Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:44]=[C:43]([CH3:45])[CH:42]=[C:41]([Cl:46])[C:3]=1[O:4][CH2:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH:15]([C:25]2[CH:30]=[CH:29][C:28](B3OC(C)(C)C(C)(C)O3)=[CH:27][C:26]=2[CH3:40])[CH2:16][NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:10][CH:9]=1.Br[C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][C:49]=1[CH2:54][CH2:55][CH2:56][OH:57]>>[Cl:46][C:41]1[CH:42]=[C:43]([CH3:45])[CH:44]=[C:2]([Cl:1])[C:3]=1[O:4][CH2:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH:15]([C:25]2[CH:30]=[CH:29][C:28]([C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][C:49]=3[CH2:54][CH2:55][CH2:56][OH:57])=[CH:27][C:26]=2[CH3:40])[CH2:16][NH:17][C:18](=[O:24])[O:19][C:20]([CH3:22])([CH3:23])[CH3:21])=[CH:10][CH:9]=1
Reactant: OCCCc1ccccc1Br
Reactant: Cc1cc(Cl)c(OCCOc2ccc(CC(CNC(=O)OC(C)(C)C)c3ccc(B4OC(C)(C)C(C)(C)O4)cc3C)cc2)c(Cl)c1
Product: Cc1cc(Cl)c(OCCOc2ccc(CC(CNC(=O)OC(C)(C)C)c3ccc(-c4ccccc4CCCO)cc3C)cc2)c(Cl)c1

Procedure:
Prepared according to the procedure described in EXAMPLE 7, step 2 using tert-butyl {3-{4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]phenyl}-2-[2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]propyl}carbamate from EXAMPLE 9, step 1 and commercially available 3-(2-bromophenyl)propan-1-ol as starting materials. Purification by column chromatography on silica gel (Combi-Flash by ISCO), eluting with Hex/EtOAc (10 to 75% in 30 min) afforded the desired compound as a colorless oil.
Reaction SMILES: [NH2:1][C:2](=[C:8]1[CH2:14][N:13]([CH3:15])[C:12](=[O:16])[C:11]2[CH:17]=[CH:18][CH:19]=[CH:20][C:10]=2[NH:9]1)[C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH:21](OCC)(OCC)OCC>C1(C)C=CC=CC=1>[CH3:15][N:13]1[C:12](=[O:16])[C:11]2[CH:17]=[CH:18][CH:19]=[CH:20][C:10]=2[N:9]2[CH:21]=[N:1][C:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])=[C:8]2[CH2:14]1
Reactant: CCOC(OCC)OCC
Reactant: CCOC(=O)C(N)=C1CN(C)C(=O)c2ccccc2N1
Solvent: Cc1ccccc1
Product: CCOC(=O)c1ncn2c1CN(C)C(=O)c1ccccc1-2

Procedure:
1.10 g of ethyl α-amino-1,3,4,5-tetrahydro-4-methyl-5-oxo-2H-1,4-benzodiazepin-2-ylidene-acetate are dissolved in 15 ml of toluene and treated with 1.0 ml of triethyl orthoformate. The mixture is heated to reflux for 50 minutes, subsequently cooled and evaporated in vacuo. The crystalline residue is suspended in 25 ml of ethyl acetate, filtered off and dried. There is obtained ethyl 5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a][1,4]-benzodiazepine-3-carboxylate of melting point 165° C.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].C(=S)=S.[CH2:8]([N:10]([CH2:17][CH3:18])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH3:9].[C:19](Cl)(=[O:23])[C:20](Cl)=[O:21]>C(Cl)(Cl)Cl.O>[CH2:17]([N:10]([CH2:8][CH3:9])[C:11]1[CH:16]=[CH:15][C:14]([C:19](=[O:23])[C:20]([C:14]2[CH:15]=[CH:16][C:11]([N:10]([CH2:17][CH3:18])[CH2:8][CH3:9])=[CH:12][CH:13]=2)=[O:21])=[CH:13][CH:12]=1)[CH3:18]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CCN(CC)c1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: S=C=S
Product: CCN(CC)c1ccc(C(=O)C(=O)c2ccc(N(CC)CC)cc2)cc1

