br)=[N:15][C:14]2[C:9]1=[N:10][CH:11]=[N:12][CH:13]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:18]([O:20][CH:21]=[CH:22][Sn](CCCC)(CCCC)CCCC)[CH3:19]>CN(C=O)C>[CH2:1]([N:8]1[C:16]([CH:19]=[CH:18][O:20][CH2:21][CH3:22])=[N:15][C:14]2[C:9]1=[N:10][CH:11]=[N:12][CH:13]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCC[Sn](C=COCC)(CCCC)CCCC
Reactant: Brc1nc2cncnc2n1Cc1ccccc1
Solvent: CN(C)C=O
Product: CCOC=Cc1nc2cncnc2n1Cc1ccccc1
Temperature: 65 °C

Procedure:
A mixture of 9-benzyl-8-bromopurine 13 (1.0 g, 3.4 mmol) bis(triphenylphosphine)palladium(II)chloride (0.242 g, 0.30 mmol) and ethoxyvinyl(tributyl)tin (1.49 g, 4.14 mmol) in dry DMF (50 mL) was heated under N2 at 65° C. for 48 h. DMF was distilled off under reduced pressure and the resulting residue was redissolved in EtOAc (50 mL) and filtered through a pad of celite. The EtOAc was distilled off and the residue obtained was purified by flash chromatography. Yield 0.579 g, (59.7%). 1H NMR (CDCl3): δ 1.33 (t, 3H, CH3, J=7.5 Hz), 3.99 (q, 2H, CH2, J=13.7 Hz), 4.66 (d, 1H, CH, J=3 Hz), 5.34 (d, 1H, CH, J=3 Hz), 5.48 (s, 2H, benzylic CH2), 7.30-7.38 (m, 5H, Ar—H), 9.09 (s, 1H, purine C8—H), 9.2 (s, 1H, purine C2—H). 13C NMR (CDCl3): δ 14.2, 47.3, 64.2, 91.8, 126.8, 126.8, 127.7, 128.6, 128.6, 133.1, 136.4, 148.2, 151.2, 151.9, 152.8, 153.0.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][CH2:11][CH2:12][SH:13])=[CH:9][C:4]=2[O:3][CH2:2]1.[SH:14][CH2:15][CH2:16][OH:17]>>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][CH2:11][CH2:12][S:13][S:14][CH2:15][CH2:16][OH:17])=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: SCCCc1ccc2c(c1)OCO2
Reactant: OCCS
Product: OCCSSCCCc1ccc2c(c1)OCO2
Yield: 43.8 %

Procedure:
8.4 g of the title compound was prepared from 27.8 g of 3-(1,3-benzodioxol-5-yl)propanethiol and 5.5 g of 2-mercaptoethanol as a colorless oil according to the same procedure as that described in Example 1.
Reaction SMILES: [C:1]1([C:7]2([C:14]#[N:15])[CH2:12][CH2:11][C:10](=O)[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1>>[C:14]([C:7]1([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:12][CH2:11][C:10]([N:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)=[CH:9][CH2:8]1)#[N:15]
Reactant: C1CCNC1
Reactant: N#CC1(c2ccccc2)CCC(=O)CC1
Product: N#CC1(c2ccccc2)CC=C(N2CCCC2)CC1

Procedure:
Using the procedure of step A at example 1 and starting from 79.6 g of 4-phenyl 4-cyanocyclohexanone and 56.8 g pyrrolidine there is obtained with a theoretical yield 4-cyano 4-phenyl 1-pyrrolidino cyclohex-1-ene.
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20](SC)=[N:19][C:18]4=[O:24])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:27]([F:30])([F:29])[F:28])[CH:3]=1.[NH:31]1[CH2:37][CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1>>[Cl:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20]([N:31]5[CH2:37][CH2:36][CH2:35][NH:34][CH2:33][CH2:32]5)=[N:19][C:18]4=[O:24])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:27]([F:28])([F:30])[F:29])[CH:3]=1
Reactant: C1CNCCNC1
Reactant: CSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Product: O=C1N=C(N2CCCNCC2)SC1=Cc1ccc2c(cnn2Cc2ccc(Cl)cc2C(F)(F)F)c1

