Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[CH:3]1.[S:7]([Cl:11])(=O)(=[O:9])[OH:8].Cl.S(Cl)(Cl)=O>>[CH3:1][N:2]1[CH:6]=[C:5]([S:7]([Cl:11])(=[O:9])=[O:8])[N:4]=[CH:3]1
Reactant: Cn1ccnc1
Reactant: O=S(=O)(O)Cl
Agent: Cl
Solvent: O=S(Cl)Cl
Product: Cn1cnc(S(=O)(=O)Cl)c1
Temperature: 150 °C
Reaction time: 6 h

Procedure:
1-Methylimidazole (250 g, 3.05 mol) is added dropwise to chlorosulfuric acid (600 ml, 9.03 mol), in such a way that an internal temperature of 30° C. is not exceeded, without aspirating the hydrogen chloride formed. After addition is complete, the reaction mixture is stirred at 150° C. for 6 h. Thionyl chloride (340 ml, 4.66 mol) is added at 60° C. and the mixture is then heated at a bath temperature of 100° C. for 6 h. After cooling to room temperature, the viscous reaction mixture is poured onto sufficient ice such that that the end about 7.5 l of a water-ice mixture remains. The precipitate deposited is filtered off with suction and briefly sucked dry in air. It is then either dried in a thin layer in a vacuum drying oven at 50° C. and 15 torr, or it is preferably taken up using dichloromethane, dried over sodium sulfate and freed from solvent in vacuo. Yield: 176 g (32% of theory) of colorless crystals were obtained (melting point: 89°-90° C.). To remove the isomeric 5-imidazolesulfonic acid formed as a by-product from the mother liquor, the latter is largely concentrated in vacuo at 15 torr in a rotary evaporator. On addition of ethanol, an imidazolesulfonic acid mixture crystallizes out, which can be recrystallized from ethanol.
Reaction SMILES: [CH2:1]([N:8]([CH2:14]OC)[CH2:9][Si](C)(C)C)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:17]1(=[O:23])[NH:21][C:20](=[O:22])[CH:19]=[CH:18]1.FC(F)(F)C(O)=O>ClCCl>[CH2:1]([N:8]1[CH2:9][C@@H:19]2[C:20](=[O:22])[NH:21][C:17](=[O:23])[C@@H:18]2[CH2:14]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Reactant: O=C1C=CC(=O)N1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1NC(=O)[C@@H]2CN(Cc3ccccc3)C[C@H]12
Temperature: 25 °C
Reaction time: 27 h
Yield: 90.6 %

Procedure:
A solution of N-benzyl-N-methoxymethyl-N-(trimethylsilylmethyl)amine (76.68 g, 0.29 mol, prepared as in Organic Syntheses (1989), 67, 133-140) in dichloromethane (130 mL) was added to an ice-cooled mixture of maleimide (25.53. g, 0.26 mol) and trifluoroacetic acid (2.2 mL, 0.028 mol) in dichloromethane (350 ml) over 40 min so that the reaction temperature remained between 0-5° C. The resulting bright yellow solution was allowed to warm gradually and stirred at room temperature for 27 h. The mixture was washed with saturated NaHCO3(aq) (80 mL) and the organic phase was dried (MgSO4) and concentrated under vacuum. The residual oil was stirred with 10% EtOAc-heptane (300 mL) for 15 h, and the resulting precipitate was isolated by filtration, washed with 10% EtOAc-heptane (150 mL) and dried under vacuum at 50° C. to provide the crude, title compound as a white solid (54.25 g). This was stirred with methanol (500 mL) and 50% aqueous H2NOH (4.2 mL) at room temperature for 20 h. The mixture was concentrated under vacuum and the residue was taken up in EtOAc (500 mL) and filtered to remove some insoluble material. The filtrate was concentrated under vacuum to leave the pure, title compound as an off-white solid (49.9 g, 83% yield). 1H NMR (300 MHz, CD3OD) δ ppm 2.32-2.43 (m, 2H), 3.18 (d, J=9.8 Hz, 2H), 3.20-3.26 (m, 2H), 3.59 (s, 2H), 7.13-7.35 (m, 5H); MS (DCI/NH3) m/z 231 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1([CH3:8])[CH2:4][CH:3]1[C:5](O)=[O:6].O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1.C(N(CC)CC)C.[Br:31][C:32]1[C:33]([F:42])=[C:34]2[C:40]([NH2:41])=[CH:39][NH:38][C:35]2=[N:36][CH:37]=1.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[Br:31][C:32]1[C:33]([F:42])=[C:34]2[C:40]([NH:41][C:5]([CH:3]3[CH2:4][C:2]3([CH3:8])[CH3:1])=[O:6])=[CH:39][NH:38][C:35]2=[N:36][CH:37]=1
Reactant: Nc1c[nH]c2ncc(Br)c(F)c12
Reactant: CC1(C)CC1C(=O)O
Agent: O=C([O-])[O-]
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1(C)CC1C(=O)Nc1c[nH]c2ncc(Br)c(F)c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 47.4 %

