Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:17])[C:3]1([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:8][CH2:7][CH:6]([CH:9]=[O:10])[CH2:5][CH2:4]1.[BH4-].[Na+].C(O)C>[OH-].[Na+].C(O)C.O.O>[CH3:1][N:2]([CH3:17])[C:3]1([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:8][CH2:7][CH:6]([CH2:9][OH:10])[CH2:5][CH2:4]1
Reactant: CN(C)C1(c2ccccc2)CCC(C=O)CC1
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CN(C)C1(c2ccccc2)CCC(CO)CC1
Reaction time: 2 h

Procedure:
4-Dimethylamino-4-phenylcyclohexanecarbaldehyde (2.35 g, 10.2 mmol) was stirred in a mixture of 1 M NaOH (10.2 ml) and ethanol/water (2:1, 60 ml) for 30 min at RT under argon as inert gas. A solution of sodium borohydride (769 mg, 20.3 mmol) in water (40 ml) was then added dropwise at RT over 60 min and the mixture was stirred for 2 h. For the work-up, the ethanol was driven off under vacuum and the aqueous residue was extracted with EE (6×20 ml). The combined extracts were washed with saturated NaCl solution (2×20 ml), dried and concentrated. The resulting residue (2.2 g of brown oil) was a mixture of the two diastereoisomers of (4-dimethylamino-4-phenylcyclohexyl)methanol.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]([C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=2)=O)=O)[CH:6]=[CH:7][CH:8]=1.[NH:21]([C:25]1[NH:26][C:27]2[CH:33]=[CH:32][CH:31]=[CH:30][C:28]=2[N:29]=1)[C:22]([NH2:24])=[NH:23].[OH-].[Na+]>CO.O>[N:29]1[C:28]2[CH:30]=[CH:31][CH:32]=[CH:33][C:27]=2[NH:26][C:25]=1[N:21]=[C:22]1[NH:24][C:9]2([C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=3)[NH:24][C:22](=[N:21][C:25]3[NH:29][C:28]4[CH:30]=[CH:31][CH:32]=[CH:33][C:27]=4[N:26]=3)[NH:23][C:11]2([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=2)[NH:23]1
Reactant: N=C(N)Nc1nc2ccccc2[nH]1
Reactant: COc1cccc(C(=O)C(=O)c2cccc(OC)c2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1cccc(C23NC(=Nc4nc5ccccc5[nH]4)NC2(c2cccc(OC)c2)NC(=Nc2nc4ccccc4[nH]2)N3)c1

Procedure:
Following the procedure of Example 1, 3,3'-dimethoxybenzil (1.0 g, 3.69 mmol) and 2-guanidinobenzimidazole (540 mg, 3.08 mmol) in methanol (40 mL) was treated with a solution of sodium hydroxide (200 mg, 5 mmol) in 5 mL of water. The title compound was isolated as pale yellow crystals (655 mg, 73% yield). mp: 276-278 ° C. (dec);MS (ESI) m/z 585 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[N:3]=1.[NH:9]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10]1.CCCCCCC=CCCC>C1COCC1.C(OCC)(=O)C>[Br:8][C:4]1[N:3]=[C:2]([N:9]2[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10]2)[CH:7]=[CH:6][CH:5]=1
Reactant: Brc1cccc(Br)n1
Reactant: OC1CCNC1
Agent: CCCC=CCCCCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: OC1CCN(c2cccc(Br)n2)C1
Temperature: 25 °C

Procedure:
A mixture of 2,6-dibromopyridine (2.37 g, 0.01 mol), pyrrolidin-3-ol (1.0 g, 0.01 mol), 1,8-diazabicclo[5.4.0)-7-undecene (1.5 mL) in 10 mL of THF was heated at 70° C. under a nitrogen atmosphere for 11 hours. The reaction mixture was then cooled to room temperature, diluted with ethyl acetate (30 mL). The resulting solution was washed with water and brine, dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (10-30% ethyl acetate/hexane) to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:15])[CH2:9][N:10]2[CH:14]=[N:13][CH:12]=[N:11]2)=[CH:4][CH:3]=1.[SH:16][CH2:17][CH2:18]O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1.C(O)CCC.C1CCCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:9][N:10]3[CH:14]=[N:13][CH:12]=[N:11]3)[S:16][CH2:17][CH2:18][O:15]2)=[CH:4][CH:3]=1
Reactant: O=C(Cn1cncn1)c1ccc(Cl)cc1
Reactant: OCCS
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCCCC1
Solvent: CCCCO
Solvent: Cc1ccccc1
Product: Clc1ccc(C2(Cn3cncn3)OCCS2)cc1
Yield: 27.9 %