Procedure:
5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-[1,4]diazepan-1-yl-thiazol-4-one was prepared from 5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-methylsulfanyl-thiazol-4-one and [1,4]diazepane following General Procedure D.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([N:10]=[C:11]=[S:12])[CH:8]=2)[CH:3]=[N:2]1.Cl.[CH2:14]([O:16][C:17](=[O:21])[CH2:18][CH2:19][NH2:20])[CH3:15].C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH2:14]([O:16][C:17](=[O:21])[CH2:18][CH2:19][NH:20][C:11](=[S:12])[NH:10][C:7]1[CH:8]=[C:9]2[C:4]([CH:3]=[N:2][NH:1]2)=[CH:5][CH:6]=1)[CH3:15]
Reactant: S=C=Nc1ccc2cn[nH]c2c1
Reactant: CCOC(=O)CCN
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCOC(=O)CCNC(=S)Nc1ccc2cn[nH]c2c1
Yield: 37.1 %

Procedure:
A solution of 5 g (28.6 mmol) of lH-indazol-6-yl isothiocyanate, 5.3 g (34.3 mmol) of beta-alanine ethyl ester hydrochloride and 4.8 ml (34.3 mmol) of triethylamine in 50 ml of chloroform is left at room temperature under agitation for one hour. The chloroform phase is washed with water (2 × 10 ml) and with a 1 N hydrochloric acid solution (2 × 10 ml). It is dried and concentrated to dryness. The residue (8 g) is triturated in ethyl ether (3 × 20 ml). There is obtained 3.1 g of (lH-indazol-6-yl)thiocarbamoyl-beta-alanine ethyl ester (yield 28%, melting point 145° C.).
Reaction SMILES: [H-].[Na+].[O:3]1[CH2:7][CH:6]([OH:8])[CH:5]2[O:9][CH2:10][CH:11]([OH:12])[CH:4]12.Br[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CN(C=O)C>[CH2:14]([O:8][CH:6]1[CH:5]2[O:9][CH2:10][CH:11]([OH:12])[CH:4]2[O:3][CH2:7]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: OC1COC2C(O)COC12
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: OC1COC2C(OCc3ccccc3)COC12
Temperature: 0 °C
Reaction time: 1 h
Yield: 50 %

Procedure:
To a solution of sodium hydride (3.24 g, 81.0 mmol) in anhydrous DMF (20 mL) was added hexahydrofuro[3,2-b]furan-3,6-diol (10.1 g, 69.1 mmol) at 0° C. and the mixture was stirred for 1 h at 0° C. To the mixture was added bromomethylbenzene (11.73 g, 68.58 mmol) and the resulting mixture was stirred at rt for 4.5 h, and then quenched with H2O 2O (50 mL). The separated water layer was extracted with EtOAc (250 mL×3). The combined organic layers were washed with H2O (50 mL×6), dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v)=2/1) to give the title compound as light yellow oil (8.1 g, 50%).
Reaction SMILES: C([O:8][CH2:9][CH2:10][C:11]1([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:13][CH2:12]1)C1C=CC=CC=1.[H][H]>C(O)C.[OH-].[OH-].[Pd+2]>[C:17]([O:16][C:15](=[O:21])[NH:14][C:11]1([CH2:10][CH2:9][OH:8])[CH2:12][CH2:13]1)([CH3:20])([CH3:18])[CH3:19]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)NC1(CCOCc2ccccc2)CC1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(C)OC(=O)NC1(CCO)CC1
Temperature: 25 °C
Yield: 98.6 %

