Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[CH:7]2.[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][C:21](=O)[CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12].N1CCCC1>C(O)C>[C:11]([O:15][C:16]([N:18]1[CH2:19][CH:20]=[C:21]([C:7]2[C:6]3[C:10](=[C:2]([F:1])[CH:3]=[CH:4][CH:5]=3)[NH:9][CH:8]=2)[CH2:22][CH2:23]1)=[O:17])([CH3:14])([CH3:12])[CH3:13]
Reactant: Fc1cccc2cc[nH]c12
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Solvent: CCO
Solvent: C1CCNC1
Product: CC(C)(C)OC(=O)N1CC=C(c2c[nH]c3c(F)cccc23)CC1
Yield: 65.3 %

Procedure:
A stirred solution of 7-fluoroindole (400 mg, 3.0 mmol), t-butyl-4-oxo-1-piperidinecarboxylate (650 mg, 3.3 mmol), and pyrrolidine (0.62 mL, 7.4 mmol) in ethanol (10 mL) was heated at reflux for 16 hours. Solvent was evaporated and the residue subjected to chromatography on silica gel with 20% ethyl acetate/hexanes to afford a yellow solid (620 mg, 66%).
Reaction SMILES: [F:1][CH2:2][CH2:3][N:4]1[C:13]2[C:8](=[CH:9][C:10]([CH:15]=O)=[C:11]([OH:14])[CH:12]=2)[CH2:7][CH2:6][CH2:5]1.C[O:18][C:19](=O)[CH2:20][C:21]1[N:22]=[C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][N:24]2[CH:30]=1.N1CCCCC1>C1C=CC=CC=1.C(#N)C>[Cl:29][C:26]1[CH:27]=[CH:28][C:23]2[N:24]([CH:30]=[C:21]([C:20]3[C:19](=[O:18])[O:14][C:11]4[C:10]([CH:15]=3)=[CH:9][C:8]3[CH2:7][CH2:6][CH2:5][N:4]([CH2:3][CH2:2][F:1])[C:13]=3[CH:12]=4)[N:22]=2)[CH:25]=1
Reactant: COC(=O)Cc1cn2cc(Cl)ccc2n1
Reactant: O=Cc1cc2c(cc1O)N(CCF)CCC2
Solvent: CC#N
Solvent: C1CCNCC1
Solvent: c1ccccc1
Product: O=c1oc2cc3c(cc2cc1-c1cn2cc(Cl)ccc2n1)CCCN3CCF
Yield: 67.4 %

Procedure:
200 mg (0.896 mmol) 1-(2-Fluoro-ethyl)-7-hydroxy-1,2,3,4-tetrahydro-quinoline-6-carbaldehyde and 201 mg (1 eq.) (6-chloro-imidazo[1,2-a]pyridin-2-yl)-acetic acid methyl ester in 6 mL benzene and 3 mL acetonitrile are treated with 0.177 mL (2 eq.) piperidine and refluxed for 18 h. The reaction mixture is allowed to reach room temperature and the precipitate filtered, washed with acetonitrile and dried under high vacuum to yield 240 mg (67%) of desired product as a yellow powder.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([CH3:10])[CH:3]=1.[NH2-].[K+].N.[C:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1)#[N:15]>O1CCCC1>[ClH:1].[NH2:7][C:6]1[C:5]2[C:4](=[CH:3][C:2]([Cl:1])=[CH:9][CH:8]=2)[CH:10]=[C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)[N:15]=1
Reactant: N#Cc1ccccn1
Reactant: Cc1cc(Cl)ccc1C#N
Agent: N
Agent: [K+]
Agent: [NH2-]
Solvent: C1CCOC1
Product: Cl
Product: Nc1nc(-c2ccccn2)cc2cc(Cl)ccc12
Reaction time: 8 h