Procedure:
2,2-Dimethylcyclopropanecarboxylic acid (0.992 g, 8.69 mmol), bis(2-oxooxazolidin-3-yl)phosphinic chloride (2.21 g, 8.69 mmol) and triethylamine (2.20 g, 21.7 mmol) were added to 5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-amine (1 g, 4.35 mmol) in DCM (100 mL). The reaction was stirred at room temperature for 1 hour, and then 2N aqueous Na2CO3 was added. The mixture was filtered, and the solid rinsed with water and dried to yield N-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-2,2-dimethylcyclopropanecarboxamide (672 mg, 47.4% yield) as a solid.
Reaction SMILES: [C:1](Cl)(=[O:7])[CH:2]=[CH:3][CH:4]=[CH:5][CH3:6].[C:9]1([C:15]#[C:16][C:17]2[CH:35]=[CH:34][C:20]([C:21]([NH:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[S:30](=[O:33])(=[O:32])[NH2:31])=[O:22])=[CH:19][CH:18]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>CN(C)C1C=CN=CC=1.O1CCCC1>[C:9]1([C:15]#[C:16][C:17]2[CH:35]=[CH:34][C:20]([C:21]([NH:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[S:30]([NH:31][C:1](=[O:7])/[CH:2]=[CH:3]/[CH:4]=[CH:5][CH3:6])(=[O:33])=[O:32])=[O:22])=[CH:19][CH:18]=2)[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: CC=CC=CC(=O)Cl
Reactant: NS(=O)(=O)c1ccccc1NC(=O)c1ccc(C#Cc2ccccc2)cc1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: CC=C/C=C/C(=O)NS(=O)(=O)c1ccccc1NC(=O)c1ccc(C#Cc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 47.8 %

Procedure:
In a stream of nitrogen and at 0° C., 0.10 ml (0.96 mmol) of 2,4-hexadienoyl chloride was added to an anhydrous tetrahydrofuran (10 ml) solution containing 300 mg (0.80 mmol) of 4-phenylethynyl-N-(2-sulfamoylphenyl)benzamide produced in Reference Example 10 and 195 mg (1.60 mmol) of 4-dimethylaminopyridine, the mixture was stirred at room temperature for 1 hour and then the solvent was evaporated under a reduced pressure. The resulting residue was dissolved in ethyl acetate, washed with water, a potassium hydrgensulfate aqueous solution and saturated brine in that order and dried over anhydrous sodium sulfate, and then the solvent was evaporated under a reduced pressure. The thus formed crude crystals were recrystallized from methanol to obtain 180 mg (yield: 48.0%) of the title compound.
Reaction SMILES: [H-].[Na+].[Br:3][CH:4]1[CH2:10][CH:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH3:17])[CH2:8][CH:7]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[NH:6][C:5]1=[O:24].C([CH:29](I)[C:30]([NH2:32])=[O:31])(C)(C)C>>[C:9]([NH:32][C:30](=[O:31])[CH2:29][N:6]1[CH:7]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:8][CH:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH3:17])[CH2:10][CH:4]([Br:3])[C:5]1=[O:24])([CH3:11])([CH3:10])[CH3:8]
Reactant: CC(C)(C)C(I)C(N)=O
Reactant: Cc1ccccc1C1CC(Br)C(=O)NC(c2ccccc2)C1
Agent: [H-]
Agent: [Na+]
Product: Cc1ccccc1C1CC(Br)C(=O)N(CC(=O)NC(C)(C)C)C(c2ccccc2)C1
Temperature: 25 °C
Reaction time: 60 h
Yield: 184.9 %