Procedure:
To a solution in ethanol (112 mL) of the compound (16.3 g) obtained in step (3) above, 20% palladium hydroxide/carbon (3.25 g) was added and the mixture was stirred at 60° C. for 23 hours in a hydrogen atmosphere. After being cooled to room temperature, the reaction mixture was filtered through Celite (registered trademark). The filtrate was concentrated under reduced pressure to give tert-butyl[1-(2-hydroxyethyl)cyclopropyl]carbamate as a colorless solid (11.1 g).
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[NH4+].[Cl-].C(OC([N:14]1[CH2:19][CH2:18][CH:17]([O:20][C:21]2[C:22]([C:31]#[N:32])=[C:23]3[C:28](=[CH:29][CH:30]=2)[CH:27]=[N:26][CH:25]=[CH:24]3)[CH2:16][CH2:15]1)=O)(C)(C)C.ClCCl>CN(C=O)C>[NH:14]1[CH2:19][CH2:18][CH:17]([O:20][C:21]2[C:22]([C:31]3[NH:32][N:3]=[N:2][N:1]=3)=[C:23]3[C:28](=[CH:29][CH:30]=2)[CH:27]=[N:26][CH:25]=[CH:24]3)[CH2:16][CH2:15]1
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc3cnccc3c2C#N)CC1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: c1cc2c(-c3nnn[nH]3)c(OC3CCNCC3)ccc2cn1
Temperature: 160 °C
Reaction time: 3 h
Yield: 13.5 %

Procedure:
Under argon atmosphere 78 mg (1.2 mmol) of NaN3 and 64 mg (1.2 mmol) of NH4Cl were added to a solution of 35 mg (0.1 mmol) 4-(5-Cyano-isoquinolin-6-yloxy)-piperidine-1-carboxylic acid tert-butyl ester (15) in 1 mL of DMF. The mixture was heated to approximately 160° C. and 7 bar pressure for 3 h in a microwave reactor (CEM Discovery). After cooling to room temperature aqueous NH4Cl-solution and dichloromethane was added. The mixture was filtered through a phase separation cartridge and the aqueous layer was washed twice with dichloromethane. The organic layers were combined and the solvents were distilled off. The remainder was subjected to preparative HPLC to yield 4 mg (8%) of compound 32 as trifluoroacetate. LCMS Method #3, retention time 0.90 min, detected mass 297.04 [M+H]+
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]([CH2:11][C:12]([OH:14])=O)[N:3]1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[CH2:21]([N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.O.O.[C:36]([OH:41])(=[O:40])[C:37]([OH:39])=[O:38]>CO>[C:36]([OH:41])(=[O:40])[C:37]([OH:39])=[O:38].[CH2:21]([N:28]1[CH2:33][CH2:32][N:31]([C:12]([CH2:11][CH:4]2[C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[C:2](=[O:1])[N:3]2[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)=[O:14])[CH2:30][CH2:29]1)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: O=C(O)CC1c2ccccc2C(=O)N1c1ccccc1
Reactant: c1ccc(CN2CCNCC2)cc1
Agent: O=C(O)C(=O)O
Solvent: O
Solvent: CO
Product: O=C(CC1c2ccccc2C(=O)N1c1ccccc1)N1CCN(Cc2ccccc2)CC1
Yield: 83.5 %

Procedure:
An oily product (4.3 g), which was prepared from 2.67 g of 3-oxo-2-phenylisoindoline-1-acetic acid and 1.94 g of 1-benzylpiperazine in the same manner as Example 3, was dissolved in 4 ml of methanol, and to this solution a solution of 1.5 g of oxalic acid dihydrate in 6 ml of methanol was added, and the crystals precipitated were collected by filtration. Yield, 4.90 g; m.p., 207°-210° C. (recrystallization from methanol).
Reaction SMILES: [Li]CCCC.[B:6](OC(C)C)([O:11]C(C)C)[O:7]C(C)C.O.[CH3:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]>>[C:22]1([B:6]([OH:11])[OH:7])[CH:21]=[CH:20][CH:25]=[CH:24][CH:23]=1
Reactant: CCCCCC
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: [Li]CCCC
Solvent: O
Product: OB(O)c1ccccc1
Reaction time: 8 h

