Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]12[CH2:9][CH:6]([CH2:7][CH2:8]1)[CH:5]([CH3:10])[C:4](=[O:11])[CH2:3]2.[BH4-].[Na+]>C(O)(C)C>[CH3:1][C:2]12[CH2:9][CH:6]([CH2:7][CH2:8]1)[CH:5]([CH3:10])[CH:4]([OH:11])[CH2:3]2
Reactant: CC1C(=O)CC2(C)CCC1C2
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)O
Product: CC1C(O)CC2(C)CCC1C2
Temperature: 25 °C
Yield: 88.8 %

Procedure:
1,4-Dimethyl-bicyclo[3.2.1]octan-3-one (325 g, 2.14 mol, obtained as above in EXAMPLE III) was added to a a NaBH4 suspension (24 g, 0.64 mol) in isopropanol (600 mL), and refluxed for 30 minutes. The reaction mixture was cooled to room temperature, and quenched with acetone followed by acetic acid. The organic layer was separated and concentrated to provide crude 1,4-dimethyl-bicyclo[3.2.1]octan-3-ol (300 g, 1.9 mol), which was added to a solution of sodium amide (NaNH2, 94 g, 2.4 mol) in tetrahydrofuran (THF, 1 L) while at reflux, and aged for 5 hours. Allyl chloride (CH2CHCH2Cl, 170 g, 2.2 mol) was subsequently added at 45° C. and aged for another 2 hours. The reaction mixture was subsequently washed with water and a Na2CO3 solution. Fractional distillation of the organic layer provided 3-allyloxy-1,4-dimethyl-bicyclo[3.2.1]octane (220 g) having a boiling point of 120° C. at a pressure of 30 mmHg
Reaction SMILES: I/[CH:2]=[C:3]1\[CH2:4][CH2:5][C:6](=[O:8])[O:7]\1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:28][Si:29]([C:32]#[CH:33])([CH3:31])[CH3:30]>C(N(CC)CC)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:28][Si:29]([CH3:31])([CH3:30])[C:32]#[C:33]/[CH:2]=[C:3]1\[CH2:4][CH2:5][C:6](=[O:8])[O:7]\1
Reactant: O=C1CC/C(=C\I)O1
Reactant: C#C[Si](C)(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: C[Si](C)(C)C#C/C=C1\CCC(=O)O1

Procedure:
To a solution of 5(E)-iodomethylidenetetrahydro-2-furanone (820 mg), palladium (II) acetate (40 mg) and triphenylphosphine (80 mg) in 5 ml of triethylamine under argon was added 42 ml of trimethylsilylacetylene. The solution was refluxed for 4 hours and then partitioned between 150 ml of methylene chloride and 50 ml of water. The methylene chloride layer, dried over magnesium sulphate, was evaporated to an oil. This oil was purified by column chromatography on silica gel (10% ethyl acetate:petrolium ether, IR: 2130, 1820, 1762 cm-1.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([CH2:7][NH:8][C:9]2[CH:18]=[CH:17][C:16]3[C:15]([NH2:19])=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=2)=[CH:4][CH:3]=1.[N:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH:26]=O>>[CH3:1][C:2]1[O:6][C:5]([CH2:7][NH:8][C:9]2[CH:18]=[CH:17][C:16]3[C:15]([NH:19][CH2:26][C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][N:20]=4)=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(CNc2ccc3c(N)cccc3n2)o1
Reactant: O=Cc1ccccn1
Product: Cc1ccc(CNc2ccc3c(NCc4ccccn4)cccc3n2)o1