Procedure:
To a 1000 mL 3-necked round-bottomed flank equipped with addition funnel and nitrogen inlet was added 3.9 grams (97.6 mmol) sodium hydride, which was then washed with hexane, and 400 mL dry tetrahydrofuran. To the stirring suspension was added a solution of 31.8 grams (88.8 mmol) 3-Bromo-5-(2-methylphenyl)-7-phenyl-2,3,4,5,6,7-hexahydroazepin-2-one and 23.5 grams (97.6 mmol) t-butyl iodoacetamide. The reaction was stirred at room temperature for 60 hours, quenched with ammonium chloride solution, then poured into water, extracted twice into ethyl acetate, washed with brine, dried over sodium sulfate, and evaporated. The residue was chromatographed on silica gel using 2/1-hexane/ethyl acetate an eluent to afford 38.7 grams (92%) of a foam, a mixture of diastereomers.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([C:11](O)=[O:12])[CH2:7][CH2:6]1.S(Cl)([Cl:18])=O>>[F:1][C:2]([F:15])([F:14])[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([C:11]([Cl:18])=[O:12])[CH2:7][CH2:6]1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)C1CCN(CCC(F)(F)F)CC1
Product: O=C(Cl)C1CCN(CCC(F)(F)F)CC1
Temperature: 80 °C
Yield: 68 %

Procedure:
A suspension of 1-(3,3,3-trifluoropropyl)piperidine-4-carboxylic acid (4.40 g, 20.0 mmol) in thionyl chloride (20 mL) was heat to 80° C. for 15 h. The solution was cooled and concentrated in vacuo to yield a brown foam (3.0 g, 68%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([C:13]#[C:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[C:11]([NH:21]C(=O)C)[N:10]([CH2:25][CH2:26][OH:27])[N:9]=2)=[CH:4][CH:3]=1>C(O)C.[OH-].[Na+]>[NH2:21][C:11]1[N:10]([CH2:25][CH2:26][OH:27])[N:9]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[C:12]=1[C:13]#[C:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CC(=O)Nc1c(C#Cc2ccccc2)c(-c2ccc(F)cc2)nn1CCO
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Nc1c(C#Cc2ccccc2)c(-c2ccc(F)cc2)nn1CCO
Yield: 36.2 %