Procedure:
In an Ar atmosphere, the crystals of 2-(4-bromophenyl)-naphthalene obtained in Synthesis Step C1-3, 10 g, and 500 mL of anhydrous tetrahydrofuran were put into a 1-L flask, and then 22 mL of a 1.6 mol/L n-BuLi solution in hexane was added dropwise at −60° C. over 30 minutes. Thirty minutes later, 7 g of triisopropyl borate was added dropwise, and then the reaction was allowed to proceed overnight with no temperature control. After the completion of the reaction, 100 mL of water was added dropwise, and the obtained solution was subjected to extraction with 2 L of toluene and separated. The isolated organic layer was concentrated, the residue was recrystallized, and the crystals were collected by filtration and dried. In this way, a phenylboronic acid derivative was obtained as a white solid weighing 5 g.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([P:10](=[O:17])([O:14][CH2:15][CH3:16])[O:11][CH2:12][CH3:13])=[CH:6][CH:5]=1)([O-])=O.[H][H]>[Pd].CCO>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([P:10](=[O:17])([O:11][CH2:12][CH3:13])[O:14][CH2:15][CH3:16])=[CH:6][CH:5]=1
Reactant: [H][H]
Reactant: CCOP(=O)(OCC)c1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CCO
Product: CCOP(=O)(OCC)c1ccc(N)cc1
Temperature: 25 °C
Yield: 97.8 %

Procedure:
A mixture of diethyl (4-nitrophenyl)phosphonate (150 mg, 0.58 mmol), EtOH (40 ml) and 10% Pd/C (30 mg) was hydrogenated under 50 psi of hydrogen pressure at 40° C. for 6 h. After cooling to room temperature, the reaction mixture was filtered and the filtrate concentrated in vacuo to afford 130 mg of desired diethyl (4-aminophenyl)phosphonate (yield: 98%), which was used directly in further chemistries without purification.
Reaction SMILES: Br[CH:2]([C:4]1[N:13]([CH3:14])[C:12](=[O:15])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1)[CH3:3].[NH2:16][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.[I-].[K+].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:26]([O:25][C:23]([N:20]1[CH2:21][CH2:22][CH:17]([NH:16][CH:2]([C:4]2[N:13]([CH3:14])[C:12](=[O:15])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=2)[CH3:3])[CH2:18][CH2:19]1)=[O:24])([CH3:29])([CH3:27])[CH3:28]
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: CC(Br)c1nc2ccccc2c(=O)n1C
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: CC(NC1CCN(C(=O)OC(C)(C)C)CC1)c1nc2ccccc2c(=O)n1C
Temperature: 65 °C

Procedure:
A mixture of 2-(1-bromo-ethyl)-3-methyl-3H-quinazolin-4-one (801 mg, 3 mmol), 4-amino-1-N-Boc piperidine (661 mg, 3.3 mmol), potassium iodide (498 mg, 3 mmol) and potassium carbonate (622 mg, 4.5 mmol) in acetonitrile (12 mL) was heated at 65° C. for 3 days. The reaction mixture was then concentrated in vacuo. The residue was dissolved in dichloromethane and washed with saturated sodium thiosulphate solution and water. The organic layer was dried over magnesium sulfate and concentrated in vacuo to yield 4-[1-(3-Methyl-4-oxo-3,4-dihydro-quinazolin-2-yl)-ethylamino]-piperidine-1-carboxylic acid tert-butyl ester (HPLC ret. time 2.20, 10-99% CH3CN, 5 min run, ESI-MS m/z 387.4 (MH+).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[OH:11].[OH-].[Na+].[OH-].[K+].[C:16](=[O:18])=[O:17]>>[OH:11][C:2]1[C:3]([C:16]([OH:18])=[O:17])=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:1]=1
Reactant: O=C=O
Reactant: Oc1ccc2ccccc2c1
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)c1cc2ccccc2cc1O
Temperature: 260 °C
Reaction time: 0.5 h

