Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1)[C:7]2=[O:12].[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][C:28](O)=[O:29])=[CH:23][C:22]=1[C:31]([F:34])([F:33])[F:32].F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][C:28]([NH:1][C:2]2[CH:11]=[CH:10][CH:9]=[C:8]3[C:3]=2[CH:4]=[CH:5][N:6]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[C:7]3=[O:12])=[O:29])=[CH:23][C:22]=1[C:31]([F:32])([F:33])[F:34]
Reactant: Nc1cccc2c(=O)n(Cc3ccccn3)ccc12
Reactant: O=C(O)Cc1ccc(Cl)c(C(F)(F)F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(Cc1ccc(Cl)c(C(F)(F)F)c1)Nc1cccc2c(=O)n(Cc3ccccn3)ccc12
Temperature: 50 °C
Reaction time: 16 h
Yield: 71.1 %

Procedure:
To a solution of 5-amino-2-(pyridin-2-ylmethyl)isoquinolin-1(2H)-one (100.00 mg, 0.4 mmol) in N,N-dimethylformamide (0.7 mL, 0.009 mol) was added 2-(4-chloro-3-(trifluoromethyl)phenyl)acetic acid (190 mg, 0.000796 mol), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (303 mg, 0.000796 mol) and N,N-diisopropylethylamine (277 uL, 0.00159 mol). The reaction mixture was stirred for 16 hours at 50° C. Checked LC/MS, the reaction was completed. The DMF reaction solution was directly applied to prep. HPLC to obtain the pure product (134.2 mg). MS m/z=472.3 (M+1). 1H NMR (DMSO) δ 10.13 (s, 1 H), 8.48 (d, J=4.8 Hz, 1 H), 8.06 (d, J=7/9 Hz, 1 H), 7.90 (s, 1 H), 7.84 (d, J=7.1 Hz, 1 H), 7.76 (td, J=7.7, 1.8 Hz, 1 H), 7.75-7.68 (m, 2 H), 7.63 (d, J=7.7 Hz, 1 H), 7.47 (t, J=7.9 Hz, 1 H), 7.32-7.22 (m, 2 H), 6.73 (d, J=7.6 Hz, 1 H), 5.28 (s, 2 H), 3.93 (s, 2 H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH:6]=[O:7])#[N:2].[CH2:11](O)[CH2:12][OH:13]>O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC=CC=1>[O:7]1[CH2:11][CH2:12][O:13][CH:6]1[C:5]1[CH:4]=[C:3]([CH:10]=[CH:9][CH:8]=1)[C:1]#[N:2]
Reactant: N#Cc1cccc(C=O)c1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: N#Cc1cccc(C2OCCO2)c1
Yield: 100 %

Procedure:
A mixture of 3-cyanobenzaldehyde (9.81 g), ethylene glycol (9.31 g), p-toluenesulfonic acid monohydrate (0.07 g) and toluene (200 ml) was heated under reflux for 15 hrs., while removing generated water with a Dean-Stark trap. After cooling, the reaction mixture was concentrated, and the residue was diluted with ethyl acetate. This solution was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated to give 3-(1,3-dioxolan-2-yl)benzonitrile (13.1 g, yield 100%) as a colorless oil. NMR (CDCl3) δ: 4.01–4.17 (4H, m), 5.83 (1H, s), 4.50 (1H, t, J=7.6 Hz), 7.63–7.74 (2H, m), 7.80 (1H, t, J=1.6 Hz).
Reaction SMILES: [CH2:1]([C@:3]1([OH:28])[C:25]2[CH:24]=[C:23]3[N:10]([CH2:11][C:12]4[C:13]3=[N:14][C:15]3[CH:16]=[C:17]([F:22])[CH:18]=[CH:19][C:20]=3[CH:21]=4)[C:9](=[O:26])[C:8]=2[CH2:7][O:6][C:5](=[O:27])[CH2:4]1)[CH3:2].[CH:29](=O)[CH2:30]C>>[CH2:1]([C@:3]1([OH:28])[C:25]2[CH:24]=[C:23]3[N:10]([CH2:11][C:12]4[C:13]3=[N:14][C:15]3[CH:16]=[C:17]([F:22])[CH:18]=[CH:19][C:20]=3[C:21]=4[CH2:29][CH3:30])[C:9](=[O:26])[C:8]=2[CH2:7][O:6][C:5](=[O:27])[CH2:4]1)[CH3:2]
Reactant: CC[C@@]1(O)CC(=O)OCc2c1cc1n(c2=O)Cc2cc3ccc(F)cc3nc2-1
Reactant: CCC=O
Product: CCc1c2c(nc3cc(F)ccc13)-c1cc3c(c(=O)n1C2)COC(=O)C[C@]3(O)CC