Procedure:
A solution of 15.15 g (0.1 mol) of 4-chloro-2-methylbenzonitrile in 40 ml of anhydrous tetrahydrofuran was added under a nitrogen atmosphere to a suspension of 0.2 mol of potassium amide in liquid ammonia at -33° C. After 10 minutes a solution of 15.7 g (0.15 mol) of 2-cyanopyridine in 60 ml of anhydrous tetrahydrofuran was added. The mixture was kept overnight (ca. 16 hours), during which time the ammonia evaporated, and it was then hydrolyzed with 200 ml of water. The tetrahydrofuran was subsequently distilled off and the aqueous residue was extracted with chloroform. After evaporation of the chloroform the crude product was sublimed at 220°-250° C. The sublimate was crystallized from chloroform, dissolved in diethyl ether and converted into the hydrochloride by addition of an ethereal solution of hydrogen chloride. The precipitate obtained was filtered off and twice crystallized from ethanol, to yield 1-amino-6-chloro-3-(2-pyridyl)isoquinoline hydrochloride, melting point 243° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:15]([O:16][CH3:17])=[CH:14][C:6]2[S:7][C:8]([C:10]([O:12]C)=[O:11])=[CH:9][C:5]=2[CH:4]=1.[OH-].[Na+].Cl>CO.C1COCC1.O>[CH3:1][O:2][C:3]1[C:15]([O:16][CH3:17])=[CH:14][C:6]2[S:7][C:8]([C:10]([OH:12])=[O:11])=[CH:9][C:5]=2[CH:4]=1
Reactant: COC(=O)c1cc2cc(OC)c(OC)cc2s1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: COc1cc2cc(C(=O)O)sc2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.4 %

Procedure:
To a stirred solution of methyl 5,6-dimethoxybenzo[b]thiophene-2-carboxylate (1.0 g, 4 mmol) in MeOH (20 mL) and THF (10 mL) was added 2N NaOH (10 mL) dropwise at room temperature. The resulting mixture was stirred at room temperature for 2 hours before adjusting the pH value to 3 with 1 N HCl and diluting with water. The resulting suspension was filtered and the solid was dried under vacuum to afford 5,6-dimethoxybenzo[b]thiophene-2-carboxylic acid as a white solid (890 mg, 94%). LC-MS (ES-API); rt 8.17 min; m/z calculated for C11H10O4S [M+Na]+ 261.0, found 260.9.
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:11]2[C:12]([O:16][CH3:17])=[N:13][CH:14]=[CH:15][C:10]=2[N:9]([CH:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)[N:8]=1)(=O)=O.CC1(C)C(C)(C)OB([C:33]2[CH:38]=[CH:37][C:36]([S:39]([NH2:42])(=[O:41])=[O:40])=[CH:35][CH:34]=2)O1.C(=O)([O-])[O-].[Na+].[Na+].O>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:18]1([N:9]2[C:10]3[CH:15]=[CH:14][N:13]=[C:12]([O:16][CH3:17])[C:11]=3[C:7]([C:33]3[CH:38]=[CH:37][C:36]([S:39]([NH2:42])(=[O:41])=[O:40])=[CH:35][CH:34]=3)=[N:8]2)[CH2:19][CH2:20][CH2:21][CH2:22]1
Reactant: CC1(C)OB(c2ccc(S(N)(=O)=O)cc2)OC1(C)C
Reactant: COc1nccc2c1c(OS(=O)(=O)C(F)(F)F)nn2C1CCCC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: COc1nccc2c1c(-c1ccc(S(N)(=O)=O)cc1)nn2C1CCCC1
Yield: 96.1 %