Procedure:
A stirred autoclave is charged with 1220 parts of β-naphthol, 608 parts of aqueous caustic soda solution (50% by weight) and 27 parts of aqueous caustic potash solution (85% by weight). The mixture is well mixed under nitrogen, heated to an internal temperature of 260° C and kept for 30 minutes at this temperature. The dehydration is then practically complete. Carboxylation is carried on for 3 hours at a temperature of 260° C with dry carbon dioxide at a pressure of 7 atmospheres. The absorption of CO2 is monitored by a gas meter. After the absorption is ended 350 parts of β-naphthol is distilled off at 20 mm of Hg and then in the manner above described carbon dioxide is again forced in and the mixture carboxylated for 2 hours. A total of 300 parts of carbon dioxide is absorbed in a carboxylation period of 300 minutes. The reaction mixture is stirred with 5000 parts of water and dissolved. The solution is cooled to 80° to 90° C, acidified with 50% by weight sulfuric acid to a pH of 6.5 and then extracted for fifteen minutes with a total of 800 parts of a mixture of m-xylene and p-xylene in the ratio 2.3:1. The phases are then separated and the aqueous phase is acidified to a pH of 3 at 90° C with 50% by weight sulfuric acid. The precipitated 2-hydroxynaphthalene-3-carboxylic acid is separated by filtration from the hot solution at 80° C. 530 parts of 2-hydroxynaphthalene-3-carboxylic acid is obtained. This is 73% of theory based on reacted naphtholate deducting the β-naphthol obtained. It contains 99% by weight of 2-hydroxynaphthalene-3-carboxylic acid and 0.5% by weight of β-naphthol. The melting point is 218° to 220° C.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8](Cl)=[O:9])[CH2:4][CH2:3]1.[NH:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1>C1(C)C=CC=CC=1>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]([N:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[O:9])[CH2:4][CH2:3]1
Reactant: CN1CCN(C(=O)Cl)CC1
Reactant: C1CCNC1
Solvent: Cc1ccccc1
Product: CN1CCN(C(=O)N2CCCC2)CC1

Procedure:
In 50 ml of toluene was dissolved 8.1 g (0.05 mole) of 1-methyl-4-chlorocarbonylpiperazine at room temperature and a solution of 10.7 g (0.15 mole) of pyrrolidine in 50 ml of toluene was dropped to the above solution at 0° C. over a period of 30 minutes. The mixture was refluxed for 1 hour to complete the reaction. The reaction mixture was cooled, and the precipitated yellow crystal (pyrrolidine hydrochloride) was removed by filtration. The filtrate was dried with anhydrous sodium sulfate and toluene as the solvent was removed by distillation under reduced pressure to obtain crude 1-methyl-4-(pyrrolidinocarbonyl)piperazine as the distillation residue. The crude product was purified by distillation under reduced pressure to obtain 6.6 g of a pure product having a boiling point of 109.5 to 110.0° C. at 0.5-0.6 mm Hg obs. The yield was 66.9%. The elementary analysis values are as follows:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:28])[C:7]=1[NH:8][C:9](=[O:27])[C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18]C(=O)C2C=CC=CC=2)[CH:11]=1.O.C(=O)([O-])[O-].[K+].[K+].Cl>CO>[Cl:28][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([Cl:1])[C:7]=1[NH:8][C:9](=[O:27])[C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([OH:18])[CH:11]=1
Reactant: COc1ccc(C(=O)Nc2c(Cl)cncc2Cl)cc1OC(=O)c1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: COc1ccc(C(=O)Nc2c(Cl)cncc2Cl)cc1O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of N-(3,5-dichloropyrid-4-yl)-3-benzoyloxy-4-methoxybenzamide (13.4 g; that is prepared as described in Reference Example 11) in methanol (160 mL) and water (60 mL) is treated with anhydrous potassium carbonate (18 g), and stirred overnight at room temperature. It is then brought to pH 7 by treatment with dilute hydrochloric acid (2N), and concentrated. The residue is treated with water (100 mL) and filtered, and the resulting solid is dried, to give N-(3,5-dichloropyrid-4-yl)-3-hydroxy-4-methoxybenzamide (8.8 g), m.p. 227°-228° C.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH2:14])(=[O:13])=[O:12])=[CH:7][C:6]=1[N:15]=[C:16]=[S:17])([CH3:3])[CH3:2].[NH3:18]>CO>[CH:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH2:14])(=[O:13])=[O:12])=[CH:7][C:6]=1[NH:15][C:16]([NH2:18])=[S:17])([CH3:3])[CH3:2]
Reactant: N
Reactant: CC(C)Oc1ccc(S(N)(=O)=O)cc1N=C=S
Solvent: CO
Product: CC(C)Oc1ccc(S(N)(=O)=O)cc1NC(N)=S
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Crude 4-isopropoxy-3-isothiocyanato-benzenesulfonamide (17.8 g, 65.2 mmol, example 2, step e) was treated with a 2 M solution of ammonia in MeOH (250 mL) and the resulting solution was stirred at room temperature for 18 h. The reaction mixture was then concentrated to about half the volume until a large amount of tan solid precipitated. The suspension was cooled to 0° C. for 30 minutes and was filtered. The solid was washed with methanol and ether to give the title compound as a cream colored solid.
Reaction SMILES: [F:1][C:2]1([F:29])[CH2:4][CH:3]1[CH2:5][N:6]1[C:14]2[C:9](=[N:10][C:11]([C:15]3[CH:16]=[C:17]([CH:22]=[CH:23][C:24]=3[CH3:25])[C:18](OC)=[O:19])=[CH:12][CH:13]=2)[N:8]([CH3:26])[S:7]1(=[O:28])=[O:27].CC(C[AlH]CC(C)C)C>C1COCC1>[F:29][C:2]1([F:1])[CH2:4][CH:3]1[CH2:5][N:6]1[C:14]2[C:9](=[N:10][C:11]([C:15]3[CH:16]=[C:17]([CH2:18][OH:19])[CH:22]=[CH:23][C:24]=3[CH3:25])=[CH:12][CH:13]=2)[N:8]([CH3:26])[S:7]1(=[O:27])=[O:28]
Reactant: COC(=O)c1ccc(C)c(-c2ccc3c(n2)N(C)S(=O)(=O)N3CC2CC2(F)F)c1
Agent: CC(C)C[AlH]CC(C)C
Solvent: C1CCOC1
Product: Cc1ccc(CO)cc1-c1ccc2c(n1)N(C)S(=O)(=O)N2CC1CC1(F)F
Temperature: -78 °C

