Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([NH:8][C@H:9]([C:17]([NH:19][C@H:20]([C:24]([NH:26][C@H:27]([C:38]([OH:40])=[O:39])[CH2:28][C:29]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[NH:31][CH:30]=1)=[O:25])[CH:21]([CH3:23])[CH3:22])=[O:18])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=O)(C)(C)C.C(O)(=O)C.[ClH:45]>O1CCOCC1>[ClH:45].[NH2:8][C@H:9]([C:17]([NH:19][C@H:20]([C:24]([NH:26][C@H:27]([C:38]([OH:40])=[O:39])[CH2:28][C:29]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[NH:31][CH:30]=1)=[O:25])[CH:21]([CH3:23])[CH3:22])=[O:18])[CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: CC(C)[C@H](NC(=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O
Agent: Cl
Solvent: CC(=O)O
Solvent: C1COCCO1
Product: CC(C)[C@H](NC(=O)[C@@H](N)Cc1ccccc1)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O

Procedure:
The title compound is prepared using the previously described procedures and the following reagants: 1.85 grams (3.4 mmoles) t-butyloxycarbonyl-phenylalanyl-valyl-tryptophan, 10 ml of glacial acetic acid and 7.25 ml of 6.07 N hydrochloric acid in dioxane. Yield is 1.6 g (100 percent). Analysis calculated for C25H30N4O4.HCl.2H2O: C, 56.99; H, 6.93; N, 9.17. Found: C, 56.70; H, 6.43; N, 8.82.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@@H:19]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)[N:11]3[C:12](=[O:18])[C:13]([CH:16]=O)=[CH:14][CH:15]=[C:10]3[N:9]2[S:27]([C:30]2[CH:31]=[C:32]([CH:35]=[CH:36][CH:37]=2)[C:33]#[N:34])(=[O:29])=[O:28])=[CH:4][CH:3]=1.[C:38]([N:41]1[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]1)(=[O:40])[CH3:39]>>[C:38]([N:41]1[CH2:46][CH2:45][N:44]([CH2:16][C:13]2[C:12](=[O:18])[N:11]3[C@H:19]([C:20]4[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=4)[C@H:8]([C:5]4[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=4)[N:9]([S:27]([C:30]4[CH:31]=[C:32]([CH:35]=[CH:36][CH:37]=4)[C:33]#[N:34])(=[O:29])=[O:28])[C:10]3=[CH:15][CH:14]=2)[CH2:43][CH2:42]1)(=[O:40])[CH3:39]
Reactant: CC(=O)N1CCNCC1
Reactant: N#Cc1cccc(S(=O)(=O)N2c3ccc(C=O)c(=O)n3[C@H](c3ccc(Cl)cc3)[C@@H]2c2ccc(Cl)cc2)c1
Product: CC(=O)N1CCN(Cc2ccc3n(c2=O)[C@H](c2ccc(Cl)cc2)[C@H](c2ccc(Cl)cc2)N3S(=O)(=O)c2cccc(C#N)c2)CC1

Procedure:
rac-3-[cis-6-(4-Acetyl-piperazin-1-ylmethyl)-2,3-bis-(4-chloro-phenyl)-5-oxo-2,3-dihydro-5H-imidazo[1,2-a]pyridine-1-sulfonyl]-benzonitrile was prepared according to general method E by reaction of rac-3-[cis-2,3-bis-(4-chloro-phenyl)-6-formyl-5-oxo-2,3-dihydro-5H-imidazo[1 2-a]pyridine-1-sulfonyl]-benzonitrile with N-acetyl-piperazine. The compound was isolated by preparative HPLC. The expected product was characterized by LC/MS (M+H) where the mass was observed as 662.12; the expected mass is 661. LC/MS indicated a purity of 100% as measured by UV 214 nM.
Reaction SMILES: C([S-])C.[Na+].[C:5]([O:9][C:10]([N:12]1[CH2:16][CH2:15][C@@H:14]([C:17]2[CH:22]=[CH:21][C:20]([Br:23])=[CH:19][C:18]=2[O:24]C)[CH2:13]1)=[O:11])([CH3:8])([CH3:7])[CH3:6].OS([O-])(=O)=O.[K+].[O-]S([O-])(=O)=O.[Na+].[Na+].O>CN(C=O)C>[C:5]([O:9][C:10]([N:12]1[CH2:16][CH2:15][C@@H:14]([C:17]2[CH:22]=[CH:21][C:20]([Br:23])=[CH:19][C:18]=2[OH:24])[CH2:13]1)=[O:11])([CH3:8])([CH3:6])[CH3:7]
Reactant: COc1cc(Br)ccc1[C@@H]1CCN(C(=O)OC(C)(C)C)C1
Agent: CC[S-]
Agent: O=S(=O)([O-])O
Agent: O=S(=O)([O-])[O-]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC[C@@H](c2ccc(Br)cc2O)C1
Temperature: 105 °C
Yield: 81.1 %