Procedure:
A solution of 1-cyclopentyl-4-methoxy-1H-pyrazolo[4,3-c]pyridin-3-yl trifluoromethanesulfonate (150 mg) obtained in Step C of Example 12, 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamide (145 mg), tetrakis(triphenylphosphine)palladium(0) (47.4 mg) and 2M aqueous sodium carbonate solution (1.03 mL) in DME (10 mL) was heated overnight with reflux under nitrogen atmosphere. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (147 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:16][C:17]2[C:18]3[C:25]4[CH2:26][NH:27][CH2:28][C:24]=4[S:23][C:19]=3[N:20]=[CH:21][N:22]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1.Cl.[CH3:30][N:31]([CH3:38])[CH2:32]/[CH:33]=[CH:34]/[C:35](O)=[O:36]>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:16][C:17]2[C:18]3[C:25]4[CH2:26][N:27]([C:35](=[O:36])/[CH:34]=[CH:33]/[CH2:32][N:31]([CH3:38])[CH3:30])[CH2:28][C:24]=4[S:23][C:19]=3[N:20]=[CH:21][N:22]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1
Reactant: Clc1cc(Nc2ncnc3sc4c(c23)CNC4)ccc1OCc1ccccn1
Reactant: CN(C)C/C=C/C(=O)O
Agent: Cl
Product: CN(C)C/C=C/C(=O)N1Cc2sc3ncnc(Nc4ccc(OCc5ccccn5)c(Cl)c4)c3c2C1

Procedure:
In analogy to Example 89, the title compound was prepared from N-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-6,7-dihydro-5H-pyrrolo[3′,4′:4,5]thieno[2,3-d]pyrimidin-4-amine from Example 31A (38 mg, 0.094 mmol) and (2E)-4-(dimethylamino)but-2-enoic acid hydrochloride from Example 1A (22 mg, 0.13 mmol) to yield 18 mg (37%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@@H:8]([NH:23][S:24]([C:26]([CH3:29])([CH3:28])[CH3:27])=[O:25])[C:9]1[S:13][C:12]([NH:14]C(=O)OC(C)(C)C)=[N:11][C:10]=1[CH3:22].C(O)(C(F)(F)F)=O>>[NH2:14][C:12]1[S:13][C:9]([C@@H:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])[NH:23][S@@:24]([C:26]([CH3:29])([CH3:27])[CH3:28])=[O:25])=[C:10]([CH3:22])[N:11]=1.[NH2:14][C:12]1[S:13][C:9]([C@H:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])[NH:23][S@@:24]([C:26]([CH3:29])([CH3:27])[CH3:28])=[O:25])=[C:10]([CH3:22])[N:11]=1
Reactant: Cc1nc(NC(=O)OC(C)(C)C)sc1[C@H](NS(=O)C(C)(C)C)c1ccccc1Cl
Solvent: O=C(O)C(F)(F)F
Product: Cc1nc(N)sc1[C@@H](N[S@](=O)C(C)(C)C)c1ccccc1Cl
Product: Cc1nc(N)sc1[C@H](N[S@](=O)C(C)(C)C)c1ccccc1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (R)-tert-Butyl 5-((2-chlorophenyl)(1,1-dimethylethylsulfinamido)methyl)-4-methylthiazol-2-ylcarbamate, (19.0 g, 41.6 mmol) in CH2Cl3 (83 mL) was added TFA (83 mL). The reaction was stirred at room temperature for 1 h. The reaction was concentrated and then partitioned between CH2Cl2 and saturated aqueous NaHCO3 solution. The aqueous layer was basified to pH>12 by adding 1N NaOH solution and extracted with Ch2Cl2. The combined organic layers were dried over MgSO4 and concentrated. The crude product was adsorbed onto silica gel and purified by column chromatography (70-100% EtOAc/hexanes. The EtOAc contained 2% NH4OH and was stirred to maintain the mixture) to provide (R)-N-((R)-(2-amino-4-methylthiazol-5-yl)(2-chlorophenyl)methyl)-2-methylpropane-2-sulfinamide and (R)-N-((S)-(2-amino-4-methylthiazol-5-yl)(2-chlorophenyl)methyl)-2-methylpropane-2-sulfinamide and a mixture of both diastereomers (7.1 g, 47%). First eluted product (Isomer A) (white solid, 3.0 g, 20%, >99% de); 1H NMR (400 MHz, CDCl3) δ 7.60 (dd, J=1.6, 7.7 Hz, 1H), 7.38-7.22 (m, 3H), 6.15 (d, J=2.5 Hz, 1H), 4.94 (s, 2H), 3.87 (d, J=2.3 Hz, 1H), 2.34 (s, 3H), 1.27 (s, 9H); HPLC ret. time 3.08 min, 10-99% CH3CN, 15 min run; ESI-MS 358.3 m/z (MH+). Second eluted product (Isomer B) (yellow waxy solid, 5.0 g, 33% 98% de); 1H NMR (400 MHz, CDCl3) δ 7.64 (dd, J=7.7, 1.7 Hz, 1H), 7.36 (dd, J=7.8, 1.4 Hz, 1H), 7.32-7.21 (m, 2H), 6.19 (d, J=1.8 Hz, 1H), 4.86 (s, 2H), 3.65 (d, J=1.2 Hz, 1H), 2.33 (s, 3H), 1.26 (s, 9H); HPLC ret. time 3.77 min, 10-99% CH3CN, 15 min run; ESI-MS 358.3 m/z (MH+).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[N:22]1[CH2:26][CH2:25][C@@H:24]([OH:27])[CH2:23]1)[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:10][CH:9]=1)=[O:6].[N:28]1[CH:33]=[C:32](B(O)O)[CH:31]=[N:30][CH:29]=1.C([O-])([O-])=O.[Na+].[Na+].COCCOC>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CCO.O>[OH:27][C@@H:24]1[CH2:25][CH2:26][N:22]([C:21]2[CH:20]=[CH:19][C:4]([C:5]([NH:7][C:8]3[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:10][CH:9]=3)=[O:6])=[CH:3][C:2]=2[C:32]2[CH:33]=[N:28][CH:29]=[N:30][CH:31]=2)[CH2:23]1
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1ccc(N2CC[C@@H](O)C2)c(Br)c1
Reactant: OB(O)c1cncnc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: COCCOC
Solvent: O
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1ccc(N2CC[C@@H](O)C2)c(-c2cncnc2)c1
Temperature: 25 °C