Procedure:
To 11.6 g of anhydrous aluminum chloride, 60 ml of carbon disulfide was added, followed by dropwise addition of 30 g of N,N-diethylaniline under ice-cooling. Then, 10 g of oxalyl chloride was added dropwise thereto at 5° C. or lower, followed by the reaction for 1 hour with stirring. After the reaction, the reaction solution was poured into 100 ml of water and 200 ml of chloroform. The chloroform layer obtained by separation was washed with 2N hydrochloric acid, dried and concentrated. The residue was recrystallized from ethyl acetate to give yellow 1,2-bis(4-diethylaminophenyl)ethane-1,2-dione in an amount of 7.0 g.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:10]2[C:14](=[O:15])[CH2:13][CH:12]([C:16](O)=[O:17])[CH2:11]2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].CCN(CC)CC.ClC(OCC(C)C)=O.[BH4-].[Na+].C([O-])(O)=O.[Na+]>C(Cl)Cl.O.CCOC(C)=O>[F:1][C:2]1[CH:3]=[C:4]([N:10]2[CH2:11][CH:12]([CH2:16][OH:17])[CH2:13][C:14]2=[O:15])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: COc1ccc(N2CC(C(=O)O)CC2=O)cc1F
Agent: CC(C)COC(=O)Cl
Agent: O=C([O-])O
Agent: [BH4-]
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(N2CC(CO)CC2=O)cc1F
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 1-(3-fluoro-4-methoxyphenyl)-5-oxopyrrolidine-3-carboxylic acid (Step 1, 2 g, 7.9 mmol), Et3N (1.65 mL, 9.48 mmol) in 30 mL of CH2Cl2 at 0° C. was added isobutyl chloroformate (1.23 mL, 9.48 mmol) via a syringe. The reaction was stirred at 0° C. for 1 h. The white precipitate was removed by filtration. The filtrate was cooled to 0° C. and NaBH4 (0.9 g, 23.7 mmol) in water solution (3 mL) was added to the reaction. After 1 h, the mixture was diluted with 100 mL of EtOAc and 30 mL of satd. NaHCO3 solution. The organic phase was separated and washed with 30 mL of brine, dried over Na2SO4 and concentrated in vacuo. The residue was chromatographed by a silica gel column (5% to 80% EtOAc/hexane) to give the title as a colorless glass. MS (ESI pos. ion) m/z: 240.4 (M+H). Calc'd Exact Mass for C12H14FNO3: 239.24.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][S:10]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[S:20]([NH2:23])(=[O:22])=[O:21])(=[O:12])=[O:11])=[CH:4][CH:3]=1.[CH3:24][C:25]([CH3:29])([CH3:28])[C:26]#[CH:27]>>[CH3:24][C:25]([CH3:29])([CH3:28])[C:26]#[C:27][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][S:10]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[S:20]([NH2:23])(=[O:22])=[O:21])(=[O:12])=[O:11])=[CH:4][CH:3]=1
Reactant: C#CC(C)(C)C
Reactant: NS(=O)(=O)c1ccccc1NS(=O)(=O)CCc1ccc(Br)cc1
Product: CC(C)(C)C#Cc1ccc(CCS(=O)(=O)Nc2ccccc2S(N)(=O)=O)cc1
Yield: 16 %

Procedure:
The title compound was synthesized as described for Example 179a) in 16% yield, starting from 2-(2-(4-bromophenyl)ethylsulfonamido)benzenesulfonamide and 3,3-dimethyl-1-butyne.
Reaction SMILES: [F:1][C:2]1[CH:25]=[C:24]([N+:26]([O-:28])=[O:27])[CH:23]=[CH:22][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([C:14]3[CH:15]=[N:16][N:17]([CH2:19][CH:20]=O)[CH:18]=3)[S:13][C:6]=12.CC(O)=O.[CH3:33][N:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CN1C(=O)CCC1.C([O-])(O)=O.[Na+]>[F:1][C:2]1[CH:25]=[C:24]([N+:26]([O-:28])=[O:27])[CH:23]=[CH:22][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([C:14]3[CH:15]=[N:16][N:17]([CH2:19][CH2:20][N:37]4[CH2:38][CH2:39][N:34]([CH3:33])[CH2:35][CH2:36]4)[CH:18]=3)[S:13][C:6]=12
Reactant: O=CCn1cc(-c2cc3nccc(Oc4ccc([N+](=O)[O-])cc4F)c3s2)cn1
Reactant: CN1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: CC(=O)O
Product: CN1CCN(CCn2cc(-c3cc4nccc(Oc5ccc([N+](=O)[O-])cc5F)c4s3)cn2)CC1
Temperature: 25 °C
Yield: 45.8 %