Procedure:
The title compound, MS: m/e=345.3 (M+H+), was prepared from N2-(5-methyl-furan-2-ylmethyl)-quinoline-2,5-diamine and 2-pyridinecarboxaldehyde as described in example 21 step C.
Reaction SMILES: [CH3:1][C:2]([NH2:12])([C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[C:6]([Cl:11])[CH:5]=1)[CH3:3].C=O.[C:15](=O)(O)[O-].[Na+]>>[CH2:15]=[N:12][C:2]([CH3:1])([C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[C:6]([Cl:11])[CH:5]=1)[CH3:3]
Reactant: O=C([O-])O
Reactant: CC(C)(N)c1cc(Cl)cc(Cl)c1
Agent: C=O
Agent: [Na+]
Product: C=NC(C)(C)c1cc(Cl)cc(Cl)c1

Procedure:
1-Methyl-1-(3,5-dichlorophenyl)ethylamine (7.5 g) was gradually added to formalin (37% aqueous HCHO solution) (4.6 g) at room temperature. This mixture was subjected as it is to reaction for 7 hours. A saturated sodium bicarbonate solution was added to the reaction mixture, the resultant was extracted with ether and this organic layer was washed with saturated saline solution, and then dried over anhydrous sodium sulfate. The solvent was removed by evaporation under reduced pressure to obtain 8.6 g of N-methylene-1-methyl-1-(3,5-dichloro-phenyl)ethylamine as white crystals.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[N:12]=[C:11]([CH:13]3[CH2:18][CH:17]([C:19]4[CH:24]=[CH:23][C:22]([O:25][C:26]([F:29])([F:28])[F:27])=[CH:21][CH:20]=4)[CH2:16][NH:15][CH2:14]3)[O:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.[Cl:37][C:38](OC(Cl)(Cl)Cl)=[O:39]>ClCCl>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[N:12]=[C:11]([CH:13]3[CH2:18][CH:17]([C:19]4[CH:24]=[CH:23][C:22]([O:25][C:26]([F:29])([F:27])[F:28])=[CH:21][CH:20]=4)[CH2:16][N:15]([C:38]([Cl:37])=[O:39])[CH2:14]3)[O:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: Fc1cccc(-c2noc(C3CNCC(c4ccc(OC(F)(F)F)cc4)C3)n2)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Cl)N1CC(c2ccc(OC(F)(F)F)cc2)CC(c2nc(-c3cccc(F)c3)no2)C1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
At 0° C., 1.00 g (2.46 mmol) of the compound from Example 178A and 0.34 ml (248 mg, 2.46 mmol) of triethylamine were initially charged in 167 ml of dichloromethane. 0.12 ml (242 mg, 1.23 mmol) of trichloromethyl chloroformate (diphosgene) was added dropwise. The reaction mixture was stirred at RT for 16 h, washed quickly with a little ice-water, dried over sodium sulphate, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel. Yield: 944 mg (68% of theory, 83% of theory)
Reaction SMILES: [CH:1]1([C:7]([NH:9][C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][N:14]=[C:13]3[NH:20][CH:21]=[C:22]([C:27]([O:29][CH3:30])=[O:28])[C:23](OC)=[O:24])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C1(OC2C=CC=CC=2)C=CC=CC=1>>[O:24]=[C:23]1[N:14]2[CH:15]=[N:16][C:17]3[CH:18]=[CH:19][C:10]([NH:9][C:7]([CH:1]4[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]4)=[O:8])=[CH:11][C:12]=3[C:13]2=[N:20][CH:21]=[C:22]1[C:27]([O:29][CH3:30])=[O:28]
Reactant: COC(=O)C(=CNc1ncnc2ccc(NC(=O)C3CCCCC3)cc12)C(=O)OC
Solvent: c1ccc(Oc2ccccc2)cc1
Product: COC(=O)c1cnc2c3cc(NC(=O)C4CCCCC4)ccc3ncn2c1=O
Temperature: 260 °C
Reaction time: 0.25 h
Yield: 97.6 %