Procedure:
Sodium ethanethiolate (80%, 218.7 mg, 1.704 mmol) was added to a solution of (S)-3-(4-bromo-2-methoxy-phenyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (303 mg, 0.8505 mmol) in DMF (3.1 mL) under argon atmosphere. The reaction mixture was heated at 105° C. for 3.5 hours, then cooled to 5° C. A solution of 10% KHSO4/Na2SO4 was added until pH reached 2-3. Water was added, and the resulting mixture was extracted with EtOAc. The combined organic extracts were washed with water and brine, dried over Na2SO4, filtered, and evaporated under reduced pressure. The residue was purified via flash chromatography (hexane/EtOAc, with a gradient from 90/10 to 85/15) to give 236 mg (81% yield) of (S)-3-(4-bromo-2-hydroxy-phenyl)-pyrrolidine-1-carboxylic acid tert-butyl ester as a foam.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:14]=[C:13]2[C:8]([C:9]([CH3:28])([CH3:27])[CH2:10][CH:11]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[CH:16]=3)[NH:12]2)=[CH:7][CH:6]=1)=[O:4].[OH-].[Na+].Cl>CO.O1CCCC1.O>[CH3:27][C:9]1([CH3:28])[C:8]2[C:13](=[CH:14][C:5]([C:3]([OH:4])=[O:2])=[CH:6][CH:7]=2)[NH:12][CH:11]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)[CH:16]=2)[CH2:10]1
Reactant: COC(=O)c1ccc2c(c1)NC(c1cccc(N3CCOCC3)c1)CC2(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CC1(C)CC(c2cccc(N3CCOCC3)c2)Nc2cc(C(=O)O)ccc21
Temperature: 70 °C
Reaction time: 6 h
Yield: 90.1 %

Procedure:
To a stirred mixture solution of 4,4-dimethyl-2-(3-morpholin-4-yl-phenyl)-1,2,3,4-tetrahydro-quinoline-7-carboxylic acid methyl ester (380.0 mg, 1.0 mmol) in methanol (10.0 mL) and tetrahydrofuran (10.0 mL) was added 50% sodium hydroxide in water (1.5 mL). The reaction mixture was stirred at 70° C. for 6 h. The mixture was neutralized with a 3 N aqueous hydrochloric acid solution and extracted with ethyl acetate (2×100 mL), washed with water, dried over anhydrous sodium sulfate and then concentrated in vacuo to afford 4,4-dimethyl-2-(3-morpholin-4-yl-phenyl)-1,2,3,4-tetrahydro-quinoline-7-carboxylic acid (330.0 mg, 90%) as a light white solid which was used for next step without further purification: MS (ESI) M+1=367.1.
Reaction SMILES: Br[CH2:2][C:3]1[CH:7]=[C:6]([CH3:8])[O:5][N:4]=1.[N-:9]=[N+:10]=[N-:11].[Na+].O>CC(C)=O>[N:9]([CH2:2][C:3]1[CH:7]=[C:6]([CH3:8])[O:5][N:4]=1)=[N+:10]=[N-:11]
Reactant: Cc1cc(CBr)no1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: Cc1cc(CN=[N+]=[N-])no1
Reaction time: 48 h
Yield: 242.3 %