Procedure:
(R)-3-Bromo-4-(3-hydroxypyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)benzamide (Stage 2.1, 80 mg, 0.180 mmol), pyrimidin-5-ylboronic acid (66.8 mg, 0.539 mmol), Pd(PPh3)2Cl2 (7.57 mg, 10.78 μmol) and Na2CO3 (57.1 mg, 0.539 mmol) were added to a MW vial and treated with a mixture of DME (762 μL), water (218 μL) and EtOH (109 μL). The vial sealed, evacuated/purged with argon and then the RM was subjected to MW irradiation at 80° C. for 2 h. The RM was cooled to RT, diluted with THF (1 mL), treated with Si-Thiol (Silicycle, 1.27 mmol/g, 70.7 mg, 0.090 mmol), filtered and the filtrate was evaporated off under reduced pressure to give a residue which was purified by flash chromatography (RediSep® Silica gel column, 4 g, cyclohexane/EtOAc-EtOH+0.1% NH4OH (8:2), from 30% to 80% EtOAc-EtOH+0.1% NH4OH (8:2)) to yield the title compound as an off-white solid. UPLC-MS (condition 1) tR=2.37 min, m/z=445.0 [M+H]+, m/z=443.2 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.70-1.81 (m, 1H) 1.82-1.93 (m, 1H) 2.68 (dd, J=10.15, 1.10 Hz, 1H) 2.97-3.11 (m, 2H) 3.17-3.27 (m, 1H) 4.17-4.25 (m, 1H) 4.87 (d, J=3.67 Hz, 1H) 6.98 (d, J=9.05 Hz, 1H) 7.33 (d, J=8.31 Hz, 2H) 7.79-7.90 (m, 3H) 7.94 (dd, J=8.80, 2.20 Hz, 1H) 8.86 (s, 2H) 9.16 (s, 1H) 10.09 (s, 1H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH2:6][CH2:5]1.C(N(CC)CC)C.[S:22](Cl)([CH3:25])(=[O:24])=[O:23]>O1CCCC1>[CH3:25][S:22]([O:1][CH2:2][CH2:3][C:4]1([NH:7][C:8]([O:9][C:10]([CH3:11])([CH3:13])[CH3:12])=[O:14])[CH2:5][CH2:6]1)(=[O:24])=[O:23]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)NC1(CCO)CC1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC1(CCOS(C)(=O)=O)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 85 %