Procedure:
A mixture of dimethyl [[6-cyclohexanecarboxamido-4-quinazolinylamino]methylene]propanedioate (4 g) and diphenyl ether (31 ml) was stirred at 260° C. for 15 minutes. After cooling to ambient temperature, the resulting solid was collected by filtration, washed with hexane and dried. There was obtained methyl 4-oxo-10-cyclohexanecarboxamido-4H-pyrimido[1,2-C]quinazoline-3-carboxylate (3.6 g).
Reaction SMILES: Cl.[F:2][C:3]1[CH:13]=[CH:12][C:6]([O:7][CH:8]2[CH2:11][NH:10][CH2:9]2)=[CH:5][CH:4]=1.Br[CH2:15][CH2:16][CH2:17][NH:18][S:19]([C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([C:28]#[N:29])[CH:23]=1)(=[O:21])=[O:20].C(N(CC)CC)C>C(#N)C>[C:28]([C:24]1[CH:23]=[C:22]([S:19]([NH:18][CH2:17][CH2:16][CH2:15][N:10]2[CH2:9][CH:8]([O:7][C:6]3[CH:12]=[CH:13][C:3]([F:2])=[CH:4][CH:5]=3)[CH2:11]2)(=[O:21])=[O:20])[CH:27]=[CH:26][CH:25]=1)#[N:29]
Reactant: Fc1ccc(OC2CNC2)cc1
Reactant: N#Cc1cccc(S(=O)(=O)NCCCBr)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: N#Cc1cccc(S(=O)(=O)NCCCN2CC(Oc3ccc(F)cc3)C2)c1
Temperature: 25 °C
Reaction time: 70 h

Procedure:
A suspension of 3-(4-fluoro-phenoxy)-azetidine hydrochloride (0.049 g, 0.24 mmol) in acetonitrile (1.0 ml) is treated with the crude N-(3-bromo-propyl)-3-cyano-benzenesulfonamide (0.072 g) in acetonitrile (1.0 ml) and triethylamine (0.1 ml, 0.72 mmol). The resulting homogenous reaction mixture is stirred at ambient temperature for 70 hours, the solvent evaporated and the residue partitioned between ethylacetate and aqueous NaHCO3 solution. The ethylacetate phase is washed with brine, dried over MgSO4 and evaporated. The crude product is purified by flash silica chromatography (elution ethylacetate) to afford 3-cyano-N-{3-[3-(4-fluoro-phenoxy)-azetidin-1-yl]-propyl}-benzenesulfonamide. [MH]+ 390.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH:6]=[CH:7][C:8](=[O:12])[C:9]=1[O:10][CH3:11])=[O:5].[Cl:13][C:14](=[CH2:19])[CH:15]=[CH:16]OC>ClCCl>[Cl:13][C:14]1[CH:19]=[C:6]2[C:7](=[CH:16][CH:15]=1)[C:8]([O:12][C:3](=[O:2])[CH3:9])=[C:9]([O:10][CH3:11])[C:3]([O:2][CH3:1])=[C:4]2[O:5][C:4](=[O:5])[CH3:6]
Reactant: C=C(Cl)C=COC
Reactant: COC1=C(OC)C(=O)C=CC1=O
Solvent: ClCCl
Product: COc1c(OC)c(OC(C)=O)c2cc(Cl)ccc2c1OC(C)=O
Reaction time: 12 h
Yield: 117.1 %