Procedure:
To a slurry of 44.3 g 1-(4-chlorophenyl)-2-(1H-1,2,4-triazol-1-yl) ethanone in 800 ml dry toluene and 400 ml 1-butanol was added 31.2 g 2-mercaptoethanol and 51.0 g p-toluenesulfonic acid. The mixture was refluxed under a Dean-Stark trap for 48 hours. On cooling, a white solid precipitated out, which was removed by filtration. The filtrate was evaporated, the residue dissolved in dichloromethane and washed twice with 10% aqueous sodium hydroxide and once with water. The organic layer was dried, filtered and evaporated to leave an oil which was taken up in cyclohexane. The cyclohexane was evaporated to azeotrope off any remaining 1-butanol, leaving an oily solid which was triturated with petroleum ether to give 15.7 g of product.
Reaction SMILES: C(O[CH:5]1[C:9]2[CH:10]=[C:11]([C:18]([CH3:21])([CH3:20])[CH3:19])[CH:12]=[C:13]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:8]=2[O:7][C:6]1=[O:22])(=O)C.[CH3:23][C:24]1[CH:25]=[CH:26][C:27]([CH3:30])=[CH:28][CH:29]=1>O>[C:18]([C:11]1[CH:12]=[C:13]([C:14]([CH3:16])([CH3:17])[CH3:15])[C:8]2[O:7][C:6](=[O:22])[CH:5]([C:29]3[CH:28]=[C:27]([CH3:30])[CH:26]=[CH:25][C:24]=3[CH3:23])[C:9]=2[CH:10]=1)([CH3:20])([CH3:19])[CH3:21]
Reactant: Cc1ccc(C)cc1
Reactant: CC(=O)OC1C(=O)Oc2c1cc(C(C)(C)C)cc2C(C)(C)C
Solvent: O
Product: Cc1ccc(C)c(C2C(=O)Oc3c2cc(C(C)(C)C)cc3C(C)(C)C)c1
Yield: 59.9 %

Procedure:
To a solution of 15.3 g (50.0 mmol) of 3-acetoxy-5,7-di-tert-butyl-3H-benzofuran-2-one (compound (206), Table 2, Example 2a) in 25 ml (0.20 mol) of p-xylene is added 1.0 g of Fulcat 22B and the mixture is refluxed for 17 hours on a water separator. The Fulcat 22B catalyst is then removed by filtration and excess p-xylene is removed by distillation on a vacuum rotaray evaporator. Crystallisation of the residue from 20 ml of methanol yields 10.5 g (60%) of 5,7-di-tert-butyl-3-(2,5-dimethylphenyl)-3H-benzofuran-2-one, m.p. 93°-97° C. (compound (101), Table 1).
Reaction SMILES: [O:1]=[C:2]([C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([O:25][CH3:26])[CH:23]=2)[N:18]=[CH:17][C:16]=1[F:27])[CH2:3][CH2:4][C@@H:5]1[CH2:10][CH2:9][NH:8][CH2:7][C@@H:6]1[C:11]([O:13][CH3:14])=[O:12].Br[CH2:29][CH2:30][S:31][C:32]1[CH:37]=[C:36]([F:38])[CH:35]=[CH:34][C:33]=1[F:39].[I-].[K+].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[O:1]=[C:2]([C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([O:25][CH3:26])[CH:23]=2)[N:18]=[CH:17][C:16]=1[F:27])[CH2:3][CH2:4][C@@H:5]1[CH2:10][CH2:9][N:8]([CH2:29][CH2:30][S:31][C:32]2[CH:37]=[C:36]([F:38])[CH:35]=[CH:34][C:33]=2[F:39])[CH2:7][C@@H:6]1[C:11]([O:13][CH3:14])=[O:12]
Reactant: Fc1ccc(F)c(SCCBr)c1
Reactant: COC(=O)[C@H]1CNCC[C@H]1CCC(=O)c1c(F)cnc2ccc(OC)cc12
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)[C@H]1CN(CCSc2cc(F)ccc2F)CC[C@H]1CCC(=O)c1c(F)cnc2ccc(OC)cc12
Temperature: 75 °C
Reaction time: 20 h
Yield: 48.1 %