Procedure:
To a solution of the 3-bromomethyl-5-methyl-isoxazole (150 mg, 0.9 mmol) in acetone (1 mL) was added NaN3 (166 mg, 0.26 mmol) at rt. The reaction mixture was then stirred for 48 h. Then, the reaction mixture was poured into water (10 mL) and extracted with EtOAc (3×10 mL) dried and evaporated. The product was chromatographed on silica gel eluting with EtOAc/hexane 1:1 to leave the title compound as a colorless liquid (87 mg, 74%). m/z 138.0 (M).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][C:20]([Br:23])=[CH:19][CH:18]=2)=[CH:13][CH:12]=1.CN(C)[CH:26]=[O:27].O1CCCC1.C(OCC)(=O)C>C[O-].[Na+].O>[CH3:26][O:27][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][C:20]([Br:23])=[CH:19][CH:18]=2)=[CH:13][CH:12]=1
Reactant: BrCCCCCCCCOc1ccc(-c2ccc(Br)cc2)cc1
Reactant: CN(C)C=O
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COCCCCCCCCOc1ccc(-c2ccc(Br)cc2)cc1
Temperature: 80 °C

Procedure:
A solution of 4-[4-(8-Bromooctyloxy)phenyl]bromobenzene (3.7 g) in a mixture of sodium methoxide (4.9M in methanol, 17 ml), N,N-dimethylformamide (20 ml) and tetrahydrofuran (8 ml) was heated to 80° C. for 3 hours. The reaction mixture was taken up into a mixture of ethyl acetate (200 ml) and water (100 ml). The separated organic layer was washed in turn with water, brine, dried over magnesium sulfate. Evaporation gave a residue which was subjected to column chromatography (silica gel, 100 ml) eluting with n-hexane to give 4-[4-(8-Methoxyoctyloxy)phenyl]bromobenzene (2.73 g).
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH:7]=O)=[CH:5][N:4]=[CH:3]1.[NH:9]1[CH:13]=[CH:12][CH:11]=[CH:10]1>C(O)(=O)CC>[CH3:1][N:2]1[C:6]([C:7]2[C:13]3[NH:9][C:10]([C:7]([C:6]4[N:2]([CH3:1])[CH:3]=[N:4][CH:5]=4)=[C:10]4[N:9]=[C:13]([C:7]([C:6]5[N:2]([CH3:1])[CH:3]=[N:4][CH:5]=5)=[C:10]5[NH:9][C:13](=[C:7]([C:6]6[N:2]([CH3:1])[CH:3]=[N:4][CH:5]=6)[C:10]6[CH:11]=[CH:12][C:13]=2[N:9]=6)[CH:12]=[CH:11]5)[CH:12]=[CH:11]4)=[CH:11][CH:12]=3)=[CH:5][N:4]=[CH:3]1
Reactant: Cn1cncc1C=O
Reactant: c1cc[nH]c1
Solvent: CCC(=O)O
Product: Cn1cncc1-c1c2nc(c(-c3cncn3C)c3ccc([nH]3)c(-c3cncn3C)c3nc(c(-c4cncn4C)c4ccc1[nH]4)C=C3)C=C2
Reaction time: 60 h
Yield: 21 %