Procedure:
To a cooled solution of tert-butyl [1-(2-hydroxyethyl)cyclopropyl]carbamate (8.0 g, 0.04 mol) and triethylamine (12.14 g) in anhydrous tetrahydrofuran (120 mL) at −20° C. was added a solution of mesyl chloride (17.8 g) in anhydrous tetrahydrofuran (30 mL). The resulting mixture was allowed to warm to room temperature and stirred at this temperature for 2 hours. The resulting mixture was poured into ice-water (50 mL) and the separated organic layer was washed with brine (100 mL), dried over sodium sulfate and concentrated in vacuo. The residue was triturated with petroleum ether and filtered to give 9.5 g of the pure product as an orange solid (yield was 95%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:11]#[N:12])[CH:5]=[C:6]2[C:10]=1[CH2:9][CH2:8][CH2:7]2.CN([CH:16]=[O:17])C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C.[OH2:44]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CCOCC>[C:11]([C:4]1[CH:3]=[C:2]([C:16]([OH:17])=[O:44])[C:10]2[CH2:9][CH2:8][CH2:7][C:6]=2[CH:5]=1)#[N:12]
Reactant: N#Cc1cc(Br)c2c(c1)CCC2
Reactant: O
Reactant: CN(C)C=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: N#Cc1cc2c(c(C(=O)O)c1)CCC2
Temperature: 90 °C
Yield: 60 %

Procedure:
In a flask designed for high pressure (max. 12 bar) 7-bromoindane-5-carbonitrile (1.18 g, 5.3 mmol) was mixed with DMF (50 mL), bis(triphenylphosphine)palladium(II) chloride (0.1 g, 0.14 mmol), triphenylphosphine (0.1 g, 0.38 mmol), triethylamine (1.0 g, 9.9 mmol) and water (5 mL). While stirring the flask was alternately evacuated and then loaded with carbon monoxide. The procedure was repeated 4 times and then carbon monoxide was introduced until a pressure of 6 bar was obtained. The reaction mixture was heated to 90° C. for 60 h and then cooled to room temperature. The content was transferred to a beaker by means of ether (100 mL) and water (200 mL). The organic layer was separated off and precipitated Pd was removed by decantation. The aqueous layer was acidified with conc. HCl and then extracted thrice with ether (50 mL). The combined organic solutions were washed with brine, dried over Na2SO4 and the solvent was evaporated. The solid residue was treated with cold CH2Cl2, then filtrated off and then dried. There was obtained 0.6 g (60%) of 6-cyanoindane-4-carboxylic acid as a solid material. 1H NMR (300 MHz, CDCl3): 2.1-2.2 (q, 2H), 3.0 (t, 2H), 3.4 (t, 2H), 7.7 (s, 1H), 8.2 (s, 1H).
Reaction SMILES: [ClH:1].[NH2:2][N:3]=[CH:4][NH:5][C:6]1[CH:32]=[CH:31][C:9]([C:10]([O:12][C:13]2[CH:22]=[CH:21][C:20]3[C:15](=[CH:16][CH:17]=[C:18]([C:23](=[NH:25])[NH2:24])[CH:19]=3)[C:14]=2[CH2:26][CH2:27][C:28](=[O:30])N)=[O:11])=[CH:8][CH:7]=1.Cl.CS(O)(=O)=[O:36]>>[ClH:1].[ClH:1].[NH2:2][N:3]=[CH:4][NH:5][C:6]1[CH:32]=[CH:31][C:9]([C:10]([O:12][C:13]2[CH:22]=[CH:21][C:20]3[C:15](=[CH:16][CH:17]=[C:18]([C:23](=[NH:25])[NH2:24])[CH:19]=3)[C:14]=2[CH2:26][CH2:27][C:28]([OH:30])=[O:36])=[O:11])=[CH:8][CH:7]=1
Reactant: N=C(N)c1ccc2c(CCC(N)=O)c(OC(=O)c3ccc(NC=NN)cc3)ccc2c1
Reactant: CS(=O)(=O)O
Agent: Cl
Product: N=C(N)c1ccc2c(CCC(=O)O)c(OC(=O)c3ccc(NC=NN)cc3)ccc2c1
Reaction time: 6 h