Procedure:
The product of Example 2 is treated with propionaldehyde according to a procedure similar to Stage 13e in order to produce the expected solid.
Reaction SMILES: [C:1]([C:3]1[CH:15]=[C:14]2[C:6]([C:7]3[C:8](=[O:30])[C:9]4[CH:21]=[CH:20][C:19](OS(C(F)(F)F)(=O)=O)=[CH:18][C:10]=4[C:11]([CH3:17])([CH3:16])[C:12]=3[NH:13]2)=[CH:5][CH:4]=1)#[N:2].[SH:31][CH2:32][CH2:33][C:34]([OH:36])=[O:35]>>[C:1]([C:3]1[CH:15]=[C:14]2[C:6]([C:7]3[C:8](=[O:30])[C:9]4[CH:21]=[CH:20][C:19]([S:31][CH2:32][CH2:33][C:34]([OH:36])=[O:35])=[CH:18][C:10]=4[C:11]([CH3:17])([CH3:16])[C:12]=3[NH:13]2)=[CH:5][CH:4]=1)#[N:2]
Reactant: CC1(C)c2cc(OS(=O)(=O)C(F)(F)F)ccc2C(=O)c2c1[nH]c1cc(C#N)ccc21
Reactant: O=C(O)CCS
Product: CC1(C)c2cc(SCCC(=O)O)ccc2C(=O)c2c1[nH]c1cc(C#N)ccc21

Procedure:
Under the same conditions as the method for synthesizing Compound B2-17, the title compound was prepared from Compound B1 and 3-mercaptopropionic acid.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:36]=[CH:35][C:9]2[CH2:10][N:11]([C:17]3[CH:26]=[C:25]([NH:27]C(=O)OC(C)(C)C)[C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[N:18]=3)[CH2:12][CH2:13][S:14](=[O:16])(=[O:15])[C:8]=2[CH:7]=1.FC(F)(F)C(O)=O>ClCCl.O>[NH2:27][C:25]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:18]=[C:17]([N:11]2[CH2:10][C:9]3[CH:35]=[CH:36][C:6]([O:5][CH2:4][CH2:3][CH2:2][OH:1])=[CH:7][C:8]=3[S:14](=[O:15])(=[O:16])[CH2:13][CH2:12]2)[CH:26]=1
Reactant: CC(C)(C)OC(=O)Nc1cc(N2CCS(=O)(=O)c3cc(OCCCO)ccc3C2)nc2ccccc12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: O
Product: Nc1cc(N2CCS(=O)(=O)c3cc(OCCCO)ccc3C2)nc2ccccc12
Yield: 4.9 %