Procedure:
To a refluxing solution of propionic acid (400 mL) and 1-methylimidazole-5-carboxaldehyde (53, 2.0 g, 18.16 mmol), prepared according to literature procedure (Dener, J. M.; Zhang, L-H.; Rapoport, H. J. Org. Chem. 1993, 58, 1159–1166), was added pyrrole (1.26 mL, 18.16 mmol). The reaction was covered with foil then heated under reflux for 5 h. Upon cooling, the reaction mixture was exposed to air for 60 h. The propionic acid was then removed by vacuum distillation. The residue was dissolved in 10% MeOH/CH2Cl2, then adsorbed onto silica gel (6 g). Purification by column chromatography (gradient elution, 5–10% MeOH/CH2Cl2) provided porphyrin 54 as a purple solid (600 mg, 21%): 1H NMR (300 MHz. CDCl3) δ −2.80,–2.75 s, 2H. atropisomer NH). 3.42–3.58 (multiple s, 12H. atropisomer N—CH3). 7.87–7.98 (multiple s. 4H. atropisomer), 8.06 (s, 4H), 8.95–8.99 (multiple s, 8H. atropisomer).
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[C:7]([O:12][CH2:13][CH:14]=[CH2:15])[CH:6]=1)=[S:3].[S:16]1[CH2:20][CH2:19][NH:18][CH2:17]1.C(N(CC)CC)C>C(OCC)C>[S:16]1[CH2:20][CH2:19][N:18]([C:2](=[S:3])[O:4][C:5]2[CH:10]=[CH:9][C:8]([Cl:11])=[C:7]([O:12][CH2:13][CH:14]=[CH2:15])[CH:6]=2)[CH2:17]1
Reactant: C=CCOc1cc(OC(=S)Cl)ccc1Cl
Reactant: C1CSCN1
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: C=CCOc1cc(OC(=S)N2CCSC2)ccc1Cl
Reaction time: 4 h
Yield: 66.5 %

Procedure:
O-(3-Allyloxy-4-chlorophenyl) chlorothioformate (2.63 g) was dissolved in 60 ml of diethyl ether. To this solution were added with stirring 1.01 g of thiazolidine and 1.42 ml of triethylamine. The resulting mixture was stirred for 4 hours and then washed with water. The solvent was distilled off from the ether layer. The residue was recrystallized from methanol to give 2.1 g of O-(3-allyloxy-4-chlorophenyl) 3-thiazolidinecarbothioate [Compound (33)]. The product had a melting point of 103.6°-105.6° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([OH:9])=O.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[F:31][C:32]1[CH:63]=[CH:62][C:61]([F:64])=[CH:60][C:33]=1[CH:34]=[C:35]1[CH2:40][CH2:39][N:38]([C:41]([NH:43][C:44]2[CH:49]=[CH:48][C:47]([NH:50]C(NC3C=CC=CC=3)=O)=[CH:46][CH:45]=2)=[O:42])[CH2:37][CH2:36]1.CCN(CC)CC>ClCCl.O>[F:31][C:32]1[CH:63]=[CH:62][C:61]([F:64])=[CH:60][C:33]=1[CH:34]=[C:35]1[CH2:40][CH2:39][N:38]([C:41]([NH:43][C:44]2[CH:49]=[CH:48][C:47]([NH:50][C:7](=[O:9])[C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=3)=[CH:46][CH:45]=2)=[O:42])[CH2:37][CH2:36]1
Reactant: O=C(O)c1ccccn1
Reactant: O=C(Nc1ccccc1)Nc1ccc(NC(=O)N2CCC(=Cc3cc(F)ccc3F)CC2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: O=C(Nc1ccc(NC(=O)N2CCC(=Cc3cc(F)ccc3F)CC2)cc1)c1ccccn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.6 %

Procedure:
Picolinic acid (69.0 mg, 0.56 mmol) was dissolved in dichloromethane (4.0 mL), and then HOBt (70.0 mg, 0.56 mmol), WSC (107 mg, 0.56 mmol), the compound (200 mg, 0.37 mmol) obtained in Example 73 (1) and Et3N (103 μL, 0.74 mmol) were added thereto, followed by stirring at room temperature overnight. Water was added to the reaction mixture, and after extraction with chloroform, the extract was washed with water and a saturated sodium chloride aqueous solution, and dried over anhydrous magnesium sulfate. After the desiccant was filtered off, the residue obtained by evaporation under reduced pressure was purified using medium pressure silica gel flash column chromatography (methanol:chloroform=1:50), thereby giving the title compound (132 mg, 79%) as a white solid.
Reaction SMILES: C(OC(C)C)(C)C.[F:8][C:9]([F:25])([F:24])[C:10]([C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][C:17]=1[OH:23])([OH:15])[C:11]([F:14])([F:13])[F:12].[H][H]>[Ru].O>[F:8][C:9]([F:24])([F:25])[C:10]([CH:16]1[CH2:21][CH2:20][CH:19]([OH:22])[CH2:18][CH:17]1[OH:23])([OH:15])[C:11]([F:12])([F:14])[F:13]
Reactant: [H][H]
Reactant: Oc1ccc(C(O)(C(F)(F)F)C(F)(F)F)c(O)c1
Agent: [Ru]
Solvent: CC(C)OC(C)C
Solvent: O
Product: OC1CCC(C(O)(C(F)(F)F)C(F)(F)F)C(O)C1
Temperature: 130 °C
Reaction time: 20 h