Procedure:
A mixture of 0.57 g of methyl (3R,4R)-4-[3-oxo-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]piperidine-3-carboxylate obtained as described in example 1, 0.462 g of 2-(2-bromoethylsulfanyl)-1,4-difluorobenzene, 0.253 g of potassium iodide and 1.05 g of potassium carbonate in 25 cm3 of acetonitrile is heated with stirring and under an inert atmosphere for 20 hours at a temperature in the region of 75° C. After cooling to a temperature in the region of 20° C., the reaction medium is filtered and the insoluble material is washed with 2 times 10 cm3 of acetonitrile. The filtrate is evaporated under reduced pressure (2 kPa) at a temperature in the region of 40° C. The evaporation residue is taken up with 50 cm3 of distilled water and 100 cm3 of ethyl acetate. The organic phase is washed with 3 times 30 cm3 of distilled water and 2 times 50 cm3 of a saturated aqueous sodium chloride solution, dried over magnesium sulfate and evaporated according to the conditions mentioned above. The oil obtained is purified by chromatography on a column of silica gel (particle size 70–200 μm; diameter 2.5 cm), eluting with a mixture of dichloromethane-methanol (9/10 by volume) and collecting fractions of 10 cm3. The fractions containing the expected product are pooled and then evaporated under reduced pressure (2 kPa) at a temperature in the region of 40° C. 0.4 g of methyl (3R,4R)-4-[3-oxo-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(2,5-difluorophenylsulfanyl)ethyl]-piperidine-3-carboxylate, in the form of an orange-colored viscous oil, is obtained.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])/[CH:4]=[CH:5]/[C:6]1[CH:7]=[C:8]2[C:25](=[CH:26][CH:27]=1)[O:24][C:11]1([CH2:16][CH2:15][N:14]([C:17](OC(C)(C)C)=O)[CH2:13][CH2:12]1)[CH2:10][C:9]2=[O:28].BrC[CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[F:39]>>[CH3:1][O:2][C:3](=[O:29])/[CH:4]=[CH:5]/[C:6]1[CH:7]=[C:8]2[C:25](=[CH:26][CH:27]=1)[O:24][C:11]1([CH2:12][CH2:13][N:14]([CH2:17][CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=3[F:39])[CH2:15][CH2:16]1)[CH2:10][C:9]2=[O:28]
Reactant: Fc1ccccc1CCBr
Reactant: COC(=O)/C=C/c1ccc2c(c1)C(=O)CC1(CCN(C(=O)OC(C)(C)C)CC1)O2
Product: COC(=O)/C=C/c1ccc2c(c1)C(=O)CC1(CCN(CCc3ccccc3F)CC1)O2
Yield: 85.5 %

Procedure:
(E)-3-{4-Oxo-spiro[chromane-2,4′-piperidine]-6-yl}-acrylic acid methyl ester (169 mg, 0.500 mmol, Intermediate 1, hydrochloride salt) was alkylated using 1-(2-bromo-ethyl)-2-fluoro-benzene (0.16 ml, 1.5 mmol) as described in Example 56, Step A, giving (E)-3-{1′-[2-(2-fluoro-phenyl)-ethyl]-4-oxo-spiro[chromane-2,4′-piperidine]-6-yl}-acrylic acid methyl ester (181 mg) as a white solid.
Reaction SMILES: [CH2:1]([P:3]([C:14]1[CH:19]=[C:18]([O:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][C:22]=2[Cl:31])[CH:17]=[CH:16][C:15]=1[N+:32]([O-:34])=[O:33])(=O)[O:4][CH2:5][O:6][C:7](=[O:12])[C:8]([CH3:11])([CH3:10])[CH3:9])[CH3:2].P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:36]>>[CH2:1]([P:3]([C:14]1[CH:19]=[C:18]([O:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][C:22]=2[Cl:31])[CH:17]=[CH:16][C:15]=1[N+:32]([O-:34])=[O:33])(=[S:36])[O:4][CH2:5][O:6][C:7](=[O:12])[C:8]([CH3:11])([CH3:10])[CH3:9])[CH3:2]
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: CCP(=O)(OCOC(=O)C(C)(C)C)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Product: CCP(=S)(OCOC(=O)C(C)(C)C)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]