Procedure:
A mixture solution of tert-butyl {2-[8-(3-hydroxypropoxy)-1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl]quinolin-4-yl}carbamate (359.1 mg, the crude product of the above step) and trifluoroacetic acid (1.0 mL) in dichloromethane (2.0 mL) was stirred at room temperature for 6 hours. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (100 mL). The organic layer was washed with brine (50 mL×2), dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by preparative HPLC to afford 14.2 mg of the desired product as a white solid (yield was 4.9%). MS obsd. (ESI+) [(M+H)+] 414, 1HNMR ((400 MHz, CD3OD) δ ppm 7.82-7.67 (m, 2 H), 7.54-7.48 (m, 2 H), 7.48-7.39 (m, 1 H), 7.19-7.06 (m, 2 H), 6.30 (s, 1 H), 5.04 (s, 2 H), 4.78-4.34 (m, 2 H), 4.11 (t, J=6.32 Hz, 2 H), 3.71 (t, J=6.19 Hz, 2 H), 3.62-3.49 (m, 2 H), 2.11-1.78 (m, 2 H).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[C:9]2[CH2:16][CH2:15][CH2:14][C:13](=[O:17])[C:10]=2[S:11][CH:12]=1)(C)(C)C.[ClH:19].C(OCC)(=O)C>>[ClH:19].[NH2:7][C:8]1[C:9]2[CH2:16][CH2:15][CH2:14][C:13](=[O:17])[C:10]=2[S:11][CH:12]=1
Reactant: CC(C)(C)OC(=O)Nc1csc2c1CCCC2=O
Agent: Cl
Solvent: CCOC(C)=O
Product: Nc1csc2c1CCCC2=O

Procedure:
(7-Oxo-4,5,6,7-tetrahydro-benzo[b]thiophene-3-yl)-carbamic acid t-butyl ester (18.9 g) in 4N hydrochloric acid/ethyl acetate (200 mL) was stirred for 1 hour. The resulting solid was collected by filtration, washed with ethyl acetate to provide the title compound (13.9 g) as an off-white solid.
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH2:8]O)=[C:6]([Cl:10])[C:5]([Cl:11])=[CH:4][CH:3]=1.Cl.S(Cl)(Cl)=O.Cl.[CH2:18]([O:20][C:21](=[O:24])[CH2:22][NH2:23])[CH3:19].C(N(CC)CC)C>C(Cl)Cl.C1C=CC=CC=1>[CH2:18]([O:20][C:21](=[O:24])[CH2:22][NH:23][CH2:8][C:7]1[C:2]([NH2:1])=[CH:3][CH:4]=[C:5]([Cl:11])[C:6]=1[Cl:10])[CH3:19]
Reactant: CCOC(=O)CN
Reactant: Nc1ccc(Cl)c(Cl)c1CO
Agent: Cl
Solvent: ClCCl
Solvent: c1ccccc1
Solvent: O=S(Cl)Cl
Product: CCOC(=O)CNCc1c(N)ccc(Cl)c1Cl
Reaction time: 2.5 h

Procedure:
A solution of 6-amino-2,3-dichlorobenzyl alcohol (10.0 g., 0.0521 mol) in 250 ml. of boiling benzene was treated with a slow-stream of dry hydrogen chloride for 0.5 hour. The finely divided suspension was cooled slightly, thionyl chloride (12.4 g, 0.104 mol) was added in one portion, and reflux was continued for 2.5 hours. The solution was evaporated in vacuo to remove excess thionyl chloride and hydrogen chloride, and the residue was redissolved in 250 ml. benzene. This solution was added over 1 hour to a reluxing mixture of glycine ethyl ester hydrochloride (29.1 g, 0.208 mol) and triethylamine (31.6 g, 0.313 mol) in 600 ml. CH2Cl2. Reflux was continued for 1 hour, the mixture was allowed to stand overnight and was then extracted with 1N HCl. The extract was washed with CH2Cl2 and ether, made slightly alkaline with concentrated NH4OH and extracted with ether. After drying (K2CO3) and evaporation there remained 8.3 g (58%) of the title product as a light yellow oil which crystallized. The analytical sample was obtained from Skellysolve B as white needles, mp. 60°-61° C.
Reaction SMILES: [C:1]([NH:4][CH:5]1[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1)(=[O:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Cl[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1.O>CS(C)=O>[C:1]([NH:4][CH:5]1[CH2:10][CH2:9][N:8]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)[CH2:7][CH2:6]1)(=[O:3])[CH3:2]
Reactant: Clc1ccccn1
Reactant: CC(=O)NC1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CC(=O)NC1CCN(c2ccccn2)CC1