Procedure:
A solution of N-(3-(4-fluorophenyl)-1-(2-hydroxyethyl)-4-(phenylethynyl)-1H-pyrazol-5-yl)acetamide (382 mg, 1.05 mmol) in ethanol (4 mL) and 25% NaOH (6 mL) was heated to 83° C. for 16 h. The reaction mixture was partitioned between ethyl acetate and water. The aqueous phase was washed with ethyl acetate twice and the organic phases combined, dried over MgSO4, filtered and evaporated, purification using chromatography (silica gel, gradient 0 to 10% methanol/CH2Cl2) gave 2-(5-amino-3-(4-fluorophenyl)-4-(phenylethynyl)-1H-pyrazol-1-yl)ethanol as a solid (122 mg), which was used as such in the subsequent step.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5]([C@@H:7]1[C@@H:11]([NH:12][C:13]([C:15]2[S:16][C:17]([Cl:20])=[CH:18][CH:19]=2)=[O:14])[CH2:10][NH:9][CH2:8]1)=[O:6])[CH3:3].BrC([C:26]1[CH:31]=[CH:30][C:29]([N:32]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]2=[O:38])=[CH:28][C:27]=1[F:39])C(N)=O>C1COCC1>[CH2:2]([O:4][C:5]([C@@H:7]1[C@@H:11]([NH:12][C:13]([C:15]2[S:16][C:17]([Cl:20])=[CH:18][CH:19]=2)=[O:14])[CH2:10][N:9]([CH2:15][C:13](=[O:14])[NH:12][C:26]2[CH:31]=[CH:30][C:29]([N:32]3[CH:37]=[CH:36][CH:35]=[CH:34][C:33]3=[O:38])=[CH:28][C:27]=2[F:39])[CH2:8]1)=[O:6])[CH3:3]
Reactant: CCOC(=O)[C@H]1CNC[C@@H]1NC(=O)c1ccc(Cl)s1
Reactant: NC(=O)C(Br)c1ccc(-n2ccccc2=O)cc1F
Agent: Cl
Solvent: C1CCOC1
Product: CCOC(=O)[C@H]1CN(CC(=O)Nc2ccc(-n3ccccc3=O)cc2F)C[C@@H]1NC(=O)c1ccc(Cl)s1

Procedure:
40.4 Using general procedure A with THF as solvent (3S,4R)-4-[(5-chloro-thiophene-2-carbonyl)-amino]-pyrrolidine-3-carboxylic acid ethyl ester hydrochloride was reacted with 2-bromo-[2-fluoro-4-(2-oxopyridin-1-yl)-phenyl]-acetamide to give (3S,4R)-4-[(5-chloro-thiophene-2-carbonyl)-amino]-1-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl-carbamoyl]-methyl}-pyrrolidine-3-carboxylic acid ethyl ester. Light brown solid. MS 547.2 [M+H+].
Reaction SMILES: [C:1]([N:6]1[C:10](=[O:11])[C:9]2=[CH:12][CH:13]=[CH:14][CH:15]=[C:8]2[C:7]1=[O:16])(OCC)=O.[S:17]1[CH:21]=[CH:20][CH:19]=[C:18]1[CH2:22]CN>C(O)C>[S:17]1[CH:21]=[CH:20][CH:19]=[C:18]1[CH2:22][CH2:1][N:6]1[C:7](=[O:16])[C:8]2=[CH:15][CH:14]=[CH:13][CH:12]=[C:9]2[C:10]1=[O:11]
Reactant: NCCc1cccs1
Reactant: CCOC(=O)N1C(=O)c2ccccc2C1=O
Solvent: CCO
Product: O=C1c2ccccc2C(=O)N1CCc1cccs1
Reaction time: 22.5 h

Procedure:
N-Carboethoxyphthalimide (4.93 g, 22.5 mmol) was added to a solution of 2-(2-thienyl)ethylamine (2.75 g, 21.6 mmol) in ethanol (20 ml) and was stirred for 20-25 hours. The precipitated product was collected by filtration, washed with cold methanol and dried. The product obtained (5.45 g) was used in the next step without purification.
Reaction SMILES: I(Cl)(=O)=O.I([Cl:8])(=O)=O.C([N+](C)(C)C)C1C=CC=CC=1.[CH3:20][N:21]([CH3:35])/[CH:22]=[CH:23]/[C:24]([C:26]1[N:30]([CH:31]([CH3:33])[CH3:32])[C:29]([CH3:34])=[N:28][CH:27]=1)=[O:25].O.C(=O)([O-])O.[Na+]>CO.C(Cl)Cl.C(Cl)Cl>[Cl:8]/[C:23](=[CH:22]/[N:21]([CH3:20])[CH3:35])/[C:24]([C:26]1[N:30]([CH:31]([CH3:32])[CH3:33])[C:29]([CH3:34])=[N:28][CH:27]=1)=[O:25]
Reactant: Cc1ncc(C(=O)/C=C/N(C)C)n1C(C)C
Reactant: O=I(=O)Cl
Agent: C[N+](C)(C)Cc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: CO
Product: Cc1ncc(C(=O)/C(Cl)=C\N(C)C)n1C(C)C