Procedure:
A 2,000 ml inner capacity of pressure-resistant reactor having a stirrer and a thermometer and formed of SUS316 was charged with 800 ml of diisopropyl ether, 350 g (1.27 mol) of Compound 6 and 17.5 g of 5% Ru/C (a substance containing 50% of water, produced by N.E. CHEMCAT), and then closed. Thereafter, stirring was started and then the interior of the reactor was substituted with hydrogen, followed by setting hydrogen pressure at 3.0 MPa. The temperature of the reactor was increased up to 130° C., upon which stirring was continued for 20 hours.
Reaction SMILES: [Li]C(C)(C)C.Br[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH3:14])[CH:8]=1.[CH3:15][N:16]([CH2:18][CH:19]1[C:25](=[O:26])[CH2:24][CH:23]2[CH2:27][CH:20]1[CH2:21][CH2:22]2)[CH3:17]>CCCCCC.C1COCC1>[CH3:17][N:16]([CH2:18][CH:19]1[C:25]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH3:14])[CH:8]=2)([OH:26])[CH2:24][CH:23]2[CH2:27][CH:20]1[CH2:21][CH2:22]2)[CH3:15]
Reactant: CN(C)CC1C(=O)CC2CCC1C2
Reactant: COc1cccc(Br)c1
Agent: [Li]C(C)(C)C
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COc1cccc(C2(O)CC3CCC(C3)C2CN(C)C)c1
Temperature: -78 °C
Reaction time: 1 h
Yield: 51.5 %

Procedure:
Add dropwise a solution of t-BuLi (19.2 mL, 25.0 mmol) in hexane via syringe to a solution of 1-bromo-3-methoxy-benzene (3.74 g, 20.0 mmol) in THF (60 mL) at −78° C. under N2. After being stirred at −78° C. for 1 hour, add dropwise a solution of 2-dimethylaminomethyl-bicyclo[3.2.1]octan-3-one (1.81 g, 10.0 mmol) in THF (10 mL) to the reaction mixture and stir the resultant mixture at −78° C. for additional 1 hour. Quench the reaction with saturated aqueous NH4Cl solution (20 mL). Extract the aqueous mixture with EtOAc (50 mL×3). The combined organic layers are washed with brine (15 mL), dried over Na2SO4, filtered, and concentrated under vacuum. Purify the residue by silica gel chromatography (CH2Cl2:MeOH=30:1) to afford 2-dimethylaminomethyl-3-(3-methoxy-phenyl)-bicyclo[3.2.1]octan-3-ol as white solid (1.49 g, yield: 51%). MS (m/z): 290 (M+1).
Reaction SMILES: [O:1]=[C:2]1[N:6]([CH3:7])[C:5]([CH2:14][OH:15])([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:4](=[O:16])[N:3]1[C:17]1[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[C:19]([C:25]([F:28])([F:27])[F:26])[CH:18]=1.[CH3:29][C:30]([CH3:43])([O:32][C:33]([NH:35][C@@H:36]([CH:40]([CH3:42])[CH3:41])[C:37](O)=[O:38])=[O:34])[CH3:31].Cl.CN(C)CCCN=C=NCC.O>CN(C)C1C=CN=CC=1.ClCCl>[C:21]([C:20]1[CH:23]=[CH:24][C:17]([N:3]2[C:4](=[O:16])[C:5]([CH2:14][O:15][C:37](=[O:38])[C@@H:36]([NH:35][C:33]([O:32][C:30]([CH3:29])([CH3:43])[CH3:31])=[O:34])[CH:40]([CH3:42])[CH3:41])([C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:6]([CH3:7])[C:2]2=[O:1])=[CH:18][C:19]=1[C:25]([F:28])([F:26])[F:27])#[N:22]
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CN1C(=O)N(c2ccc(C#N)c(C(F)(F)F)c2)C(=O)C1(CO)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: O
Product: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)OCC1(c2ccccc2)C(=O)N(c2ccc(C#N)c(C(F)(F)F)c2)C(=O)N1C