Procedure:
A mixture of 12.5 g of 4-acetamidopiperidine, 15 g of potassium carbonate, 10 g of 2-chloropyridine in 100 ml of dimethylsulfoxide, is heated with stirring for 50 hours to 130° C., then it is cooled, poured into water and the suspension thus obtained is extracted with diethyl ether. The aqueous phase is extracted with methylene chloride, the organic phase is washed with water, it is dried over anhydrous sodium sulfate and evaporated to dryness. Thus, 4-acetamido-1-(2-pyridyl) piperidine is obtained which, after crystallisation in isopropanol and recrystallisation in ethyl acetate, melts at 165° to 168° C. Yield: 4.7 g (24.5% of the theoretical).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:17])[CH3:16])=[C:11]([OH:18])[C:10]=1[CH2:19][CH2:20][CH3:21])[CH3:2].[S:23]([O:27][CH2:28][CH2:29][O:30][CH2:31][CH2:32]OS(=O)(=O)C)(=[O:26])(=[O:25])[CH3:24].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.CN(C)C=O>[CH2:1]([O:3][C:4](=[O:22])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:17])[CH3:16])=[C:11]([O:18][CH2:32][CH2:31][O:30][CH2:29][CH2:28][O:27][S:23]([CH3:24])(=[O:26])=[O:25])[C:10]=1[CH2:19][CH2:20][CH3:21])[CH3:2]
Reactant: CS(=O)(=O)OCCOCCOS(C)(=O)=O
Reactant: CCCc1c(OCCCC(=O)OCC)ccc(C(C)=O)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CN(C)C=O
Product: CCCc1c(OCCCC(=O)OCC)ccc(C(C)=O)c1OCCOCCOS(C)(=O)=O
Yield: 66.5 %

Procedure:
A mixture of 4 g (0.013 mol) of 4-(4-acetyl-3-hydroxy-2-propylphenoxy)butanoic acid ethyl ester, 17 g (0.065 mol) of diethylene glycol dimesylate and 3.6 g (0.026 mol) of anhydrous potassium carbonate in 80 ml of anhydrous acetone and 40 ml of anhydrous dimethylformamide was stirred at reflux for 20 hours. An additional 1.8 g of potassium carbonate was added and reflux was continued for a total of 44 hours. The reaction mixture was filtered and concentrated in vacuo to an orange oil which was treated with ethyl acetate and sodium chloride solution. The yellow oil obtained on concentration of the ethyl acetate was purified by HPLC, eluting with 15% ethyl acetate/toluene to yield 4.1 g (67% yield) of 4-[4-acetyl-3-[2-[2-[(methylsulfonyl)oxy]ethoxy]-ethoxy]-2-propylphenoxy]butanoic acid ethyl ester as a yellow oil.
Reaction SMILES: [CH3:1][C:2]([CH3:21])([CH3:20])[C:3]([C:5]1[O:6][C:7]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:8]=2[C:9]=1[CH2:10][C:11]([OH:13])=O)=[O:4].C1C=CC2N(O)N=NC=2C=1.[CH2:32]([C@H:35]1[CH2:39][CH2:38][C@@H:37]([CH2:40][CH2:41][CH3:42])[NH:36]1)[CH2:33][CH3:34].CCN(C(C)C)C(C)C>CN(C=O)C.C(Cl)CCl>[CH2:32]([C@H:35]1[CH2:39][CH2:38][C@@H:37]([CH2:40][CH2:41][CH3:42])[N:36]1[C:11](=[O:13])[CH2:10][C:9]1[C:8]2[CH:14]=[C:15]([O:18][CH3:19])[CH:16]=[CH:17][C:7]=2[O:6][C:5]=1[C:3](=[O:4])[C:2]([CH3:20])([CH3:1])[CH3:21])[CH2:33][CH3:34]
Reactant: COc1ccc2oc(C(=O)C(C)(C)C)c(CC(=O)O)c2c1
Reactant: CCC[C@@H]1CC[C@H](CCC)N1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCC[C@@H]1CC[C@H](CCC)N1C(=O)Cc1c(C(=O)C(C)(C)C)oc2ccc(OC)cc12
Temperature: 40 °C