Procedure:
Benzyltrimethylammonium dichloroiodate (2.6 g 7.5 mmol) was added in portions to a stirred solution of (2E)-3-(dimethylamino)-1-(1-isopropyl-2-methyl-1H-imidazol-5-yl)prop-2-en-1-one (Method 24 of WO 03/076436; 1.1 g 5 mmol) in MeOH/DCM (15/30 ml) at room temperature. After 1 hour water (10 ml) and DCM (20 ml) were added followed after a further 30 minutes by saturated sodium hydrogen carbonate solution (20 ml). The organics were separated, re-extracted the aqueous with DCM (25 ml). The combined organics were washed with 5% (w/v) sodium thiosulphate solution (30 to 35 ml) and brine (25 ml), dried (Na2SO4) and evaporated to give the title compound as an oil (crude yield 1.68 g still wet). M/z 256.
Reaction SMILES: [Na].C([O:4][C:5](=[O:8])[CH2:6][SH:7])C.Cl/[C:10](=[C:12]1\[C@H:13]2[C@@H:15]([CH2:16][C:17]\1=O)[C:14]2([CH3:20])[CH3:19])/[CH3:11].[Li+].[OH-]>C(O)C>[CH3:19][C:14]1([CH3:20])[C@@H:15]2[CH2:16][C:17]3[C:12]([C@H:13]12)=[C:10]([CH3:11])[S:7][C:6]=3[C:5]([OH:4])=[O:8]
Reactant: C/C(Cl)=C1\C(=O)C[C@@H]2[C@H]1C2(C)C
Reactant: CCOC(=O)CS
Agent: [Li+]
Agent: [Na]
Agent: [OH-]
Solvent: CCO
Product: Cc1sc(C(=O)O)c2c1[C@H]1[C@@H](C2)C1(C)C
Temperature: 30 °C
Reaction time: 1 h
Yield: 66.6 %

Procedure:
Alternatively, (1aS,5a R)-1,1,2-trimethyl-1,1a,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalene-4-carboxylic acid is also obtained by the following procedure: To a solution of sodium (2.80 g, 122 mmol) in ethanol (400 mL) a solution of mercapto-acetic acid ethyl ester (14.64 g, 122 mmol) in ethanol (40 mL) is added. The solution is stirred for 5 min before (1S, 5R)-2-(1-chloro-(E)-ethylidene)-6,6-dimethyl-bicyclo[3.1.0]hexan-3-one (15.0 g, 81.2 mmol) in ethanol (40 mL) is added dropwise. The solution becomes slightly warm (approx. 30° C.) and turns orange to brown. A fine precipitate forms. Stirring is continued at rt for 1 h. Then, a solution of sodium (2.24 g, 97.5 mmol) in ethanol (75 mL) is added rapidly and the mixture is heated to 75° C. for 1 h. A 2N aq. solution of LiOH (75 mL) is added and stirring is continued at 75° C. for 2 h, then at rt for 16 h. About ⅔ of the solvent is removed in vacuo, the remaining mixture is diluted with water (250 mL) and extracted with DCM (200 mL). The organic extract is washed twice with 1 N aq. (100 mL). The combined aqueous layers are acidified by adding 2N aq. HCl and extracted three times with diethyl ether (3×300 mL). The organic extracts are dried over MgSO4 and evaporated. The remaining residue is suspended in acetonitrile, filtered, washed with additional acetonitrile and dried under high vacuum to give the title compound (12.02 g) as a pale yellow to beige crystalline powder.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:9]([C:10]([O:12][CH3:13])=[O:11])[C:8]([C:14]([O:16][CH3:17])=[O:15])=[C:7]([C:18]([O:20][CH3:21])=[O:19])[C:6]=1[C:22]([O:24][CH3:25])=[O:23])=[O:4].C(O)[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH:36]([CH3:38])[CH3:37]>CO>[CH2:25]([O:24][C:22]([C:6]1[CH:5]([C:3]([O:2][CH2:1][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH:36]([CH3:37])[CH3:38])=[O:4])[C:9]([C:10]([O:12][CH2:13][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH:36]([CH3:37])[CH3:38])=[O:11])=[C:8]([C:14]([O:16][CH2:17][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH:36]([CH3:37])[CH3:38])=[O:15])[C:7]=1[C:18]([O:20][CH2:21][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH:36]([CH3:37])[CH3:38])=[O:19])=[O:23])[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH:36]([CH3:37])[CH3:38]
Reactant: CC(C)CCCCCCCCCCO
Reactant: COC(=O)C1=C(C(=O)OC)C(C(=O)OC)C(C(=O)OC)=C1C(=O)OC
Solvent: CO
Product: CC(C)CCCCCCCCCCOC(=O)C1=C(C(=O)OCCCCCCCCCCC(C)C)C(C(=O)OCCCCCCCCCCC(C)C)C(C(=O)OCCCCCCCCCCC(C)C)=C1C(=O)OCCCCCCCCCCC(C)C
Yield: 100.2 %