Procedure:
300 Milliliters of 3.6% hydrochloric acid was added to 3.3 g of 6-amidino-1-(2-carbamoylethyl)-2-naphthyl 4-aminoiminomethylaminobenzoate.methanesulfonic acid hydrochloride, followed by stirring for 6 hours at 75°-80° C. Furthermore, the reaction mixture was stirried for 24 hours under cooling with ice. Then, the precipitate was collected by filtration and washed with a small amount of 15% hydrochloric acid and acetone to obtain 1.58 g of the desired product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][C:22]=1[O:23][CH3:24])[CH2:5][NH:6][C:7]1[C:12]([C:13]([OH:15])=O)=[C:11]([O:16][CH3:17])[N:10]=[C:9]([S:18][CH3:19])[N:8]=1.[NH2:25][CH2:26][C:27]1[N:32]=[CH:31][CH:30]=[CH:29][N:28]=1.O.ON1C2C=CC=CC=2N=N1.CN(C)C=O>C(=O)([O-])O.[Na+]>[Cl:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][C:22]=1[O:23][CH3:24])[CH2:5][NH:6][C:7]1[C:12]([C:13](=[O:15])[NH:25][CH2:26][C:27]2[N:32]=[CH:31][CH:30]=[CH:29][N:28]=2)=[C:11]([O:16][CH3:17])[N:10]=[C:9]([S:18][CH3:19])[N:8]=1
Reactant: NCc1ncccn1
Reactant: COc1ccc(CNc2nc(SC)nc(OC)c2C(=O)O)cc1Cl
Agent: O=C([O-])O
Agent: On1nnc2ccccc21
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(CNc2nc(SC)nc(OC)c2C(=O)NCc2ncccn2)cc1Cl
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To a mixture of 4-(3-chloro-4-methoxybenzylamino)-5-carboxy-6-methoxy-2-methylthiopyrimidine (prepared in the above (2)) 183 mg, 2-aminomethylpyrimidine 70 mg, 1-hydroxybenzotriazole hydrate 67 mg and dimethylformamide 4 ml is added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimido hydrochloride 114 mg on an ice bath, and the mixture is stirred for 14 hours at room temperature. The reaction mixture is diluted with an aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The ethyl acetate layer is washed, dried and concentrated in vacuo. The residue is separated with silica gel chromatography (solvent; chloroform:ethyl acetate=20:1→10:1) to give 4-(3-chloro-4-methoxybenzylamino)-5-[N-(2-pyrimidinylmethyl)carbamoyl]-6-methoxy-2-methylthiopyrimidine as a colorless crystalline powder 208 mg. mp 171–172° C.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8](I)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:12][O:13][C:14]1[CH:28]=[C:27]([O:29][CH3:30])[CH:26]=[CH:25][C:15]=1[CH2:16][N:17]1[C@@H:21]([C:22]#[CH:23])[CH2:20][CH2:19][C:18]1=[O:24].O>C(N(CC)CC)C.[Cu](I)I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:23]#[C:22][C@@H:21]2[N:17]([CH2:16][C:15]3[CH:25]=[CH:26][C:27]([O:29][CH3:30])=[CH:28][C:14]=3[O:13][CH3:12])[C:18](=[O:24])[CH2:19][CH2:20]2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: C#C[C@H]1CCC(=O)N1Cc1ccc(OC)cc1OC
Reactant: CC(C)(C)c1ccc(I)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: O
Solvent: CCN(CC)CC
Product: COc1ccc(CN2C(=O)CC[C@@H]2C#Cc2ccc(C(C)(C)C)cc2)c(OC)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 82.8 %