Procedure:
Methyl 3-{1-[(2,2-difluorocyclopropyl)methyl]-3-methyl-2,2-dioxido-1,3-dihydro[1,2,5]thiadiazolo[3,4-b]pyridin-5-yl}-4-methylbenzoate (38-1) (8.0 g, 18.9 mmol, 1.0 eq) dissolved in THF (100 mL) and cooled to −78° C. DIBAL-H (60.0 mL, 60.0 mmol, 3.2 eq, 1.0 M in heptane) was added and the mixture was stirred at the same temperature. After 10 minutes the reaction was carefully quenched by an addition of Rochelle's Salt (15 mL) and stirred for 3 hours warming to ambient temperature. The mixture was extracted with EtOAc (300 mL), washed with water (2×50 mL) and brine (50 mL), dried over MgSO4, filtered and concentrated to afford (3-{1-[(2,2-difluorocyclopropyl)methyl]-3-methyl-2,2-dioxido-1,3-dihydro[1,2,5]thiadiazolo[3,4-b]pyridin-5-yl}-4-methylphenyl)methanol (39-1) as a tan solid. No further purification was necessary. HRMS m/z (M+H) 396.1188 found, 396.1188 required.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:9]=[CH:8][S:7][C:6]=2[CH:10]=1.[Br:11][C:12]1[CH:13]=[CH:14][C:15]([Cl:20])=[C:16]([CH:19]=1)[CH:17]=O>>[Br:11][C:12]1[CH:13]=[CH:14][C:15]([Cl:20])=[C:16]([CH2:17][C:8]2[S:7][C:6]3[CH:10]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=3[CH:9]=2)[CH:19]=1
Reactant: Clc1ccc2ccsc2c1
Reactant: O=Cc1cc(Br)ccc1Cl
Product: Clc1ccc2cc(Cc3cc(Br)ccc3Cl)sc2c1