Procedure:
7.13 g (20 mmol) of 1,2,3,4,5-pentamethoxycarbonylcyclopentadiene are treated with 20.0 g (100 mmol) of isotridecyl alcohol. 3.12 g (97.5% of the theoretical yield) of methanol are distilled off at 100° C. within 8 h, firstly at 1013 mbar, then at from 363 to 18 mbar. 24 g of 1,2,3,4,5-pentaisotridecyloxycarbonylcyclopentadiene are obtained.
Reaction SMILES: [F:1][CH:2]([F:37])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:14]=[N:13][C:12]([C:15]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([C@@H:24]4[O:29][CH2:28][CH2:27][N:26](C(OC(C)(C)C)=O)[CH2:25]4)=[CH:20][CH:19]=3)=[O:16])=[N:11]2)=[CH:6][CH:5]=1.[ClH:38].CCOCC>O1CCOCC1>[ClH:38].[F:37][CH:2]([F:1])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:14]=[N:13][C:12]([C:15]([NH:17][C:18]3[CH:19]=[CH:20][C:21]([C@@H:24]4[O:29][CH2:28][CH2:27][NH:26][CH2:25]4)=[CH:22][CH:23]=3)=[O:16])=[N:11]2)=[CH:6][CH:5]=1
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(NC(=O)c3ncn(-c4ccc(OC(F)F)cc4)n3)cc2)C1
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Product: O=C(Nc1ccc([C@H]2CNCCO2)cc1)c1ncn(-c2ccc(OC(F)F)cc2)n1
Temperature: 60 °C
Reaction time: 1.5 h
Yield: 78 %