Procedure:
Dissolve a mixture of 17 mg [2-(2,2-dimethylpropanoyl)-5-methoxy-1-benzofuran-3-yl]acetic acid from the Step B Example 1 and 18.5 mg HOBt in 1 mL dry DMF. Add 13.7 mg cis-2,5-dipropylpyrrolidine from the Step A above followed by 23.0 mg EDC and 35 μL DIEA. This solution was heated at 40° C. for 2 hours. It was purified directly on RP-HPLC using 70-100% MeCN gradient. The fractions containing pure product were pooled and lyophilized to give the title compound. LC-MS: 4.59 min. (m/Z=428.3, 344.2, 450.3).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:13]2[O:17][CH2:16][CH2:15][O:14]2)[CH:6]=[CH:7][C:8]=1[O:9][C:10](=[O:12])[CH3:11].COC1C=C(C=CC=1O)C=O.[F:29][C:30]1[C:31](=[O:37])[NH:32][C:33](=[O:36])[NH:34][CH:35]=1>ClCCl>[OH:14][CH2:15][CH2:16][O:17][CH:13]([N:34]1[CH:35]=[C:30]([F:29])[C:31](=[O:37])[NH:32][C:33]1=[O:36])[C:5]1[CH:6]=[CH:7][C:8]([O:9][C:10](=[O:12])[CH3:11])=[C:3]([O:2][CH3:1])[CH:4]=1
Reactant: O=c1[nH]cc(F)c(=O)[nH]1
Reactant: COc1cc(C2OCCO2)ccc1OC(C)=O
Agent: COc1cc(C=O)ccc1O
Solvent: ClCCl
Product: COc1cc(C(OCCO)n2cc(F)c(=O)[nH]c2=O)ccc1OC(C)=O
Yield: 34.6 %

Procedure:
To the solution of 2-(3-methoxy-4-acetoxyphenyl)-1,3-dioxolan (22 g) prepared from 3-methoxy-4-hydroxybenzaldehyde as in Example 12 in dichloromethane (50 ml) bis(trimethylsilyl)-5-fluorouracil prepared from 5-fluorouracil (10 g) was added followed by treating as in Example 10 to give 9.8 g of crystalline 1-[α-(2-hydroxyethoxy)-3-methoxy-4-acetoxybenzyl]-5-fluorouracil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[O:12]C(=O)[NH:10][CH:9]2[CH2:14][C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[C:17]([O:22][C:23]([F:28])([F:27])[CH:24]([F:26])[F:25])[CH:16]=2)=[CH:4][CH:3]=1.[OH-].[Na+]>C(O)C>[NH2:10][CH:9]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[C:17]([O:22][C:23]([F:28])([F:27])[CH:24]([F:26])[F:25])[CH:16]=1)[CH:8]([C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)[OH:12]
Reactant: Cc1ccc(CC2NC(=O)OC2c2ccc(F)cc2)cc1OC(F)(F)C(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1ccc(CC(N)C(O)c2ccc(F)cc2)cc1OC(F)(F)C(F)F
Yield: 89.1 %