Procedure:
A mixture of 2,2-dimethylpropionyloxymethyl P-ethyl-2-nitro-5-(2-chloro-4-trifluoromethylphenoxy)phenylphosphinate (4.7 mmol) and phosphorus pentasulfide (1.2 mmol) is heated to 150°-160° under nitrogen for 3-4 hours. After cooling, the residue is purified by prep. TLC (20% ethyl acetate/hexane) to give O-(2,2-dimethylpropionyloxymethyl) P-ethyl-2-nitro-5-(2-chloro-4-trifluoromethylphenoxy)phenylphosphinothioate.
Reaction SMILES: CN(C)[CH:3]=[CH:4][C:5]1[N:10]([CH3:11])[C:9](=[O:12])[N:8]([CH2:13][CH2:14][CH2:15][O:16][CH:17]2[CH2:22]CCC[O:18]2)[C:7](=[O:23])[C:6]=1[N+:24]([O-])=O>CC(O)=O.O.[Zn]>[C:17]([O:16][CH2:15][CH2:14][CH2:13][N:8]1[C:7](=[O:23])[C:6]2[NH:24][CH:3]=[CH:4][C:5]=2[N:10]([CH3:11])[C:9]1=[O:12])(=[O:18])[CH3:22]
Reactant: CN(C)C=Cc1c([N+](=O)[O-])c(=O)n(CCCOC2CCCCO2)c(=O)n1C
Agent: [Zn]
Solvent: CC(=O)O
Solvent: O
Product: CC(=O)OCCCn1c(=O)c2[nH]ccc2n(C)c1=O
Temperature: 100 °C
Yield: 56.5 %

Procedure:
To a solution of 6-(2-(dimethylamino)vinyl)-1-methyl-5-nitro-3-(3-((tetrahydro-2H-pyran-2-yl)oxy)propyl)pyrimidine-2,4(1H,3H)-dione (530 mg, 1.4 mmol) in HOAc (5 mL) was added Zn dust (910 mg, 14 mmol). The reaction was heated at 100° C. for 2 h, cooled to RT, diluted with water (10 mL) and extracted with EA (3×20 mL). The combined organic layers were dried over Na2SO4 and concentrated to a residue which was purified by chromatography eluted with PE/EA (1:1) to give 3-(1-methyl-2,4-dioxo-1H-pyrrolo[3,2-d]pyrimidin-3(2H,4H,5H)-yl)propyl acetate (210 mg, 56% yield) as a white solid. LCMS: MH+ 266 and TR=0.646 min.
Reaction SMILES: [CH:1]1[CH:6]=[C:5]2[C:7]([C:9](O)(O)[C:10](=[O:11])[C:4]2=[CH:3][CH:2]=1)=[O:8].Cl.[CH2:15]([C:18]1[CH:23]=[CH:22][C:21]([NH:24][C:25](=[O:28])[NH:26][NH2:27])=[CH:20][CH:19]=1)[CH2:16][CH3:17]>>[CH2:15]([C:18]1[CH:19]=[CH:20][C:21]([NH:24][C:25](=[O:28])[NH:26][N:27]=[C:9]2[C:10](=[O:11])[C:4]3[C:5](=[CH:6][CH:1]=[CH:2][CH:3]=3)[C:7]2=[O:8])=[CH:22][CH:23]=1)[CH2:16][CH3:17]
Reactant: O=C1c2ccccc2C(=O)C1(O)O
Reactant: CCCc1ccc(NC(=O)NN)cc1
Agent: Cl
Product: CCCc1ccc(NC(=O)NN=c2c(=O)c3ccccc3c2=O)cc1