Procedure:
(S)-tert-Butyl 2-(4-(1-(4-(difluoromethoxy)phenyl)-1H-1,2,4-triazole-3-carboxamido)phenyl)morpholine-4-carboxylate (180 mg, 0.35 mmol) was dissolved in dioxane (1.3 ml) and a solution of HCl in dioxane (4M, 1.3 ml, 5.2 mmol) was added. The reaction mixture was stirred for 90 min at 60° C. After cooling ether was added, the solid was filtered off, washed with ether and dried in vacuo at 60° C. to afford (S)-1-(4-(difluoromethoxy)phenyl)-N-(4-(morpholin-2-yl)phenyl)-1H-1,2,4-triazole-3-carboxamide hydrochloride (123 mg, 78%) as a white solid. MS (ISP): 416.4 ([M+H]+).
Reaction SMILES: [Cl-].[Cl-].[CH2:3]([C:6]1([Zr+2:11][C:12]2([CH2:17][CH2:18][CH3:19])[CH:16]=[CH:15][CH:14]=[CH:13]2)[CH:10]=[CH:9][CH:8]=[CH:7]1)[CH2:4][CH3:5].C([Sn]([F:33])(CCCC)CCCC)CCC.CCCCC>ClCCl>[F-:33].[F-:33].[CH2:17]([C:12]1([Zr+2:11][C:6]2([CH2:3][CH2:4][CH3:5])[CH:10]=[CH:9][CH:8]=[CH:7]2)[CH:16]=[CH:15][CH:14]=[CH:13]1)[CH2:18][CH3:19]
Reactant: CCCC[Sn](F)(CCCC)CCCC
Agent: CCCC1([Zr+2]C2(CCC)C=CC=C2)C=CC=C1
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCCCC
Product: [F-]
Temperature: -35 °C
Reaction time: 1 h

Procedure:
To a straw yellow solution of bis(propylcyclopentadienyl) zirconium dichloride [(PrCp)2ZrCl2] (1.00 g, 2.66 mmol, 1.00 eq.) in dichloromethane (10 mL) was added tributyltin fluoride (1.72 g, 5.57 mmol, 2.10 eq.). The reaction rapidly lightened, turning almost colorless. The reaction was stirred 1 h and was then filtered to give a colorless solution and a small amount of white solid. The solution was evaporated in vacuo, leaving a damp, white solid. Pentane (10 mL) was added and the mixture was cooled to −35° C. The mixture was filtered, and resulting white solid was washed with pentane (3×3 mL) cooled to −35° C. The white solid was dried in vacuo to yield 0.75 g (82%). 1H NMR(CD2Cl2): δ 0.92 (t, 6H, CH2CH2CH3), 1.56 (m, 4H, CH2CH2CH3), 2.44 (t, 4H, CH2CH2CH3), 6.05 (m, 4H, ring-H), 6.30 (m, 4H, ring-H). 19F NMR(CD2Cl2): δ 20.4 (s).
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:19][CH2:20][CH3:21])[C@@H:5]([NH:7][CH2:8][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH:11]=[CH:12][N:13]=[CH:14]2)[CH3:6])[CH3:2].[CH:22]1[C:34]2[CH:33]([CH2:35][O:36][C:37]([NH:39][C@@H:40]([CH2:44][C:45]3[CH:50]=[CH:49][C:48]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[CH:47][CH:46]=3)[C:41](O)=[O:42])=[O:38])[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:26]=2[CH:25]=[CH:24][CH:23]=1>>[C:52]([O:51][C:48]1[CH:47]=[CH:46][C:45]([CH2:44][C@H:40]([NH:39][C:37](=[O:38])[O:36][CH2:35][CH:33]2[C:34]3[CH:22]=[CH:23][CH:24]=[CH:25][C:26]=3[C:27]3[C:32]2=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:41]([N:7]([C@@H:5]([CH3:6])[CH:4]([O:19][CH2:20][CH3:21])[O:3][CH2:1][CH3:2])[CH2:8][C:9]2[CH:18]=[CH:17][CH:16]=[C:15]3[C:10]=2[CH:11]=[CH:12][N:13]=[CH:14]3)=[O:42])=[CH:50][CH:49]=1)([CH3:55])([CH3:53])[CH3:54]
Reactant: CCOC(OCC)[C@H](C)NCc1cccc2cnccc12
Reactant: CC(C)(C)Oc1ccc(C[C@H](NC(=O)OCC2c3ccccc3-c3ccccc32)C(=O)O)cc1
Product: CCOC(OCC)[C@H](C)N(Cc1cccc2cnccc12)C(=O)[C@H](Cc1ccc(OC(C)(C)C)cc1)NC(=O)OCC1c2ccccc2-c2ccccc21
Yield: 76.8 %