Procedure:
To a solution of (4RS,5SR)-5-(4-fluorophenyl)-4-((4-methyl-3-((1,1,2,2-tetrafluoroethyl)oxy)phenyl)methyl)-1,3-oxazolidin-2-one (2.7 g, 6.73 mmol) in ethanol (10 ml) was added 8N aqueous sodium hydroxide solution (4.2 ml, 33.6 mmol), and the mixture was heated under reflux for 4 hrs. The reaction solution was concentrated, diluted with water (100 ml), and the mixture was extracted with ethyl acetate (100 ml×2). The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue-was recrystallized from ethyl acetate-hexane to give (1RS,2SR)-2-amino-1-(4-fluorophenyl)-3-(4-methyl-3-((1,1,2,2-tetrafluoroethyl)oxy)phenyl)-1-propanol (2.25 g, 89%).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[CH:8]([NH:12][S:13]([CH:16]([CH3:18])[CH3:17])(=[O:15])=[O:14])[CH2:7][CH2:6]2.[F:19][C:20]([F:32])([F:31])[C:21]1[C:25]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:24][NH:23][N:22]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:17][CH:16]([S:13]([NH:12][CH:8]1[C:9]2[C:5](=[CH:4][C:3]([CH2:2][N:23]3[CH:24]=[C:25]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[C:21]([C:20]([F:19])([F:31])[F:32])=[N:22]3)=[CH:11][CH:10]=2)[CH2:6][CH2:7]1)(=[O:15])=[O:14])[CH3:18]
Reactant: CC(C)S(=O)(=O)NC1CCc2cc(CCl)ccc21
Reactant: CCOC(=O)c1c[nH]nc1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(Cc2ccc3c(c2)CCC3NS(=O)(=O)C(C)C)nc1C(F)(F)F
Yield: 52.4 %

Procedure:
To N-(5-(chloromethyl)-2,3-dihydro-1H-inden-1-yl)propane-2-sulfonamide (0.250 mmol, 72 mg) in DMF (4 mL) was added ethyl 3-(trifluoromethyl)-1H-pyrazole-4-carboxylate (0.250 mmol, 52.1 mg) and Potassium carbonate (0.750 mmol, 104 mg). The resultant solution was heated to 60° C. with stirring. After 1.5 h the reaction mixture was concentrated to remove DMF before partitioning between EtOAc/H2O and the phases mixed and separated. The organic layer was washed with water (×4) and brine before drying and concentration to a yellow oil. Purification on 10 g Si eluting with 1% MeOH/DCM gave the desired compound as an off-white solid (60 mg, 0.131 mmol, 52.2%). 1H NMR (400 MHz, CDCl3) δ 1.33 (t, 3H) 1.44 (d, 6H) 1.95 (m, 1H) 2.65 (m, 1H) 2.85 (m, 1H) 3.00 (m, 1H) 3.25 (m, 1H) 4.15 (d, 1H) 4.29 (q, 2H) 4.95 (m, 1H) 5.30 (s, 2H) 7.14 (s, 1H) 7.18 (d, 1H) 7.48 (d, 1H) 7.88 (s, 1H).
Reaction SMILES: [ClH:1].Cl.[Cl:3][C:4]1[CH:43]=[CH:42][C:7]2[NH:8][CH2:9][CH2:10][CH2:11][CH:12]([O:13][C:14]([CH:16]([N:36]3[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]3)[C:17](=[O:35])[C:18]3[CH:23]=[CH:22][C:21]([NH:24][C:25](=[O:33])[C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=4[CH3:32])=[CH:20][C:19]=3[CH3:34])=[O:15])[C:6]=2[CH:5]=1.C=O.[C:46]([O-])(=O)C.[Na+].[B-]C#N.[Na+].[OH-].[Na+]>O.CO>[ClH:3].[ClH:1].[Cl:3][C:4]1[CH:43]=[CH:42][C:7]2[NH:8][CH2:9][CH2:10][CH2:11][CH:12]([O:13][C:14]([CH:16]([N:36]3[CH2:37][CH2:38][N:39]([CH3:46])[CH2:40][CH2:41]3)[C:17](=[O:35])[C:18]3[CH:23]=[CH:22][C:21]([NH:24][C:25](=[O:33])[C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=4[CH3:32])=[CH:20][C:19]=3[CH3:34])=[O:15])[C:6]=2[CH:5]=1
Reactant: CC(=O)[O-]
Reactant: Cc1ccccc1C(=O)Nc1ccc(C(=O)C(C(=O)OC2CCCNc3ccc(Cl)cc32)N2CCNCC2)c(C)c1
Agent: C=O
Agent: Cl
Agent: [B-]C#N
Solvent: CO
Solvent: O
Product: Cc1ccccc1C(=O)Nc1ccc(C(=O)C(C(=O)OC2CCCNc3ccc(Cl)cc32)N2CCN(C)CC2)c(C)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 116.9 %