Procedure:
ninhydrin, 4-(4-propylphenyl)-semicarbazide hydrochloride
Reaction SMILES: [CH3:1][C:2]1[N:6]=[C:5]([CH3:7])[N:4]([C:8]2[N:13]=[C:12](S(C)(=O)=O)[N:11]=[C:10]([C@@H:18]3[CH2:20][C@H:19]3[C:21]3[N:25]([CH3:26])[C:24]4[CH:27]=[CH:28][CH:29]=[CH:30][C:23]=4[N:22]=3)[CH:9]=2)[N:3]=1.[C-:31]#[N:32].[Na+].O>CS(C)=O>[CH3:1][C:2]1[N:6]=[C:5]([CH3:7])[N:4]([C:8]2[CH:9]=[C:10]([C@@H:18]3[CH2:20][C@H:19]3[C:21]3[N:25]([CH3:26])[C:24]4[CH:27]=[CH:28][CH:29]=[CH:30][C:23]=4[N:22]=3)[N:11]=[C:12]([C:31]#[N:32])[N:13]=2)[N:3]=1
Reactant: Cc1nc(C)n(-c2cc([C@@H]3C[C@H]3c3nc4ccccc4n3C)nc(S(C)(=O)=O)n2)n1
Reactant: [C-]#N
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: Cc1nc(C)n(-c2cc([C@@H]3C[C@H]3c3nc4ccccc4n3C)nc(C#N)n2)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of trans-2-(2-(6-(3,5-dimethyl-1H-1,2,4-triazol-1-yl)-2-(methylsulfonyl)pyrimidin-4-yl)cyclopropyl)-1-methyl-1H-benzo[d]imidazole (1-6, 750 mg, 1.77 mmol, 1.0 eq) and sodium cyanide (173 mg, 3.54 mmol, 2.0 eq) in DMSO (5.3 mL) was allowed to stir at room temperature for 1 hour. The reaction appeared complete by LCMS. Water was added to the reaction mixture and the resulting precipitate was isolated by suction filtration and washed with water. The precipitate was then triturated with ethyl acetate to afford trans-4-(3,5-dimethyl-1H-1,2,4-triazol-1-yl)-6-(2-(1-methyl-1H-benzo[d]imidazol-2-yl)cyclopropyl)pyrimidine-2-carbonitrile (21) as an off-white solid. 1H NMR (300 MHz, CDCl3) δ 8.12 (s, 1H), 7.69 (ddd, 1H, J=6.3, 5.1, 1.8 Hz), 7.37-7.18 (m, 3H), 3.85 (s, 3H), 3.03 (ddd, 1H, J=9.3, 4.5, 3.9 Hz), 2.94 (m, 1H), 2.91 (s, 3H), 2.41 (s, 3H), 2.13-1.98 (m, 2H). LRMS m/z (M+H) 371.0 found, 371.2 required. m.p. 229-231° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]3[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:11]=3[N:12]=2)=[CH:4][CH:3]=1.[I:19]Cl>C(O)(=O)C>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:9][C:10]3[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:11]=3[N:12]=2)=[CH:6][C:7]=1[I:19]
Reactant: ClI
Reactant: COc1ccc2nc(-c3ccc(N)cc3)sc2c1
Solvent: CC(=O)O
Product: COc1ccc2nc(-c3ccc(N)c(I)c3)sc2c1
Yield: 56.1 %

Procedure:
2-(4'-Aminophenyl)-6-methoxybenzothiazole (0.22 g, 0.84 mmol) was treated with iodine monochloride (0.21 g, 1.3 mmol) in acetic acid according to the above-described general procedure for iodination. Crude product was purified by flash chromatography on silica gel, using ethyl acetate-hexane (1:3) as eluent, to give brown small crystals (0.18 g, 54.9%), m.p. 179.2-181.1° C.
Reaction SMILES: [CH3:1][C:2]1([C:7]2[N:8]=[C:9]([CH2:12][N:13]3[CH:17]=[CH:16][C:15]([NH2:18])=[N:14]3)[S:10][CH:11]=2)[O:6]CCO1.[CH3:19][C:20]1[O:21][C:22]([C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([O:34][C:35]([F:38])([F:37])[F:36])[CH:29]=2)=[C:23]([C:25](O)=[O:26])[N:24]=1>>[C:2]([C:7]1[N:8]=[C:9]([CH2:12][N:13]2[CH:17]=[CH:16][C:15]([NH:18][C:25]([C:23]3[N:24]=[C:20]([CH3:19])[O:21][C:22]=3[C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([O:34][C:35]([F:37])([F:36])[F:38])[CH:29]=3)=[O:26])=[N:14]2)[S:10][CH:11]=1)(=[O:6])[CH3:1]
Reactant: CC1(c2csc(Cn3ccc(N)n3)n2)OCCO1
Reactant: Cc1nc(C(=O)O)c(-c2cccc(OC(F)(F)F)c2)o1
Product: CC(=O)c1csc(Cn2ccc(NC(=O)c3nc(C)oc3-c3cccc(OC(F)(F)F)c3)n2)n1