Procedure:
A dichloromethane (10 ml) solution of 2,3-dimethoxybenzo-1,4-quinone (1.0 g, 5.9 mmol) and 3-chloro-1-methoxy-1,3-butadiene (1.4 g, 12.0 mmol) is stirred for 24 hours at room temperature under an inert atmosphere. After this time, 80 mg of d,1-camphorsulfonic acid is added and the solution is stirred an additional 12 hours. The mixture is then concentrated and subsequently dissolved in pyridine (15 ml) and acetic anhydride (3.0 g). After stirring for five hours under an inert atmosphere, the solution is concentrated to dryness and taken up in dichloromethane. The organics are washed with water, brine, and then dried (sodium sulfate) and concentrated to afford 1.17 g (58%) of pure 6-chloro-1,4-diacetoxy-2,3-dimethoxynaphthalene.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=1)#[N:2].[H-].[Na+].C(O)(=O)C.[CH:15]([OH:18])([CH3:17])[CH3:16]>>[N:5]1[CH:6]=[CH:7][CH:8]=[C:3]([C:1](=[NH:2])[O:18][CH:15]([CH3:17])[CH3:16])[CH:4]=1
Reactant: CC(C)O
Reactant: N#Cc1cccnc1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(C)OC(=N)c1cccnc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
3-cyanopyridine (10.0 g, 96.1 mmol) was dissolved in isopropanol (50 ml). Sodium hydride (0.23 g, 9.6 mmol) from which oily matters had been removed by washing with ether was added to the solution, and the mixture was stirred at room temperature for 3 hours. After the reaction was completed, acetic acid (0.64 g, 10.7 mmol) was added to neutralize the reaction solution, and the solution was concentrated under reduced pressure. After concentrating the solution, diethyl ether (80 ml) was added to the concentrated residue, and insoluble products were removed by filtration. The filtrate was concentrated under reduced pressure, and hexane (80 ml) was added to the concentrated residue, and depositing unreacted 3-cyanopyridine was removed by filtration. The hexane solution was then concentrated under reduced pressure to give the crude product of isopropyl 3-pyridinecarboximidate as a pale yellow oil in a yield of 5.68 g.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH3:10])[CH3:9])=[CH:4][C:3]=1[N:11]([S:26]([C:29]1[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[C:31]([O:37][CH3:38])[CH:30]=1)(=[O:28])=[O:27])[CH2:12][C:13]([N:15]([CH2:24][CH3:25])[CH2:16][C:17]1[CH:22]=[N:21][CH:20]=[C:19]([CH3:23])[N:18]=1)=O.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:40]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH3:10])[CH3:9])=[CH:4][C:3]=1[N:11]([S:26]([C:29]1[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[C:31]([O:37][CH3:38])[CH:30]=1)(=[O:28])=[O:27])[CH2:12][C:13]([N:15]([CH2:24][CH3:25])[CH2:16][C:17]1[CH:22]=[N:21][CH:20]=[C:19]([CH3:23])[N:18]=1)=[S:40]
Reactant: CCN(Cc1cncc(C)n1)C(=O)CN(c1cc(N(C)C)ccc1Cl)S(=O)(=O)c1ccc(OC)c(OC)c1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Solvent: Cc1ccccc1
Product: CCN(Cc1cncc(C)n1)C(=S)CN(c1cc(N(C)C)ccc1Cl)S(=O)(=O)c1ccc(OC)c(OC)c1
Temperature: 80 °C
Reaction time: 3 h
Yield: 92.3 %

Procedure:
To a solution of 2-[(2-chloro-5-dimethylamino-phenyl)-(3,4-dimethoxy-benzenesulfonyl)-amino]-N-ethyl-N-(6-methyl-pyrazin-2-ylmethyl)-acetamide (20 mg) in dry toluene (0.2 mL) was added in one portion phosphorus pentasulfide (10 mg). The reaction mixture was stirred at 80° C. under nitrogen for 3 h. After cooling to RT, the reaction mixture was concentrated under reduced pressure and the residue was purified by FC (EA/n-heptane: 8/2 to EA) to give 12 mg (57%) of the title compound as a foam.
Reaction SMILES: Cl.Cl.[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([CH:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C@H:20]4[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]4)[CH2:14][CH2:13]3)[C:6]=2[CH2:5][CH2:4]1.[C:27]([CH2:29][C:30](O)=[O:31])#[N:28]>>[C:27]([CH2:29][C:30]([NH:26][C@H:23]1[CH2:22][CH2:21][C@H:20]([CH2:19][CH2:18][N:15]2[CH2:16][CH2:17][CH:12]([C:11]3[C:6]4[CH2:5][CH2:4][O:3][C:7]=4[CH:8]=[CH:9][CH:10]=3)[CH2:13][CH2:14]2)[CH2:25][CH2:24]1)=[O:31])#[N:28]
Reactant: N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3CCO4)CC2)CC1
Reactant: N#CCC(=O)O
Agent: Cl
Product: N#CCC(=O)N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3CCO4)CC2)CC1