Procedure:
1-{7-Chloro-1-[2-methyl-4-(2-methyl-benzoylamino)-benzoyl]-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yloxycarbonylmethyl}-piperazine dihydrochloride (400 mg, 0.62 mmol), formalin (0.15 ml, 1.9 mmol), sodium acetate (61 mg, 0.74 mmol), and sodium cyanotrihydroborate (119 mg, 1.9 mmol) were added to methanol (5 ml), and the mixture was stirred at room temperature for 1 hour. Water and aqueous sodium hydroxide solution were added to the reaction mixture, and the precipitates were collected by filtration, washed with water, and then dried. The obtained solid was dissolved in ethyl acetate, and a 4N hydrogen chloride ethyl acetate solution (0.5 ml) was added thereto. The precipitates were then collected by filtration, washed with ethyl acetate and dried to obtain 240 mg of 1-{7-chloro-1-[2-methyl-4-(2-methyl-benzoylamino)-benzoyl]-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yloxycarbonylmethyl}-4-methyl-piperazine dihydrochloride as white powder.
Reaction SMILES: C(OC([NH:8][C@H:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]1[NH:15][C:16]1[CH:25]=[C:24]([C:26]#[N:27])[C:19]([C:20]([O:22][CH3:23])=[O:21])=[C:18]([NH:28][C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([S:35]([CH3:38])(=[O:37])=[O:36])[CH:30]=2)[N:17]=1)=O)(C)(C)C.Cl>CC(O)=O>[NH2:8][C@H:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]1[NH:15][C:16]1[CH:25]=[C:24]([C:26]#[N:27])[C:19]([C:20]([O:22][CH3:23])=[O:21])=[C:18]([NH:28][C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([S:35]([CH3:38])(=[O:37])=[O:36])[CH:30]=2)[N:17]=1
Reactant: COC(=O)c1c(C#N)cc(N[C@@H]2CCCC[C@@H]2NC(=O)OC(C)(C)C)nc1Nc1cccc(S(C)(=O)=O)c1
Agent: Cl
Solvent: CC(=O)O
Product: COC(=O)c1c(C#N)cc(N[C@@H]2CCCC[C@@H]2N)nc1Nc1cccc(S(C)(=O)=O)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 84.7 %

Procedure:
To a solution of methyl 6-((1R,2S)-2-(tert-butoxycarbonylamino)cyclohexylamino)-4-cyano-2-(3-(methylsulfonyl)phenylamino)nicotinate (178.3 mg, 0.328 mmol) in HOAc (4 mL) was added HCl (4 mL, 132 mmol). The mixture was stirred at RT for 4 h and then concentrated under reduced pressure. Water (15 mL) and 1M HCl (15 mL) were added to the concentrate and the aqueous layer was washed with EtOAc (10 mL). The washed aqueous layer was basified with saturated aqueous NaHCO3 (50 mL) and extracted with EtOAc (2×30 mL). The organic layers were combined, washed with saturated aq NaHCO3 (20 mL), water (20 mL) and brine (20 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure to give the title compound as a brown solid (123.2 mg, 85%). 1H-NMR (CDCl3) δ ppm 1.45-16.4 (m, 6H), 1.77-1.79 (m, 4H), 3.06 (s, 3H), 3.17-3.18 (m, 1H), 3.94 (s, 3H), 4.10-4.14 (m, 1H), 6.03-6.05 (m, 1H), 6.29 (s, 1H), 7.48-7.51 (m, 1H), 7.58-7.60 (m, 1H), 7.71-7.72 (m, 1H), 8.53 (s, 1H), 11.01 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[Cl-].[Al+3].[Cl-].[Cl-].[CH2:15]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:16][CH2:17][CH3:18]>C(=S)=S>[CH2:15]([C:19]1[CH:24]=[CH:23][C:22]([C:4]([C:3]2[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=2[F:1])=[O:5])=[CH:21][CH:20]=1)[CH2:16][CH2:17][CH3:18]
Reactant: CCCCc1ccccc1
Reactant: O=C(Cl)c1ccccc1F
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: CCCCc1ccc(C(=O)c2ccccc2F)cc1
Reaction time: 18 h
Yield: 62.4 %