Procedure:
A solution of 0.3 g of 4-[2,5-dioxo-4-(hydroxymethyl)-3-methyl-4-phenylimidazolidin-1-yl]-2-trifluoromethylbenzonitrile, 0.217 g of (2S)-2-[(1,1-dimethylethoxy)carbonylamino]-3-methylbutanoic acid, 0.122 g of 4-dimethylamino pyridine and 0.3 g of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride in 50 mL of dichloromethane is stirred for 18 hours then poured into water and extracted with ethyl acetate. The organic layer is dried over magnesium sulfate, filtered and evaporated. The crude product is purified by chromatography over silica gel while eluting with 70/30 heptane/ethyl acetate mixture to provide the desired compound.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][CH3:12])=[N:6][N:5]2[C:13]=1[S:14]([NH2:17])(=[O:16])=[O:15].[CH3:18][O:19][C:20]1[CH:25]=[C:24]([O:26][CH3:27])[N:23]=[C:22]([NH:28][C:29](=O)[O:30]C2C=CC=CC=2)[N:21]=1.C1CCN2C(=NCCC2)CC1.Cl>O.C(#N)C>[Cl:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][CH3:12])=[N:6][N:5]2[C:13]=1[S:14]([NH:17][C:29]([NH:28][C:22]1[N:21]=[C:20]([O:19][CH3:18])[CH:25]=[C:24]([O:26][CH3:27])[N:23]=1)=[O:30])(=[O:15])=[O:16]
Reactant: COc1cc(OC)nc(NC(=O)Oc2ccccc2)n1
Reactant: CCCc1ccc2nc(Cl)c(S(N)(=O)=O)n2n1
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Solvent: O
Product: CCCc1ccc2nc(Cl)c(S(=O)(=O)NC(=O)Nc3nc(OC)cc(OC)n3)n2n1
Temperature: 25 °C

Procedure:
2-Chloro-6-n-propylimidazo[1,2-b]pyridazin-3-ylsulfonamide (0.49 g, 1.78 mmol), phenyl N-(4,6-dimethoxypyrimidin-2-yl)carbamate (0.55 g, 2 mmol) and acetonitrile (5 ml) were introduced into a 25-ml eggplant type flask and stirred at room temperature, and DBU (0.31 g, 2 mmol) was added all at once thereto, and the mixture was stirred at room temperature for 3 hours. After the reaction was completed, the reaction solution was poured into water (50 ml) and adjusted to about pH 2 with dilute hydrochloric acid, whereby crystals were formed. The crystals were collected by filtration, washed with water, acetone and ether in this order and dried under reduced pressure to give the title compound as pale brown crystals. The yield was 0.71 g (89.5%).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][CH3:13])[CH:5]=[C:4]([C:14]#[N:15])[N:3]=1.[NH2:16][C@H:17]1[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18]1.CCN(CC)CC>CN1C(=O)CCC1>[C:14]([C:4]1[N:3]=[C:2]([NH:16][C@H:17]2[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18]2)[C:11]2[C:6]([CH:5]=1)=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][CH3:13])#[N:15]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](N)C1
Reactant: COc1cccc2cc(C#N)nc(Cl)c12
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Product: COc1cccc2cc(C#N)nc(N[C@H]3CCN(C(=O)OC(C)(C)C)C3)c12
Temperature: 130 °C
Yield: 98.2 %