Procedure:
To a solution of 146 (450 mg, 1.13 mmol, Scheme 36) in NMP (10 mL) was added AcOH (0.129 mL, 2.259 mmol) and 1-methylpiperazine (113 mg, 2.259 mmol) and the reaction mixture was stirred at RT for an hour. Sodium triacetoxyborohydride (718 mg, 6.10 mmol) was added and the mixture was stirred at RT overnight. The mixture was diluted with saturated NaHCO3 solution then solid NaHCO3 was added to neutralize the acid. The mixture was extracted with DCM and the extract was dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by column chromatography (eluent 10% MeOH to 50% MeOH in EtOAc) to afford title compound 152 (250 mg, 27% yield) as a brown oil. MS (m/z)=483.53 (M+H).
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:11][CH2:10][N:9]([C:12]2[N:21]=[C:20]([N:22]3[CH2:27][CH2:26][CH:25]([N:28]4[C:37](=[O:38])[C:36]5[C:31](=[CH:32][CH:33]=[C:34]([CH3:39])[CH:35]=5)[N:30]([CH3:40])[C:29]4=[O:41])[CH2:24][CH2:23]3)[C:19]3[C:14](=[CH:15][C:16]([O:44][CH3:45])=[C:17]([O:42][CH3:43])[CH:18]=3)[N:13]=2)[CH2:8][CH2:7]1)=[O:5])C.[OH-].[Na+]>CO>[C:4]([CH:6]1[CH2:11][CH2:10][N:9]([C:12]2[N:21]=[C:20]([N:22]3[CH2:23][CH2:24][CH:25]([N:28]4[C:37](=[O:38])[C:36]5[C:31](=[CH:32][CH:33]=[C:34]([CH3:39])[CH:35]=5)[N:30]([CH3:40])[C:29]4=[O:41])[CH2:26][CH2:27]3)[C:19]3[C:14](=[CH:15][C:16]([O:44][CH3:45])=[C:17]([O:42][CH3:43])[CH:18]=3)[N:13]=2)[CH2:8][CH2:7]1)([OH:5])=[O:3]
Reactant: CCOC(=O)C1CCN(c2nc(N3CCC(n4c(=O)c5cc(C)ccc5n(C)c4=O)CC3)c3cc(OC)c(OC)cc3n2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1cc2nc(N3CCC(C(=O)O)CC3)nc(N3CCC(n4c(=O)c5cc(C)ccc5n(C)c4=O)CC3)c2cc1OC
Yield: 80.5 %

Procedure:
In 10 ml of methanol was dissolved 400 mg (0.65 mmol) of Compound 3 obtained in Example 3, and 5 ml of 2 N aqueous solution of sodium hydroxide was added to the solution, followed by heating under reflux for one hour. After cooling, the solvent was evaporated, and water and concentrated hydrochloric acid were added to the residue. The precipitated crystals were collected by filtration, and then washed with water and methanol to give 308.0 mg (yield: 81%) of Compound 4 as white crystals.
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[C@@H:4](/[CH:5]=[C:6](\[Br:14])/[C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10])[C@H:3]1[C:15]([OH:17])=[O:16].[C:19]([C@@H:21](O)[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([O:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:23]=1)#[N:20]>C(Cl)(Cl)Cl>[CH3:1][C:2]1([CH3:18])[C@@H:4](/[CH:5]=[C:6](\[Br:14])/[C:7](=[O:13])[O:8][C:9]([CH3:10])([CH3:11])[CH3:12])[C@H:3]1[C:15]([O:17][C@H:21]([C:19]#[N:20])[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([O:28][C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:23]=1)=[O:16]
Reactant: CC(C)(C)OC(=O)/C(Br)=C/[C@H]1[C@@H](C(=O)O)C1(C)C
Reactant: N#C[C@@H](O)c1cccc(Oc2ccccc2)c1
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)/C(Br)=C/[C@H]1[C@@H](C(=O)O[C@H](C#N)c2cccc(Oc3ccccc3)c2)C1(C)C