Procedure:
A 3.16 g (0.02 mole) of 2-fluoro benzoic acid chloride was dissolved in 30 ml of carbon disulfide and then, 4.0 g (0.03 mole) of anhydrous aluminum chloride was added to the solution. A 2.68 g (0.02 mole) of n-butyl benzene was further added to the mixture with stirring, and the reaction was carried out at room temperature for 18 hours. In accordance with the process of Example 1, the reaction mixture was treated to obtain 3.2 g of 4-n-butyl-2'-fluorobenzophenone having a boiling point of 180° to 190° C./5 mmHg. (yield of 62.5%).
Reaction SMILES: [CH2:1]([O:11][C:12]1[CH:20]=[CH:19][C:15]([C:16]([OH:18])=O)=[CH:14][CH:13]=1)/[CH:2]=[C:3](/[CH2:5][CH2:6][CH:7]=[C:8]([CH3:10])[CH3:9])\[CH3:4].[NH2:21][CH2:22][CH:23]1[CH2:27][CH2:26][CH2:25][N:24]1[CH2:28][CH3:29]>>[CH2:28]([N:24]1[CH2:25][CH2:26][CH2:27][CH:23]1[CH2:22][NH:21][C:16](=[O:18])[C:15]1[CH:14]=[CH:13][C:12]([O:11][CH2:1]/[CH:2]=[C:3](/[CH2:5][CH2:6][CH:7]=[C:8]([CH3:9])[CH3:10])\[CH3:4])=[CH:20][CH:19]=1)[CH3:29]
Reactant: CC(C)=CCC/C(C)=C/COc1ccc(C(=O)O)cc1
Reactant: CCN1CCCC1CN
Product: CCN1CCCC1CNC(=O)c1ccc(OC/C=C(\C)CCC=C(C)C)cc1
Yield: 98 %

Procedure:
In a manner identical to Example 15, 4-geranyloxybenzoic acid(1.45 g) was subjected to a condensation reaction with 2-aminomethyl-1-ethylpyrrolidine (0.7 ml), thereby yielding 1.96 g(98%) of the aimed compound.
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=O)=[CH:8][CH:7]=1)(=[O:4])=[O:3].Cl.[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]([CH:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)=[O:24])=[CH:19][CH:18]=1>>[Cl:16][C:17]1[CH:18]=[CH:19][C:20]([C:23]([CH:25]2[CH2:30][CH2:29][N:28]([C:10]([C:9]3[CH:8]=[CH:7][C:6]([NH:5][S:2]([CH3:1])(=[O:3])=[O:4])=[CH:14][CH:13]=3)=[O:12])[CH2:27][CH2:26]2)=[O:24])=[CH:21][CH:22]=1
Reactant: CS(=O)(=O)Nc1ccc(C(=O)O)cc1
Reactant: O=C(c1ccc(Cl)cc1)C1CCNCC1
Agent: Cl
Product: CS(=O)(=O)Nc1ccc(C(=O)N2CCC(C(=O)c3ccc(Cl)cc3)CC2)cc1
Yield: 53.9 %

Procedure:
Using 4-methanesulfonylaminobenzoic acid (800 mg) and (4-chlorophenyl)(piperidin-4-yl)methanone hydrochloride (967 mg) and by the reaction and treatment in the same manner as in Example 86, the title compound (843 mg) was obtained.