Procedure:
According to the procedure described in the synthesis method of Compound III-5, (S)-1,1-diethoxy-N-(isoquinolin-5-ylmethyl)propan-2-amine (Compound IX-9)(1.98 g, 5.21 mmol) was coupled with (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(4-tert-butoxyphenyl)propanoic acid (2.4 g, 5.21 mmol) and the obtained residue was purified by Büch silica gel column chromatography (eluent: n-hexane:ethyl acetate=7:3) to obtain the title compound (2.92 g, 76%).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:27]=[CH:28][N:29]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)=[CH:10][CH:9]=1)=[O:6].[NH:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1>C(O)C>[N:30]1([C:2]2[CH:3]=[C:4]([CH:27]=[CH:28][N:29]=2)[C:5]([NH:7][C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]([O:18][CH2:19][CH2:20][N:21]3[CH2:22][CH2:23][O:24][CH2:25][CH2:26]3)=[CH:10][CH:9]=2)=[O:6])[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1
Reactant: O=C(Nc1ccc(OCCN2CCOCC2)c2ccccc12)c1ccnc(Cl)c1
Reactant: C1COCCN1
Solvent: CCO
Product: O=C(Nc1ccc(OCCN2CCOCC2)c2ccccc12)c1ccnc(N2CCOCC2)c1
Temperature: 100 °C

Procedure:
A mixture of 2-chloro-N-[4-(2-morpholin-4-yl-ethoxy)-naphthalen-1-yl]-isonicotinamide (200 umol, 1 eq), morpholine (2 mmol, 10 eq.) and ethanol (2 ml) is heated at 100° C. for 3-4 days in a 2-dram vial with agitation. The mixture is cooled to room temperature and concentrated. The crude mixture is purified by flash column chromatography and re-crystallized from methanol to afford 2-morpholin-4-yl-N-[4-(2-morpholin-4-yl-ethoxy)-naphthalen-1-yl]-isonicotinamide. 1H NMR (300 MHz, DMSO-d6) δ 10.41 (s, 1H), 8.31 (d, 1H), 8.21 (m, 1H), 7.85 (m, 1H), 7.58 (m, 2H), 2.42 (m, 2H), 7.23 (d, 1H), 7.08 (d, 1H), 4.38 (t, 2H), 3.78 (m, 4H), 3.60 (m, 8H), 2.88 (t, 2H) 2.58 (m, 4H). MS: 463.3 (M+1).
Reaction SMILES: [NH2:1][C:2]1[N:11]([CH2:12][CH2:13][C:14]([N:16]([CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[CH3:17])=[O:15])[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:24](=[O:31])[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH:8]=2)[N:3]=1.[BH4-].[Na+]>CO.C1COCC1>[NH2:1][C:2]1[N:11]([CH2:12][CH2:13][C:14]([N:16]([CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[CH3:17])=[O:15])[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH:24]([OH:31])[C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:8]=2)[N:3]=1
Reactant: CN(C(=O)CCN1Cc2cc(C(=O)c3ccccc3)ccc2N=C1N)C1CCCCC1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CN(C(=O)CCN1Cc2cc(C(O)c3ccccc3)ccc2N=C1N)C1CCCCC1
Temperature: 25 °C

Procedure:
A mixture of 3-(2-amino-6-benzoyl-4H-quinazolin-3-yl)-N-cyclohexyl-N-methyl-propionamide (0.0056 mol) in methanol (60 mL) and THF (30 mL) was stirred at room temperature. Then, NaBH4 (0.0056 mol) was added and the reaction mixture was stirred for 30 min at room temperature. The solvent was evaporated, and the residue was stirred in H2O and then extracted with CH2Cl2. The organic layer was separated and dried, and the solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent: 94:6 CH2Cl2:(CH3OH:NH3)). The purest product fractions were collected and the solvent was evaporated to yield the title compound as a residue.