Procedure:
Using the process of Example 1, (1R,cis) 2,2-dimethyl-3(Z)-[2-bromo-3-oxo-3-tert.-butoxy-propenyl]-cyclopropane-1-carboxylic acid and (S)α-cyano-3-phenoxy-benzyl alcohol were reacted to obtain (S)α-cyano-3-phenoxy-benzyl (1R,cis) 2,2-dimethyl-3(Z)-[2-bromo-3-oxo-3-tert.-butoxy-propenyl]-cyclopropane-1-carboxylate with a specific rotation of [α]D20 =+16.5°±2° (c=0.5% in chloroform).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[Cl:26])[CH2:9][C:10]([C:12]2[CH:13]=[N:14][C:15]([O:18]C)=[CH:16][CH:17]=2)=[O:11])=[CH:4][CH:3]=1.Cl>O1CCOCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[Cl:26])[CH2:9][C:10]([C:12]2[CH:17]=[CH:16][C:15](=[O:18])[NH:14][CH:13]=2)=[O:11])=[CH:4][CH:3]=1
Reactant: COc1ccc(C(=O)CC(c2ccc(Br)cc2)c2ccccc2Cl)cn1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(CC(c1ccc(Br)cc1)c1ccccc1Cl)c1ccc(=O)[nH]c1

Procedure:
In analogy to example 162, step 2, 3-(4-bromo-phenyl)-3-(2-chloro-phenyl)-1-(6-methoxy-pyridin-3-yl)-propan-1-one was reacted with concentrated aqueous HCl in 1,4-dioxane to give the title compound as an off-white foam, MS (ESI+): m/z=413.9 [M−H]−.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10]([NH:12][CH2:13][CH:14]2[CH2:19][CH:18]([OH:20])[CH2:17][N:16]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:15]2)[C:9]2[C:4](=[N:5][CH:6]=[CH:7][N:8]=2)[CH:3]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>ClCCl.C(OCC)(=O)C>[Cl:1][C:2]1[N:11]=[C:10]([NH:12][CH2:13][CH:14]2[CH2:19][C:18](=[O:20])[CH2:17][N:16]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:15]2)[C:9]2[C:4](=[N:5][CH:6]=[CH:7][N:8]=2)[CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CC(O)CC(CNc2nc(Cl)cc3nccnc23)C1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CC(=O)CC(CNc2nc(Cl)cc3nccnc23)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of tert-butyl 3-((7-chloropyrido[4,3-b]pyrazin-5-ylamino)methyl)-5-hydroxypiperidine-1-carboxylate (1.97 g, 5.0 mmol) in dichloromethane was added Dess-Martin periodinane (2.54 g, 6.0 mmol) at room temperature. The reaction mixture was stirred at room temperature overnight, then diluted with ethyl acetate, washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give the title compound.
Reaction SMILES: [C:1]1(=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:7]([NH2:10])[CH2:8][NH2:9].C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[CH:1]1([NH:9][CH2:8][CH2:7][NH2:10])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C1CCCC1
Reactant: NCCN
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: NCCNC1CCCC1
Reaction time: 48 h
Yield: 34.5 %