Procedure:
Following general procedure B followed by C, starting from 1-[4-(2-methyl-[1,3]dioxolan-2-yl)-thiazol-2-ylmethyl]-1H-pyrazol-3-ylamine and 2-methyl-5-(3-trifluoromethoxy-phenyl)-oxazole-4-carboxylic acid. LC-MS-conditions 05: tR=0.98 min; [M+H]+=492.06.
Reaction SMILES: [CH2:1](O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:9][N:10](C)[CH3:11].[C]=O>>[CH2:1]([N:10]([CH3:11])[CH3:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCc1ccccc1
Reactant: CN(C)C
Agent: [C]=O
Product: CN(C)Cc1ccccc1
Temperature: 200 °C
Reaction time: 5 h

Procedure:
To a glass-lined, stainless steel microreactor were charged 2 ml of benzyl alcohol, 1 ml of trimethylamine, and carbon monoxide (900 psi). The reactor was shaken 5 hours at 200° C. A large yield of benzyldimethylamine was obtained.
Reaction SMILES: COC1C=CC(C2CCC3C(=CC=C(OC)C=3)C2)=C(N)C=1.BrC1C=CC(OCCN2CCCCCC2)=CC=1.[N:39]1([CH2:46][CH2:47][O:48][C:49]2[CH:54]=[CH:53][C:52]([NH:55][C:56]3[CH:61]=[C:60]([O:62]C)[CH:59]=[CH:58][C:57]=3[CH:64]3[CH2:73][CH2:72][C:71]4[C:66](=[CH:67][CH:68]=[C:69]([O:74]C)[CH:70]=4)[CH2:65]3)=[CH:51][CH:50]=2)[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]1>>[N:39]1([CH2:46][CH2:47][O:48][C:49]2[CH:50]=[CH:51][C:52]([NH:55][C:56]3[CH:61]=[C:60]([OH:62])[CH:59]=[CH:58][C:57]=3[CH:64]3[CH2:73][CH2:72][C:71]4[CH:70]=[C:69]([OH:74])[CH:68]=[CH:67][C:66]=4[CH2:65]3)=[CH:53][CH:54]=2)[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]1
Reactant: COc1ccc2c(c1)CCC(c1ccc(OC)cc1Nc1ccc(OCCN3CCCCCC3)cc1)C2
Agent: Brc1ccc(OCCN2CCCCCC2)cc1
Agent: COc1ccc(C2CCc3cc(OC)ccc3C2)c(N)c1
Product: Oc1ccc2c(c1)CCC(c1ccc(O)cc1Nc1ccc(OCCN3CCCCCC3)cc1)C2
Yield: 34.5 %

Procedure:
Synthesized from 5-methoxy-2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)phenylamine and 1-[2-(4-bromophenoxy)ethyl]azepane according to an analogous synthetic method to Example 116, [4-(2-azepan-1-ylethoxy)phenyl][5-methoxy-2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)phenyl]amine (86 mg) was used according to an analogous synthetic method to Example 111 to provide the title compound (28 mg).
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:17])=[C:4]2[C:12](=[CH:13][C:14]=1[CH3:15])[O:11][C:7]1([CH2:10][CH2:9][CH2:8]1)[CH2:6][C:5]2=[O:16].[BH4-].[Na+]>CO>[CH3:17][C:3]1[C:2]([OH:1])=[C:14]([CH3:15])[CH:13]=[C:12]2[C:4]=1[CH:5]([OH:16])[CH2:6][C:7]1([O:11]2)[CH2:8][CH2:9][CH2:10]1
Reactant: Cc1cc2c(c(C)c1O)C(=O)CC1(CCC1)O2
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Cc1cc2c(c(C)c1O)C(O)CC1(CCC1)O2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 6-hydroxy-5,7-dimethylspiro[chromene-2,1′-cyclobutan]-4(3H)-one,( 345 mg) in methanol (5 mL) was added sodium borohydride (65 mg). The mixture was stirred at room temperature for 30 min. The mixture was concentrated and the methanol removed to give 5,7-dimethyl-3,4-dihydrospiro[chromene-2,1′-cyclobutane]-4,6-diol.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[C:7]([O:10][C:11]1[CH:19]=[CH:18][C:14]([C:15]([OH:17])=O)=[CH:13][CH:12]=1)(=[O:9])[CH3:8].[CH3:20][C:21]1[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][C:22]=1[NH2:23].N1C=CC=CC=1>CN(C=O)C.C(Cl)Cl>[CH3:20][C:21]1[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][C:22]=1[NH:23][C:15](=[O:17])[C:14]1[CH:13]=[CH:12][C:11]([O:10][C:7](=[O:9])[CH3:8])=[CH:19][CH:18]=1
Reactant: Cc1ccc([N+](=O)[O-])cc1N
Reactant: CC(=O)Oc1ccc(C(=O)O)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: CC(=O)Oc1ccc(C(=O)Nc2cc([N+](=O)[O-])ccc2C)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 51 %