Procedure:
Copper iodide (74 mg) and bis(triphenylphosphine)palladium(II) dichloride (135 mg) were added to a solution of 4-tert-butyliodobenzene (3.0 g) in triethylamine (10 mL), and the mixture was stirred at room temperature for 15 minutes. (5R)-1-(2,4-Dimethoxybenzyl)-5-ethynylpyrrolidin-2-one (1.0 g) was added thereto over one hour, and the mixture was stirred at room temperature for three hours. The reaction solution was poured into water, followed by extraction with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and filtered. The solvent was then evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:0→1:1) to give (5R)-5-[(4-tert-butylphenyl)ethynyl]-1-(2,4-dimethoxybenzyl)pyrrolidin-2-one as a colorless powder (1.25 g, 84%).
Reaction SMILES: Br[CH2:2][CH2:3][N:4]1[C:28](=[O:29])[N:7]2[CH:8]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([OH:27])[CH:22]=3)[C:9]3[NH:10][C:11]4[C:16]([C:17]=3[CH2:18][C:6]2([CH3:30])[C:5]1=[O:31])=[CH:15][C:14]([O:19][CH3:20])=[CH:13][CH:12]=4.[CH:32]1([NH2:36])[CH2:35][CH2:34][CH2:33]1>>[CH:32]1([NH:36][CH2:2][CH2:3][N:4]2[C:28](=[O:29])[N:7]3[CH:8]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([OH:27])[CH:22]=4)[C:9]4[NH:10][C:11]5[C:16]([C:17]=4[CH2:18][C:6]3([CH3:30])[C:5]2=[O:31])=[CH:15][C:14]([O:19][CH3:20])=[CH:13][CH:12]=5)[CH2:35][CH2:34][CH2:33]1
Reactant: COc1ccc2[nH]c3c(c2c1)CC1(C)C(=O)N(CCBr)C(=O)N1C3c1cccc(O)c1
Reactant: NC1CCC1
Product: COc1ccc2[nH]c3c(c2c1)CC1(C)C(=O)N(CCNC2CCC2)C(=O)N1C3c1cccc(O)c1

Procedure:
The title compound is prepared similarly as described for example 30 using (3aSR,10RS)-2-(2-Bromoethyl)-10-(3-hydroxy-phenyl)-6-methoxy-3a-methyl-3a,4,9,10-tetrahydro-2,9,10a-triaza-cyclopenta[b]-fluorene-1,3-dione (example 24) and cyclobutyl amine as starting materials. MS: m/z (MH+)=475.2
Reaction SMILES: [NH2:1][C@@H:2]([CH:23]([CH3:25])[CH3:24])[C:3]([N:5]1[CH2:9][CH2:8][CH2:7][C@H:6]1[C:10]([NH:12][C@H:13]([C@@H:17]([OH:22])[C:18]([F:21])([F:20])[F:19])[CH:14]([CH3:16])[CH3:15])=[O:11])=[O:4].C(=O)([O-])[O-].[Na+].[Na+].[C:32](Cl)(=[O:41])[C:33]1[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][CH:34]=1>C1COCC1>[CH3:40][O:39][C:36]1[CH:37]=[CH:38][C:33]([C:32]([NH:1][C@@H:2]([CH:23]([CH3:25])[CH3:24])[C:3]([N:5]2[CH2:9][CH2:8][CH2:7][C@H:6]2[C:10]([NH:12][C@H:13]([C@@H:17]([OH:22])[C:18]([F:21])([F:19])[F:20])[CH:14]([CH3:16])[CH3:15])=[O:11])=[O:4])=[O:41])=[CH:34][CH:35]=1
Reactant: CC(C)[C@H](N)C(=O)N1CCC[C@H]1C(=O)N[C@@H](C(C)C)[C@@H](O)C(F)(F)F
Reactant: COc1ccc(C(=O)Cl)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc(C(=O)N[C@H](C(=O)N2CCC[C@H]2C(=O)N[C@@H](C(C)C)[C@@H](O)C(F)(F)F)C(C)C)cc1
Temperature: -5 °C