Procedure:
To a solution of cyclopentanone (2.000 mL, 22.6 mmol), ethylenediamine (10.860 g, 180.7 mmol), acetic acid (10.345 mL, 180.7 mmol), and 4 {acute over (Å)} molecular sieves (10 g) in anhydrous methanol (113 mL) was added sodium cyanoborohydride (2.839 g, 45.2 mmol). The mixture was stirred for 48 hrs, filtered to remove the solids, and concentrated in vacuo. The residue was dissolved in 3 N aqueous sodium hydroxide (150 mL) and extracted with methylene chloride (3×300 mL). The combined organic layers were washed with basic saturated aqueous sodium chloride, dried (anhydrous sodium sulfate), filtered, and concentrated to give the crude product. The material was vacuum distilled to give the desired product as a clear liquid (1.0 g, 35%). 1H NMR (300 MHz, CDCl3) δ 3.08-2.99 (quint, 1H, J=6.8 Hz), 2.80-2.76 (t, 2H, J=5.9 Hz), 2.65-2.61 (t, 2H, J=5.9 Hz), 1.87-1.77 (m, 2H), 1.72-1.60 (m, 2H), 1.57-1.46 (m, 2H), 1.35-1.24 (m, 5H).
Reaction SMILES: [Br:1][C:2]1[C:3]([C@@H:16]([NH:26]C(=O)OC(C)(C)C)[CH2:17][C:18]2[CH:23]=[C:22]([F:24])[CH:21]=[C:20]([F:25])[CH:19]=2)=[N:4][C:5]([Br:15])=[C:6]([NH:8][C:9](=[O:14])[C:10]([F:13])([F:12])[F:11])[CH:7]=1.[C:34]([OH:40])([C:36]([F:39])([F:38])[F:37])=[O:35].C(Cl)Cl>C(Cl)Cl>[NH2:26][C@H:16]([C:3]1[N:4]=[C:5]([Br:15])[C:6]([NH:8][C:9](=[O:14])[C:10]([F:11])([F:13])[F:12])=[CH:7][C:2]=1[Br:1])[CH2:17][C:18]1[CH:19]=[C:20]([F:25])[CH:21]=[C:22]([F:24])[CH:23]=1.[C:34]([OH:40])([C:36]([F:39])([F:38])[F:37])=[O:35]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1cc(F)cc(F)c1)c1nc(Br)c(NC(=O)C(F)(F)F)cc1Br
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N[C@@H](Cc1cc(F)cc(F)c1)c1nc(Br)c(NC(=O)C(F)(F)F)cc1Br
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A mixture of (S)-tert-butyl (1-(3,6-dibromo-5-(2,2,2-trifluoroacetamido)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)carbamate (46C, 563 mg, 0.94 mmol) in 5 mL of methylene chloride was cooled down to 0° C. and to it was added 10 mL of 20% TFA/methylene chloride. The reaction was allowed to stir at room temperature for 1 hour and then concentrated to dryness to afford (S)—N-(6-(1-amino-2-(3,5-difluorophenyl)ethyl)-2,5-dibromopyridin-3-yl)-2,2,2-trifluoroacetamide as a TFA salt. 2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetic acid (265 mg, 0.94 mmol), the amine (TFA salt from last step) and HATU (429 mg, 1.1 mmol) were dissolved in 10 mL DMF, cooled to 0° C., then N,N-diisopropylethylamine (0.84 mL, 4.7 mmol) was added dropwise. The reaction mixture was allowed to stir at 0° C. for 5 min, and then partitioned between EtOAc and 5% LiCl aqueous solution. The organic layer was separated, washed with NaHCO3 (sat'd aq.) and brine. After dried over MgSO4, it was filtered and concentrated to yield the title product. MS (m/z): 767.84 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:26]=[C:27]([O:29][CH2:30][C:31]2[N:32]=[C:33]([C:36]3[S:37][CH:38]=[CH:39][CH:40]=3)[S:34][CH:35]=2)[CH:28]=1)[CH2:7][N:8]1[CH:12]=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:10]([CH2:19][CH2:20][C:21]([O:23]CC)=[O:22])=[CH:9]1)[CH3:2].[OH-].[Na+].O1CCCC1.Cl>C(O)C>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:26]=[C:27]([O:29][CH2:30][C:31]2[N:32]=[C:33]([C:36]3[S:37][CH:38]=[CH:39][CH:40]=3)[S:34][CH:35]=2)[CH:28]=1)[CH2:7][N:8]1[CH:12]=[C:11]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:10]([CH2:19][CH2:20][C:21]([OH:23])=[O:22])=[CH:9]1)[CH3:2]
Reactant: CCOC(=O)CCc1cn(Cc2cc(OCC)cc(OCc3csc(-c4cccs4)n3)c2)cc1-c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CCOc1cc(Cn2cc(CCC(=O)O)c(-c3ccccc3)c2)cc(OCc2csc(-c3cccs3)n2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 87.8 %

Procedure:
After a mixture of ethyl 3-[1-[3-ethoxy-5-[2-(2-thienyl)-4-thiazolylmethoxy)benzyl]-4-phenyl-3-pyrrolyl]propionate (653 mg), 1N aqueous sodium hydroxide solution (2.5 ml), tetrahydrofuran (5 ml) and ethanol (5 ml) was stirred at room temperature for 2 hours, 1 N hydrochloric acid (2.5 ml) was added to the mixture, and then the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4) and concentrated. The resulting colorless crystals were collected by filtration to obtain 3-[1-[3-ethoxy-5-[2-(2-thienyl)-4-thiazolylmethoxy)benzyl]-4-phenyl-3-pyrrolyl]propionic acid (545 mg, yield: 88%). This was recrystallized from ethanol-hexane. Melting point: 104–105° C.
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[C:6]([CH:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1)[NH:7][C:8]2=[O:13].Br[CH2:21][CH2:22][CH2:23][OH:24]>>[CH3:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[C:6]([CH:14]1[CH2:19][CH2:18][N:17]([CH2:21][CH2:22][CH2:23][OH:24])[CH2:16][CH2:15]1)[NH:7][C:8]2=[O:13]
Reactant: Cc1cccc2c(=O)[nH]c(C3CCNCC3)cc12
Reactant: OCCCBr
Agent: Cl
Product: Cc1cccc2c(=O)[nH]c(C3CCN(CCCO)CC3)cc12
Yield: 20.5 %