Procedure:
Oxalyl chloride (0.5 ml) was added slowly to a stirred mixture of 4-acetoxybenzoic acid (1.09 g), methylene chloride (30 ml) and DMF (one drop) and the mixture was stirred at ambient temperature for 2 hours. A solution of 2-methyl-5-nitroaniline (0.76 g) and pyridine (2 ml) in methylene chloride was added over 15 minutes and the mixture was stirred for a further 2 hours. The reaction mixture washed with a 5% aqueous acetic acid solution, with water and with a 5% aqueous sodium bicarbonate solution. The organic extract was dried (MgSO4) and evaporated. The residue was recrystallised from ethyl acetate to give N-(2-methyl-5-nitrophenyl)-4-acetoxybenzamide (0.8 g), m.p. 207-208° C.; NMR Spectrum: (DMSOd6) 2.3 (s, 3H), 7.31 (d, 2H), 7.56 (d, 1H), 8.02 (m, 3H), 8.47 (d, 1H), 10.12 (s, 1H).
Reaction SMILES: [CH2:1]1[C:4]2([CH2:7][NH:6][CH2:5]2)[CH2:3][N:2]1[C:8]1[CH:9]=[CH:10][C:11]([NH:14][C:15]2[C:20](=[O:21])[N:19]([CH3:22])[N:18]=[C:17]([C:23]3[C:24]([CH2:45][OH:46])=[C:25]([N:29]4[N:38]=[CH:37][C:36]5[C:31](=[C:32]([F:43])[CH:33]=[C:34]([C:39]([CH3:42])([CH3:41])[CH3:40])[CH:35]=5)[C:30]4=[O:44])[CH:26]=[CH:27][CH:28]=3)[CH:16]=2)=[N:12][CH:13]=1.C=O.[C:49]([BH3-])#N.[Na+]>CO>[C:39]([C:34]1[CH:35]=[C:36]2[C:31](=[C:32]([F:43])[CH:33]=1)[C:30](=[O:44])[N:29]([C:25]1[CH:26]=[CH:27][CH:28]=[C:23]([C:17]3[CH:16]=[C:15]([NH:14][C:11]4[CH:10]=[CH:9][C:8]([N:2]5[CH2:3][C:4]6([CH2:7][N:6]([CH3:49])[CH2:5]6)[CH2:1]5)=[CH:13][N:12]=4)[C:20](=[O:21])[N:19]([CH3:22])[N:18]=3)[C:24]=1[CH2:45][OH:46])[N:38]=[CH:37]2)([CH3:40])([CH3:41])[CH3:42]
Reactant: Cn1nc(-c2cccc(-n3ncc4cc(C(C)(C)C)cc(F)c4c3=O)c2CO)cc(Nc2ccc(N3CC4(CNC4)C3)cn2)c1=O
Reactant: [BH3-]C#N
Agent: C=O
Agent: [Na+]
Solvent: CO
Product: CN1CC2(C1)CN(c1ccc(Nc3cc(-c4cccc(-n5ncc6cc(C(C)(C)C)cc(F)c6c5=O)c4CO)nn(C)c3=O)nc1)C2
Temperature: 25 °C
Reaction time: 4 h
Yield: 221.5 %