Procedure:
The title compound, light yellow solid (75 mg, 76%), MS (ISP) m/z=396.3 [(M+H)+], mp 194° C., was prepared in accordance with the general method of example 1 from trans-4-{2-[4-(2,3-dihydro-benzofuran-4-yl)-piperidin-1-yl]-ethyl}-cyclohexylamine dihydrochloride (intermediate B) (100 mg, 0.25 mmol) and 2-cyano-acetic acid.
Reaction SMILES: S(=O)(=O)(O)O.[OH:6][C:7]1[CH:15]=[CH:14][C:10]([CH:11]=[N:12]O)=[CH:9][CH:8]=1>CC(CC(C)=O)C>[C:11]([C:10]1[CH:14]=[CH:15][C:7]([OH:6])=[CH:8][CH:9]=1)#[N:12]
Reactant: ON=Cc1ccc(O)cc1
Agent: O=S(=O)(O)O
Solvent: CC(=O)CC(C)C
Product: N#Cc1ccc(O)cc1
Temperature: 130 °C
Reaction time: 0.5 h
Yield: 75.5 %

Procedure:
To a 30 ml of flask equipped with distillating apparatus, 30 mg of conc. sulfuric acid, 10 ml of MIBK, 598 mg of p-hydroxybenzaldoxime were introduced and the reaction mixture was heated up to 130° C. Heating under stirring with a magnetic stirrer was continued for 30 minutes, and about 3.5 ml of MIBK thereby was distilled off. Reaction solution was subjected to gaschromatography analysis to find that 392 mg (76% yield) of p-cyanophenol was produced. The conversion was 100%.
Reaction SMILES: [CH2:1]([NH:3][C:4](=[O:11])[NH:5][O:6][CH2:7][C:8]([OH:10])=O)[CH3:2].[NH2:12][C@@H:13]([CH2:37][C:38]([NH:40][C:41]([C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1)([C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)=[O:39])[C:14]([N:16]([C@@H:28]([CH3:36])[CH:29]([O:33][CH2:34][CH3:35])[O:30][CH2:31][CH3:32])[CH2:17][C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][CH:19]=1)=[O:15]>>[CH2:31]([O:30][CH:29]([O:33][CH2:34][CH3:35])[C@@H:28]([N:16]([CH2:17][C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][CH:19]=1)[C:14](=[O:15])[C@@H:13]([NH:12][C:8](=[O:10])[CH2:7][O:6][NH:5][C:4]([NH:3][CH2:1][CH3:2])=[O:11])[CH2:37][C:38](=[O:39])[NH:40][C:41]([C:42]1[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=1)([C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)[C:54]1[CH:55]=[CH:56][CH:57]=[CH:58][CH:59]=1)[CH3:36])[CH3:32]
Reactant: CCNC(=O)NOCC(=O)O
Reactant: CCOC(OCC)[C@H](C)N(Cc1cccc2ccccc12)C(=O)[C@@H](N)CC(=O)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Product: CCNC(=O)NOCC(=O)N[C@@H](CC(=O)NC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)N(Cc1cccc2ccccc12)[C@@H](C)C(OCC)OCC