Procedure:
To a solution of 1-chloro-8-methoxyisoquinoline-3-carbonitrile (230 mg, 1.05 mmol) in NMP (5 mL) was added (S)-tert-butyl 3-aminopyrrolidine-1-carboxylate (294 mg, 1.57 mmol) and Et3N (212 mg, 2.1 mmol). The reaction mixture was heated to 130° C. for 45 minutes in a microwave reactor and was subsequently quenched with H2O (20 mL). The aqueous phase was extracted with EtOAc (3×10 mL). The organic layers were combined and concentrated in vacuo. The crude product was purified by column chromatography eluting with ethyl acetate and petroleum ether (EtOAc/PE=1:20-1:2 gradient) to give the title compound (380 mg, 2 batches, 52%). 1H NMR (400 MHz, CDCl3) δ ppm 7.85 (s, 1H), 7.55 (t, 1H, J=8.0 Hz), 7.25 (s, 1H), 6.97 (d, 1H, J=8.0 Hz), 4.60-4.80 (m, 1H), 4.01 (s, 3H), 3.78-3.79 (m, 1H), 3.27-3.57 (m, 3H), 2.29-2.34 (m, 1H), 1.94-1.99 (m, 1H), 1.48 (s, 9H).
Reaction SMILES: IN1C(=O)CCC1=O.[CH3:9][O:10][C:11]1[CH:16]=[CH:15][C:14](/[C:17](/[Si](C)(C)C)=[CH:18]/[C:19]2[S:20][C:21]([CH3:24])=[CH:22][CH:23]=2)=[CH:13][CH:12]=1.C([Li])CCC.[C:34]1([CH3:53])[CH:39]=[C:38]([CH3:40])[CH:37]=[C:36]([CH3:41])[C:35]=1[B:42](F)[C:43]1[C:48]([CH3:49])=[CH:47][C:46]([CH3:50])=[CH:45][C:44]=1[CH3:51]>C(OCC)C.O.C(#N)C>[CH3:9][O:10][C:11]1[CH:16]=[CH:15][C:14](/[C:17](/[B:42]([C:43]2[C:44]([CH3:51])=[CH:45][C:46]([CH3:50])=[CH:47][C:48]=2[CH3:49])[C:35]2[C:36]([CH3:41])=[CH:37][C:38]([CH3:40])=[CH:39][C:34]=2[CH3:53])=[CH:18]/[C:19]2[S:20][C:21]([CH3:24])=[CH:22][CH:23]=2)=[CH:13][CH:12]=1
Reactant: Cc1cc(C)c(B(F)c2c(C)cc(C)cc2C)c(C)c1
Reactant: COc1ccc(/C(=C/c2ccc(C)s2)[Si](C)(C)C)cc1
Agent: O=C1CCC(=O)N1I
Agent: [Li]CCCC
Solvent: CC#N
Solvent: CCOCC
Solvent: O
Product: COc1ccc(/C(=C/c2ccc(C)s2)B(c2c(C)cc(C)cc2C)c2c(C)cc(C)cc2C)cc1
Temperature: 0 °C
Reaction time: 5 h