Procedure:
In a 25 mL round-bottomed flask, 2-(3-(5-(5-(2,6-diazaspiro[3.3]heptan-2-yl)pyridin-2-ylamino)-1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)-2-(hydroxymethyl)phenyl)-6-tert-butyl-8-fluorophthalazin-1(2H)-one (146 mg, 234 μmol), 30% formaldehyde (42.2 mg, 38.8 μl, 1.41 mmol) and sodium cyanoborohydride (177 mg, 2.81 mmol) were combined with methanol (9 ml) to give an orange solution. The reaction mixture was stirred at 25° C. for 4 h. The crude reaction mixture was concentrated in vacuo, diluted with 10 mL 0.1 M NaOH and extracted with DCM (3×15 mL). The organic layers were dried over Na2SO4 and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 40 g, 0% to 10% MeOH in DCM). The light yellow powder was dried under vacuum at 25° C. for 3 hrs to give 0.33 g (22%) of the title compound. (M+H)+=637 m/e. 1H NMR (300 MHz, CHLOROFORM-d) δ: 8.37 (s, 1H), 8.28 (d, J=2.3 Hz, 1H), 8.13 (s, 1H), 7.38-7.71 (m, 6H), 6.75-6.93 (m, 2H), 4.40 (s, 2H), 3.96 (s, 4H), 3.88 (s, 3H), 3.47 (s, 4H), 2.37 (s, 3H), 1.42 (s, 9H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][C@@H:8]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[C:12]=1[F:18])[CH2:9][OH:10])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[S:27](Cl)([CH3:30])(=[O:29])=[O:28]>C(Cl)Cl>[C:1]([O:5][C:6]([NH:7][C@@H:8]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[C:12]=1[F:18])[CH2:9][O:10][S:27]([CH3:30])(=[O:29])=[O:28])=[O:19])([CH3:4])([CH3:2])[CH3:3]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N[C@H](CO)c1cccc(Cl)c1F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@H](COS(C)(=O)=O)c1cccc(Cl)c1F
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
To a solution of [(S)-1-(3-chloro-2-fluoro-phenyl)-2-hydroxy-ethyl]-carbamic acid tert-butyl ester (550 mg, 1.9 mmol) and triethylamine (0.29 mL, 2.09 mmol) in CH2Cl2 (5.5 mL) cooled at −10° C. was added under nitrogen atmosphere mesylchloride (0.16 mL, 2.09 mmol) and the reaction mixture was stirred at 0° C. for 1.5 h. The reaction mixture was quenched with ice and water then extracted twice with EtOAc. The combined organic layers were washed with water, dried (Na2SO4), filtered and concentrated. The crude material was used without purification in the next step. MS (UPLC/MS): 412.3/414.3 [M+HCOO]−; tR (HPLC conditions a): 3.66 min.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[C:6]([N:8]([CH2:12][C:13]2[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:14]=2[O:21][CH2:22][CH2:23][OH:24])[C:9](=[O:11])[CH3:10])[CH:7]=1.C(N(C(C)C)CC)(C)C.[S:41](Cl)([CH3:44])(=[O:43])=[O:42]>ClCCl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)=[C:6]([N:8]([CH2:12][C:13]2[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:14]=2[O:21][CH2:22][CH2:23][O:24][S:41]([CH3:44])(=[O:43])=[O:42])[C:9](=[O:11])[CH3:10])[CH:7]=1
Reactant: COc1ccc(OCCO)c(CN(C(C)=O)c2cc(F)ccc2Oc2ccccc2)c1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccc(OCCOS(C)(=O)=O)c(CN(C(C)=O)c2cc(F)ccc2Oc2ccccc2)c1
Yield: 88 %

Procedure:
To a solution of 300 mg (0.71 mmol) 1e and 139 mg (1.06 mmol) diisopropyl ethyl amine in 5 ml dichloromethane was added 97 mg (0.85 mmol) mesyl chloride in 0.5 ml dichloromethane drop wisely at −10° C. The stirred reaction mixture was warmed over a period of 4 h to room temperature and diluted with dichloromethane. The organic phase was washed with saturated sodium hydrogen carbonate solution, water and brine. The organic phase was dried with magnesium sulfate. The crude product was purified by silica column chromatography (ethyl acetate:hexane gradient 1:6→1:2). The desired product 1f was obtained in 88% yield (346 mg, 0.62 mmol) as yellow oil.