Procedure:
By the reaction in the same manner as in Example 2a, using 5-methyl-3-(piperidin-4-yl)-2H-isoquinolin-1-one hydrochloride (1 g) and 3-bromo-1-propanol (751 mg), 5-methyl-3-[1-(3-hydroxypropyl)piperidin-4-yl]-2H-isoquinolin-1-one (221 mg) was obtained.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]#[C:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1.[CH3:13][N:14]1[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[NH:16][C:15]1=[O:23].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH3:13][N:14]1[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[N:16]([CH2:2][CH2:3][CH2:4][C:5]#[C:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=2)[C:15]1=[O:23]
Reactant: ClCCCC#Cc1ccccn1
Reactant: Cn1c(=O)[nH]c2ccccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cn1c(=O)n(CCCC#Cc2ccccn2)c2ccccc21
Temperature: 50 °C
Yield: 45.8 %

Procedure:
2-(5-chloropent-1-ynyl)pyridine (59 mg, 0.33 mmol), 1-methyl-1H-benzo[d]imidazol-2(3H)-one (44 mg, 0.3 mmol) and K2CO3 (70 mg, 0.51 mmol) were poured into DMF (0.45 mL) and the resulting mixture was heated at 50° C. overnight. The mixture was purified over silicagel chromatography (prepacked 25 g silicagel column, DCM 100% as eluent) to afford 40 mg of 1-methyl-3-(5-(pyridin-2-yl)pent-4-ynyl)-1H-benzo[d]imidazol-2(3H)-one as a yellow oil (Yield: 43%).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[N:11]=[CH:10][C:9]3[CH:12]=[N:13][N:14]([C:15]4[N:20]=[C:19]([N:21]5[CH2:27][CH2:26][CH2:25][N:24](C([O-])=O)[CH2:23][CH2:22]5)[CH:18]=[CH:17][CH:16]=4)[C:8]=3[CH:7]=2)[CH:3]=[N:2]1.Cl.[CH3:32]O>>[N:21]1([C:19]2[N:20]=[C:15]([N:14]3[C:8]4[CH:7]=[C:6]([C:4]5[CH:3]=[N:2][N:1]([CH3:32])[CH:5]=5)[N:11]=[CH:10][C:9]=4[CH:12]=[N:13]3)[CH:16]=[CH:17][CH:18]=2)[CH2:27][CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1
Reactant: CO
Reactant: O=C([O-])N1CCCN(c2cccc(-n3ncc4cnc(-c5cn[nH]c5)cc43)n2)CC1
Agent: Cl
Product: Cn1cc(-c2cc3c(cn2)cnn3-c2cccc(N3CCCNCC3)n2)cn1
Yield: 51.8 %

Procedure:
A solution of 4-(6-(6-(1H-pyrazol-4-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyridin-2-yl)-1,4-diazepane-1-carboxylate (440 mg, 0.93 mmol) in a solution of HCl/MeOH (2M, 10 mL) was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure. The crude was purified by reverse phase preparative HPLC to afford 224 as a yellow solid (180 mg, 51.8%). 1H NMR (500 MHz, DMSO-d6) δ (ppm) 9.095-9.098 (d, J=1.5 Hz, 1H), 8.61 (s, 1H), 8.45 (s, 1H), 8.14 (s, 1H), 7.87 (s, 1H), 7.64-7.69 (t, J=13.5 Hz, 1H), 7.13-7.16 (d, J=12.5 Hz, 1H), 6.55-6.58 (d, J=14.5 Hz, 1H), 3.90-3.91 (d, J=8 Hz, 3H), 3.78-3.87 (m, 6H), 3.01-3.05 (t, J=13 Hz, 2H), 1.87-1.91 (m, 2H); MS (ESI) m/z: 375 [M+H]+.
Reaction SMILES: [F:1][CH:2]([F:15])[O:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]=[CH:11][C:12](O)=[O:13])=[CH:6][CH:5]=1.C(Cl)(=O)C(Cl)=O.[NH3:22]>O1CCCC1.CN(C)C=O>[F:1][CH:2]([F:15])[O:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]=[CH:11][C:12]([NH2:22])=[O:13])=[CH:6][CH:5]=1
Reactant: N
Reactant: O=C(O)C=Cc1ccc(OC(F)F)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: NC(=O)C=Cc1ccc(OC(F)F)cc1
Temperature: 2.5 °C
Reaction time: 2 h