Procedure:
According to the procedure described in the synthesis method of Compound II-15, 2-(3-ethylureidooxy)acetic acid (Compound VI-13) 38 mg (0.23 mmol) was coupled with (S)-2-amino-N1—((S)-1,1-diethoxypropan-2-yl)-N1-(naphthalen-1-ylmethyl)-N4-tritylsuccinamide (Compound IV-19) 100 mg (0.16 mmol) to obtain the title compound.
Reaction SMILES: Cl.[CH3:2][CH:3]1[N:8]([CH2:9][C:10]([F:13])([F:12])[F:11])[C:7](=[O:14])[CH:6]([CH2:15][CH:16]=[CH:17][C:18]2[CH:19]=[C:20]3[CH2:43][C@@:25]4([C:33]5[C:28](=[N:29][CH:30]=[CH:31][CH:32]=5)[N:27](COCC[Si](C)(C)C)[C:26]4=[O:42])[CH2:24][C:21]3=[N:22][CH:23]=2)[CH2:5][CH:4]1[C:44]1[CH:49]=[C:48]([F:50])[CH:47]=[C:46]([F:51])[C:45]=1[F:52].[OH-].[NH4+]>CO>[CH3:2][CH:3]1[N:8]([CH2:9][C:10]([F:12])([F:11])[F:13])[C:7](=[O:14])[C@@H:6]([CH2:15][CH:16]=[CH:17][C:18]2[CH:19]=[C:20]3[CH2:43][C:25]4([C:33]5[C:28](=[N:29][CH:30]=[CH:31][CH:32]=5)[NH:27][C:26]4=[O:42])[CH2:24][C:21]3=[N:22][CH:23]=2)[CH2:5][CH:4]1[C:44]1[CH:49]=[C:48]([F:50])[CH:47]=[C:46]([F:51])[C:45]=1[F:52]
Reactant: CC1C(c2cc(F)cc(F)c2F)CC(CC=Cc2cnc3c(c2)C[C@@]2(C3)C(=O)N(COCC[Si](C)(C)C)c3ncccc32)C(=O)N1CC(F)(F)F
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: CO
Product: CC1C(c2cc(F)cc(F)c2F)C[C@H](CC=Cc2cnc3c(c2)CC2(C3)C(=O)Nc3ncccc32)C(=O)N1CC(F)(F)F
Temperature: 0 °C
Reaction time: 1 h

Procedure:
HCl gas was bubbled into a solution of (3′S)-3-(3-(6-methyl-2-oxo-1-(2,2,2-trifluoroethyl)-5-(2,3,5-trifluorophenyl)piperidin-3-yl)prop-1-en-1-yl)-1′-((2-(trimethylsilyl)ethoxy)methyl)-5,7-dihydrospiro[cyclopenta[b]pyridine-6,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one (0.091 g, 0.125 mmol) in MeOH (5 mL) cooled to 0° C. until saturated. The resulting mixture was stirred at 0° C. for 1 h and then concentrated to dryness in vacuo. To a solution of this crude mixture in MeOH (5 mL) was added ammonium hydroxide (0.27 mL, 1.99 mmol), and the reaction was stirred at ambient temperature for 30 min. The reaction was concentrated to dryness in vacuo. The crude product was purified by reverse-phase HPLC, eluting with 5% acetonitrile in water (0.1% TFA used as a modifier) initially, grading to 85% acetonitrile in water, to give the title compound as a mixture of ca. 1 major and 2 minor compounds (pairs of enantiomers). MS: m/z=601.2 (M+1). Major diastereoisomer: 1H NMR (500 MHz, CDCl3) δ 8.51 (s, 1H), 8.15 (dd, 1H, J=5.7, 1.4 Hz), 7.90 (s, 1H), 7.42 (dd, 1H, J=7.4, 1.4 Hz), 7.06 (dd, 1H, J=7.4, 5.7 Hz), 6.94-6.90 (m, 1H), 6.72-6.70 (m, 1H), 6.49-6.46 (m, 1H), 4.90-4.78 (m, 1H), 4.00-3.90 (m, 2H), 3.90-3.75 (m, 2H), 3.75-3.60 (m, 1H), 3.55 (d, 1H, J=17.5 Hz), 3.40-3.20 (m, 2H), 2.92-2.80 (m, 2H), 2.78-2.68 (m, 1H), 2.55 (dt, 1H, J=13.7, 4.1 Hz), 1.86 (bd, 1H, J=13.7 Hz), 1.08 (d, 3H, J=6.6 Hz).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([O:10][CH3:11])[C:5]([C:8]#[N:9])=[N:6][CH:7]=1.[Cl:12][C:13]1[CH:18]=[C:17](Cl)[N:16]=[CH:15][N:14]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C>C1COCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:12][C:13]1[N:14]=[CH:15][N:16]=[C:17]([NH:1][C:2]2[N:3]=[C:4]([O:10][CH3:11])[C:5]([C:8]#[N:9])=[N:6][CH:7]=2)[CH:18]=1
Reactant: Clc1cc(Cl)ncn1
Reactant: COc1nc(N)cnc1C#N
Agent: [Pd]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Solvent: C1CCOC1
Product: COc1nc(Nc2cc(Cl)ncn2)cnc1C#N
Temperature: 135 °C
Yield: 28.1 %