Procedure:
In a nitrogen atmosphere, N-iodosuccinimide (1.1 g, 5.0 mmol) was added to an acetonitrile solution of (Z)-(1-(4-methoxyphenyl)-2-(5-methyl-2-thienyl)-ethenyl)trimethylsilane (0.3 g, 1.0 mmol) at 0° C. The mixture was stirred for 5 hours while maintaining at 0° C., and then applied to an alumina column for concentration. In a nitrogen atmosphere, the residue obtained was dissolved in diethyl ether, and n-butyl lithium (0.9 mL, 1.4 mmol) was added dropwise at −78° C. The mixture was stirred for 1 hour while maintaining at −78° C., and dimesityl boron fluoride (0.37 g, 1.56 mmol) was then added thereto. The mixture was stirred at room temperature for 12 hours, and water was then added thereto, followed by extraction with ethyl acetate. The organic layer was washed with a saturated sodium chloride solution and then dried with magnesium sulfate, followed by filtration. The filtrate was concentrated, and the residue was purified by silica gel column chromatography (dichloromethane) and recrystallization (diethyl ether). Thus, (E)-(1-(4-methoxyphenyl)-2-(5-methyl-2-thienyl)ethenyl)-bis(2,4,6-trimethylphenyl)borane was obtained.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1)(=[O:3])[CH3:2].C(N(CC)CC)C.[CH3:17][O:18][CH2:19][O:20][C:21]1[C:30]([CH3:31])=[C:29]2[C:24]([C:25](=[O:37])[C:26]([CH3:36])=[C:27](S(C)(=O)=O)[O:28]2)=[CH:23][CH:22]=1.C(OCC)(=O)C>CS(C)=O>[C:1]([N:4]1[CH2:9][CH2:8][N:7]([C:27]2[O:28][C:29]3[C:24]([C:25](=[O:37])[C:26]=2[CH3:36])=[CH:23][CH:22]=[C:21]([O:20][CH2:19][O:18][CH3:17])[C:30]=3[CH3:31])[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCNCC1
Reactant: COCOc1ccc2c(=O)c(C)c(S(C)(=O)=O)oc2c1C
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: COCOc1ccc2c(=O)c(C)c(N3CCN(C(C)=O)CC3)oc2c1C
Reaction time: 5 h
Yield: 30.3 %

Procedure:
1-Acetylpiperazine (220 mg, 1.70 mmol) and triethylamine (1 mL) were added to a solution of 7-(methoxymethoxy)-3,8-dimethyl-2-(methylsulfonyl)-4H-chromen-4-one (171 mg, 0.55 mmol) obtained in Example 37-3 in dimethyl sulfoxide (5 mL), and the mixture was stirred for 5 hours under cooling with ice. Ethyl acetate was added to the reaction solution. The organic layer was washed with water and then dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform/methanol=97/3→93/7) to obtain 60 mg of the title compound (yield: 30%), which was used directly in the next reaction.
Reaction SMILES: C(OC([NH:8][C@H:9]([CH2:20][CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1)[CH:10]([OH:19])[C:11]([NH:13][O:14][CH2:15][C:16]([OH:18])=O)=[O:12])=O)(C)(C)C.Cl.[CH2:28]([O:30][C:31](=[O:35])[C@H:32]([CH3:34])[NH2:33])[CH3:29].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.CN1CCOCC1>ClCCl>[NH2:8][C@H:9]([CH2:20][CH:21]1[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]1)[CH:10]([OH:19])[C:11]([NH:13][O:14][CH2:15][C:16]([NH:33][C@@H:32]([CH3:34])[C:31]([O:30][CH2:28][CH3:29])=[O:35])=[O:18])=[O:12]
Reactant: CCOC(=O)[C@H](C)N
Reactant: CC(C)(C)OC(=O)N[C@H](CC1CCCCC1)C(O)C(=O)NOCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CCOC(=O)[C@H](C)NC(=O)CONC(=O)C(O)[C@H](N)CC1CCCCC1
Reaction time: 1 h

Procedure:
A solution of Example 118A (0.17 g, 0.45 mmol), L-alanine ethyl ester hydrochloride (0.098 g, 0.64 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.098 g, 0.51 mmol), 1-hydroxybenzotriazole (0.091 g, 0.67 mmol), and N-methylmorpholine (0.11 mL, 1.0 mmol) in dichloromethane (5 mL) at room temperature was stirred for 16 hours, diluted with dichloromethane, washed sequentially with 1 M HCl, aqueous NaHCO3, dried (MgSO4), filtered, and concentrated. The concentrate was dissolved in saturated HCl/dioxane (4 mL), stirred for 1 hour, concentrated, then purified by HPLC to provide the desired product.