Procedure:
A solution of the above 6-chlorobenzo[b]thiophen-2-ylcarboxylic acid (3.0 g) and copper powder (1.2 g) in quinoline (20 ml) was stirred at 210° C. for 40 minutes. The mixture was cooled to room temperature and diluted with diethyl ether, and insoluble materials were filtered off. The filtrate was washed successively with 10% aqueous hydrochloric acid solution and brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane) to give 6-chlorobenzo[b]thiophene (1.79 g) as colorless crystals. (3) The above 6-chlorobenzo[b]thiophene and 5-bromo-2-chlorobenzaldehyde obtained in Reference Example 16-(1) were treated in a manner similar to Reference Example 7 to give 5-bromo-2-chloro-1-(6-chlorobenzo[b]thiophen-2-ylmethyl)benzene as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:21])=[CH:4][C:5]2[CH2:6][CH2:7][C:8]3([CH2:18][CH2:19][CH3:20])[C:13]([C:14]=2[C:15]=1[Cl:16])=[CH:12][C:11](=[O:17])[CH2:10][CH2:9]3.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:29][C:30]#[N:31]>CN(C)C=O>[Cl:1][C:2]1[C:3]([O:21][CH2:29][C:30]#[N:31])=[CH:4][C:5]2[CH2:6][CH2:7][C:8]3([CH2:18][CH2:19][CH3:20])[C:13]([C:14]=2[C:15]=1[Cl:16])=[CH:12][C:11](=[O:17])[CH2:10][CH2:9]3
Reactant: CCCC12CCC(=O)C=C1c1c(cc(O)c(Cl)c1Cl)CC2
Reactant: N#CCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCC12CCC(=O)C=C1c1c(cc(OCC#N)c(Cl)c1Cl)CC2
Temperature: 65 °C

Procedure:
A stirred mixture of 3,4-dichloro-6,7,8,8a,9,10-hexahydro-2-hydroxy-6-oxo-8a-propylphenanthrene (0.4 g, 1.22 mmole), potassium carbonate (0.2 g, 1.45 mmole) and chloroacetonitrile (160 μl, 1.78 mmole) in dimethylformamide (7 ml) is heated at 65° C. for 2 hours, poured into ice water, extracted with ether, washed with water, brine, dried over MgSO4 and evaporated in vacuo. Trituration of the residual oil with butyl chloride give 2-[(3,4-dichloro-6,7,8,8a,9,10-hexahydro-6-oxo-8a-propyl-2-phenanthrenyl)oxy]acetonitrile which is removed by filtration, and dried.
Reaction SMILES: ClC1C=C([C:9](=[O:17])[CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)C=C(Cl)C=1.Br[C:19]1[CH:24]=[C:23]([F:25])[CH:22]=[C:21]([F:26])[CH:20]=1>>[F:26][C:21]1[CH:20]=[C:19]([C:9](=[O:17])[CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:24]=[C:23]([F:25])[CH:22]=1
Reactant: O=C(Cc1ccccc1)c1cc(Cl)cc(Cl)c1
Reactant: Fc1cc(F)cc(Br)c1
Product: O=C(Cc1ccccc1)c1cc(F)cc(F)c1
Yield: 10.3 %

Procedure:
Prepared following the procedure described in Intermediate 13, starting from 1-bromo-3,5-difluorobenzene, where the crude product was purified by column chromatography (PE: EtOAc=100:1) to afford Intermediate 18 (100 mg, yield 10.3%).
Reaction SMILES: [CH3:1][N:2]1[C:6]2[C:7]([CH3:20])=[CH:8][C:9](B3OC(C)(C)C(C)(C)O3)=[CH:10][C:5]=2[O:4][C:3]1=[O:21].[OH:22]O>C(O)(=O)C>[OH:22][C:9]1[CH:8]=[C:7]([CH3:20])[C:6]2[N:2]([CH3:1])[C:3](=[O:21])[O:4][C:5]=2[CH:10]=1
Reactant: Cc1cc(B2OC(C)(C)C(C)(C)O2)cc2oc(=O)n(C)c12
Reactant: OO
Solvent: CC(=O)O
Product: Cc1cc(O)cc2oc(=O)n(C)c12

Procedure:
0.20 g (0.70 mmol) 3,4-dimethyl-6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3H-benzoxazol-2-one were dissolved in 2.0 mL glacial acetic acid and combined with 0.40 mL (4.6 mmol) hydrogen peroxide solution (35% in water) and stirred. The precipitate formed was suction filtered, washed with water and dried i. vac.