Procedure:
5-Amino-3-methoxypyrazine-2-carbonitrile (9.2 mg, 0.061 mmol), 4,6-dichloropyrimidine (10 mg, 0.067 mmol), lithium bis(trimethylsilyl)amide (1M, 75 uL, 0.075 mmol), Pd2(dba)3 (3.5 mg, 5.5% mol) and 2-(di-tert-butyl-phosphino)biphenyl (2 mg, 0.0067 mmol) were mixed in THF (0.5 mL). The reaction mixture was heated at 135° C. for 60 minutes using microwave irradiation. The crude product was purified by preparative thin layer chromatography, eluting with EtOAc/n-hexane (1/2), to give the title compound as an oil (4.5 mg, 28%).
Reaction SMILES: C([O:3][C:4](=[O:19])[C@@H:5]([O:17][CH3:18])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]#[C:14][CH2:15]Cl)=[CH:9][CH:8]=1)C.[CH:20]1[CH:25]=[CH:24][C:23]([NH:26][C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([OH:33])[CH:28]=2)=[CH:22][CH:21]=1>>[CH3:18][O:17][C@@H:5]([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]#[C:14][CH2:15][O:33][C:29]2[CH:30]=[CH:31][CH:32]=[C:27]([NH:26][C:23]3[CH:22]=[CH:21][CH:20]=[CH:25][CH:24]=3)[CH:28]=2)=[CH:11][CH:12]=1)[C:4]([OH:3])=[O:19]
Reactant: Oc1cccc(Nc2ccccc2)c1
Reactant: CCOC(=O)[C@H](Cc1ccc(C#CCCl)cc1)OC
Product: CO[C@@H](Cc1ccc(C#CCOc2cccc(Nc3ccccc3)c2)cc1)C(=O)O

Procedure:
The title compound was prepare from (2S)-3-[4-(3-Chloro-prop-1-ynyl)-phenyl]-2-methoxy-propionic acid ethyl ester from Example 5, Step A and 3-hydroxydiphenylamine in a manner analogous to that described for Example 5, Step B. MS(ES) for CH23H23NO [M+H]+: 402.2.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:11][C:10]([CH2:15][O:16][CH3:17])([CH2:12][O:13][CH3:14])[C@@H:9]([OH:18])[C@H:8]([NH:19][C:20]3[CH:25]=[CH:24][C:23](=[O:26])[NH:22][N:21]=3)[C:7]=2[CH:27]=1)#[N:2].[C:28](#[N:31])[CH:29]=[CH2:30].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:11][C:10]([CH2:12][O:13][CH3:14])([CH2:15][O:16][CH3:17])[C@@H:9]([OH:18])[C@H:8]([NH:19][C:20]3[CH:25]=[CH:24][C:23](=[O:26])[N:22]([CH2:30][CH2:29][C:28]#[N:31])[N:21]=3)[C:7]=2[CH:27]=1)#[N:2]
Reactant: COCC1(COC)Oc2ccc(C#N)cc2[C@@H](Nc2ccc(=O)[nH]n2)[C@@H]1O
Reactant: C=CC#N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COCC1(COC)Oc2ccc(C#N)cc2[C@@H](Nc2ccc(=O)n(CCC#N)n2)[C@@H]1O
Yield: 58.2 %