Procedure:
To a suspension of 8.70 g (40.6 mmol) 3-(4-difluoromethoxy-phenyl)-acrylic acid in 60.0 ml tetrahydrofuran and 0.6 ml N,N-dimethylformamide a solution of 5.14 ml (60.9 mmol) oxalyl chloride in 10 ml tetrahydrofuran was added dropwise at 0° C. within 10 min. Stirring was continued at 0-5° C. for 30 min. and 2 h at room temperature thereafter. The resulting solution was cooled to 0-5° C. again and then added within 15 min. to 150 ml of a 25% aqueous ammonia solution. The separating oil was collected and stirred for 30 min. with water. The precipitated amide was collected, washed with water and dried at 40° C. in vacuo. 4.7 g (54%) 3-(4-Difluoromethoxy-phenyl)-acrylamide.
Reaction SMILES: [NH2:1][NH2:2].[F:3][C:4]([F:10])([F:9])[CH2:5][N:6]=[C:7]=[S:8]>CCO>[F:3][C:4]([F:10])([F:9])[CH2:5][NH:6][C:7]([NH:1][NH2:2])=[S:8]
Reactant: FC(F)(F)CN=C=S
Reactant: NN
Solvent: CCO
Product: NNC(=S)NCC(F)(F)F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Anhydrous hydrazine (0.634 mL, 20.20 mmol) (Sigma-Aldrich) was added to a stirring solution of 1,1,1-trifluoro-2-isothiocyanatoethane (2.85 g, 20.20 mmol) in EtOH (80 mL). The reaction was stirred at RT for 2 h. The solvent was removed in vacuo to give N-(2,2,2-trifluoroethyl)hydrazinecarbothioamide, and the material was used without purification.
Reaction SMILES: N1C=CC=CC=1.[C:7]1([CH2:13][C:14]#[C:15][CH2:16]O)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.P(Br)(Br)[Br:19]>C1(C)C=CC=CC=1>[Br:19][CH2:16][C:15]#[C:14][CH2:13][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: BrP(Br)Br
Reactant: OCC#CCc1ccccc1
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: BrCC#CCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
14.5 ml of pyridine were added to a mixture of 140.4 g (0.96 mol) of 4-phenyl-2-butyn-1-ol (prepared according to G. Dupont, Bull. Soc. Chim. Fr., 1954, page 816) and 600 ml of dry toluene, after which 119.1 g (0.44 mol) of phosphorus tribromide were added dropwise in the course of 2 hours, the temperature not being allowed to exceed 50° C. The mixture was stirred overnight at room temperature and then poured onto 1,000 ml of ice water, the organic phase was separated off and the aqueous phase was extracted several times with methyl tert-butyl ether. The combined organic phases were then washed neutral and dried. The crude product obtained after the solvent had been stripped off under reduced pressure was subjected to fractional distillation. Yield: 126 g of product having a purity of 93% according to gas chromatography; bp.: 83°-85° C. at 0.3 mbar.
Reaction SMILES: [C:1]12([C:11](Cl)=[O:12])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[F:14][C:15]1[CH:21]=[CH:20][C:18]([NH2:19])=[CH:17][CH:16]=1.C(N(CC)CC)C>C(OCC)C>[F:14][C:15]1[CH:21]=[CH:20][C:18]([NH:19][C:11]([C:1]23[CH2:10][CH:5]4[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]4)[CH2:2]2)[CH2:8]3)=[O:12])=[CH:17][CH:16]=1
Reactant: O=C(Cl)C12CC3CC(CC(C3)C1)C2
Reactant: Nc1ccc(F)cc1
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: O=C(Nc1ccc(F)cc1)C12CC3CC(CC(C3)C1)C2

Procedure:
Subject 2.29 g. of adamantane carboxylic acid chloride (11.5 mmoles) 1.11 g. (10 mmoles) of p-fluoro-aniline and 4.0 ml. of triethylamine to the process of Example 11. Crystallize the residue obtained thereby from ethyl ether to yield the title product, m.p. 170°-171°C.