Procedure:
Compound C was suspended in THF (350 ml) and powdered sodium carbonate (18.5 g) was added. The mixture was cooled to -5° C. and a solution of anisoyl chloride (11.9 g) in THF (50 ml) was added with stirring. The reaction mixture was stirred an additional 2 hours at 0° C. and then allowed to rise to ambient temperature. The reaction mixture was filtered and the filtrate acidified with 1M hydrochloric acid solution (20 ml) and washed with water. The aqueous layer was extracted with twice with diethyl ether and the combined organic layers washed with 50% saturated sodium bicarbonate solution, brine and dried. Solvent was removed by evaporation to give a colourless foam. The foam was triturated with diethyl ether and the resulting solid was collected by filtration and dried under vacuum at 40° C. for 3 hours to give (S)-1-[(S)-2-(4-methoxybenzamido)-3-methylbutyryl]-N-[(S)-2-methyl-1-((R)-2,2,2-trifluoro-1-hydroxyethyl)propyl]-pyrrolidine-2-carboxamide as a white solid, m.p. 168-170° C.; NMR (300 MHz,d6 -DMSO): 0.82-1.05(m,12H), 1.65-2.05(3m,5H), 2.05-2.25(m,1H), 3.60(m,1H), 3.82(s,3H+t,1H), 3.93(m,1H), 4.12(m,1H), 4.45(m,2H), 6.45(d,1H), 6.98(d,2H), 7.65(d,1H), 7.90(d,2H), 8.35(d,1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[C:5](Cl)=[N:6][CH:7]=1.O1CCCC1.[CH3:17][NH2:18]>CO>[Br:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[C:5]([NH:18][CH3:17])=[N:6][CH:7]=1
Reactant: O=[N+]([O-])c1cc(Br)cnc1Cl
Reactant: CN
Solvent: CO
Solvent: C1CCOC1
Product: CNc1ncc(Br)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 6 h

Procedure:
5-bromo-2-chloro-3-nitropyridine (456 mg, 1920 μmol) was dissolved in MeOH (6.0 ml) and methylamine, 2.0 M solution in tetrahydrofuran (2.5 ml, 5.0 mmol) was added. The reaction was stirred at room temperature for 6 hours, allowed to stand at room temperature overnight, and then concentrated. material was taken directly to the next step.
Reaction SMILES: [Cl:1][CH2:2][C:3](=O)[CH:4]=[CH:5][Cl:6].[C:8]([O:16][CH2:17][CH3:18])(=[O:15])[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11]>>[C:8]([C:9](=[C:3]([CH2:2][Cl:1])/[CH:4]=[CH:5]/[Cl:6])[C:10]([O:12][CH2:13][CH3:14])=[O:11])([O:16][CH2:17][CH3:18])=[O:15]
Reactant: O=C(C=CCl)CCl
Reactant: CCOC(=O)CC(=O)OCC
Product: CCOC(=O)C(C(=O)OCC)=C(/C=C/Cl)CCl
Yield: 76.9 %

Procedure:
1,4-Dichloro-3-buten-2-one (0.0556 kg, 0.4 mole) and diethyl malonate (0.064 kg, 0.4 mole) were condensed under identical conditions to those described in Example 1(b) to give the title compound 0.0865 kg (77%; purity, g.l.c., 87.85%).