Procedure:
(-)-(3S,4R)-6-Cyano-3,4-dihydro-4-[(1,6-dihydro-6-oxo-3-pyridazinyl)amino]-2,2-bis(methoxymethyl)-2H-1-benzopyran-3-ol (150 mg, 0.40 mmol) obtained in Example 8 and acrylonitrile (0.055 ml, 0.806 mmol) were dissolved in dimethylformamide (3 ml). Potassium carbonate (111 mg) was added and the mixture was reacted at 50° C. overnight. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled away under reduced pressure and the residue was purified by silica gel column chromatography (methanol:chloroform=1:30) to give 99 mg of the title compound (58%).
Reaction SMILES: [H-].[Na+].O1CCCC1.[CH3:8][O:9][C:10](=[O:30])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH2:17][S:18][C:19]1[NH:20][C:21]2[CH:27]=[C:26]([CH3:28])[C:25]([CH3:29])=[CH:24][C:22]=2[N:23]=1.Cl[CH2:32][C:33]1[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH:36]=[CH:35][CH:34]=1>O>[CH3:8][O:9][C:10](=[O:30])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH2:17][S:18][C:19]1[N:20]([CH2:32][C:33]2[C:42]3[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=3)[CH:36]=[CH:35][CH:34]=2)[C:21]2[CH:27]=[C:26]([CH3:28])[C:25]([CH3:29])=[CH:24][C:22]=2[N:23]=1
Reactant: COC(=O)c1ccccc1CSc1nc2cc(C)c(C)cc2[nH]1
Reactant: ClCc1cccc2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1ccccc1CSc1nc2cc(C)c(C)cc2n1Cc1cccc2ccccc12
Temperature: 60 °C
Reaction time: 0.75 h
Yield: 32 %

Procedure:
Sodium hydride (1.1 mg, 0.306 mmol) and 2 ml of tetrahydrofuran was added to a previously dried reaction vessel. To the mixture were added 2-((5,6-dimethylbenzimidazole-2-ylthio)methyl)benzoic acid methyl ester (50 mg, 0.153 mmol) and 1-chloromethylnaphthalene (69 μl, 0.459 mmol), which was then stirred at 60° C. for 45 minutes. Water was added thereto, followed by extraction with ethyl acetate. After drying the ethyl acetate phase with anhydrous sodium sulfate, it was concentrated, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1) to obtain 2-((5,6-dimethyl-1-(1-naphthylmethyl)benzimidazole-2-ylthio)methyl)benzoic acid methyl ester (yield 32%).
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([O:9][CH3:10])=[O:8].[Br:11]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[Br:11][CH2:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1sccc1C
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1sccc1CBr
Temperature: 25 °C
Yield: 99.7 %

Procedure:
A 1-L single-neck round-bottomed flask equipped with a magnetic stirrer, reflux condenser and nitrogen inlet was purged with nitrogen and charged with 116b (5.00 g, 32.0 mmol), N-bromosuccinimide (5.70 g, 32.0 mmol) and carbon tetra-chloride (300 mL). The solution was heated to 70° C. (oil bath temperature), and 2,2′-azobisisobutyronitrile (526 mg, 3.20 mmol) was added. The resulting mixture was refluxed for 3 h. After that time, the mixture was cooled to room temperature and filtered. The filter cake was washed with carbon tetrachloride (2×50 mL). The filtrate was diluted with ethyl acetate (300 mL) and washed with water (40 mL), saturated aqueous sodium bicarbonate (40 mL) and brine (40 mL). The organic layer was dried over sodium sulfate and concentrated under reduced pressure to afford a quantitative yield (7.50 g) of 116c as a colorless oil: 1H NMR (300 MHz, CDCl3) δ 7.39 (d, 1H, J=5.0 Hz), 7.11 (d, 1H, J=5.1 Hz), 4.85 (s, 2H), 3.83 (s, 3H).