Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([CH2:13][NH:14][C:15]3[CH:16]=[C:17]([C:20]([OH:22])=O)[NH:18][N:19]=3)=[C:11]([CH3:23])[O:10][N:9]=2)=[CH:4][CH:3]=1.O.ON1C2C=CC=CC=2N=N1.C(N(C(C)C)C(C)C)C.[OH:44][C:45]([CH3:49])([CH3:48])[CH2:46][NH2:47].[Cl-].[Na+]>CN(C=O)C>[OH:44][C:45]([CH3:49])([CH3:48])[CH2:46][NH:47][C:20]([C:17]1[NH:18][N:19]=[C:15]([NH:14][CH2:13][C:12]2[C:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)=[N:9][O:10][C:11]=2[CH3:23])[CH:16]=1)=[O:22]
Reactant: Cc1onc(-c2ccc(F)cc2)c1CNc1cc(C(=O)O)[nH]n1
Reactant: CC(C)(O)CN
Agent: On1nnc2ccccc21
Agent: [Cl-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: Cc1onc(-c2ccc(F)cc2)c1CNc1cc(C(=O)NCC(C)(C)O)[nH]n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 18.3 %

Procedure:
To a solution of 5-{[3-(4-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethyl]-amino}-2H-pyrazole-3-carboxylic acid (0.212 mmol) in DMF (5 mL) was added 1-hydroxybenzotriazole hydrate (0.318 mmol), N-ethyldiisopropylamine (0.848 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimidazole hydrochloride (0.318 mmol) and 2-hydroxy-2-methylpropylamine (0.318 mmol) and the resulting mixture stirred overnight at room temperature. The reaction mixture was then poured into aqueous sodium chloride (saturated) and the mixture was extracted with ethyl acetate. The combined organic layers were then washed with water and saturated sodium hydrogen carbonate solution and then dried over sodium sulfate, filtered and evaporated. Concentration and purification by preparative HPLC afforded the title compound (15 mg, 29%) as an off white solid. MS: m/e=388.4 [M+H]+.
Reaction SMILES: [Cl:1]Cl.[Cl:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N+]([O-])=O)[C:5]=1[Cl:13].[OH-].[Na+]>>[Cl:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([Cl:1])[C:5]=1[Cl:13]
Reactant: ClCl
Reactant: O=[N+]([O-])c1cccc(Cl)c1Cl
Agent: [Na+]
Agent: [OH-]
Product: Clc1cccc(Cl)c1Cl
Temperature: 170 °C
Yield: 0.8 %

Procedure:
Chlorine gas (400 mg, 573 millimoles) was bubbled into a solution of benzenephosphorusdichloride (789 microliters, 573 millimoles) in BPOD (10 ml) at room temperature. The initially clear colorless solution became warm and turned pale yellow, but remained clear. To this mixture was added 1,2-dichloro-3-nitrobenzene (1.0 g, 573 millimoles) and then the reaction mixture was heated to 170° C. for 5 hours. The cooled reaction mixture was then poured onto crushed ice/water (100 ml) and neutralized with 50% aqueous sodium hydroxide. After extracting with ether, the ether extracts were dried and concentrated in vacuo to yield 1,2,3-trichlorobenzene (880 mg, 94 weight %).
Reaction SMILES: C[O-].[Na+].N#N.[C:6]([O:9][CH3:10])(=[O:8])[CH3:7].[CH:11]([C:13]1[CH:21]=[CH:20][CH:19]=[C:18]2[C:14]=1[CH:15]=[CH:16][NH:17]2)=O>O1CCCC1>[NH:17]1[C:18]2[C:14](=[C:13]([CH:11]=[CH:7][C:6]([O:9][CH3:10])=[O:8])[CH:21]=[CH:20][CH:19]=2)[CH:15]=[CH:16]1
Reactant: O=Cc1cccc2[nH]ccc12
Reactant: COC(C)=O
Agent: C[O-]
Agent: N#N
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)C=Cc1cccc2[nH]ccc12
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
48 g of sodium methoxide are added to 300 ml of tetrahydrofuran with stirring at 5° C. under a protective gas (N2), the suspension is cooled to 0° C., 70 ml of methyl acetate are added dropwise at from 0 to 3° C., and the mixture is stirred at this temperature for a further 45 minutes. A solution of 43 g of 4-formylindole (3) in 300 ml of tetrahydrofuran is subsequently added with stirring, during which the temperature does not exceed 3° C. The mixture is subsequently stirred at room temperature for a further two hours. For work-up, the reaction mixture is evaporated, and the residue is dissolved in methyl acetate and extracted with water. The organic phase obtained is dried, the solvent is removed under reduced pressure, and the residue is purified by chromatography on silica gel, giving 35 g (59% of theory) of a pale-beige crystalline residue of methyl 3-(1H-indol-4-yl)acrylate (4).
Reaction SMILES: C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[C:20]1(=[O:30])[NH:24][C:23](=[O:25])[C:22]2=[CH:26][CH:27]=[CH:28][CH:29]=[C:21]12.[C:31]([NH:39][C:40]1[C:41]2[N:42]=[CH:43][N:44]([C:53]=2[N:54]=[CH:55][N:56]=1)[C@@H:45]1[O:52][C@H:49]([CH2:50]O)[C@@H:47]([OH:48])[CH2:46]1)(=[O:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1.ClCCl>[C:20]1(=[O:30])[N:24]([CH2:50][C@H:49]2[O:52][C@@H:45]([N:44]3[C:53]4[N:54]=[CH:55][N:56]=[C:40]([NH:39][C:31](=[O:38])[C:32]5[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=5)[C:41]=4[N:42]=[CH:43]3)[CH2:46][C@@H:47]2[OH:48])[C:23](=[O:25])[C:22]2=[CH:26][CH:27]=[CH:28][CH:29]=[C:21]12
Reactant: O=C1NC(=O)c2ccccc21
Reactant: O=C(Nc1ncnc2c1ncn2[C@H]1C[C@H](O)[C@@H](CO)O1)c1ccccc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: ClCCl
Product: O=C(Nc1ncnc2c1ncn2[C@H]1C[C@H](O)[C@@H](CN2C(=O)c3ccccc3C2=O)O1)c1ccccc1
Reaction time: 2 h
Yield: 30.9 %

Procedure:
To a stirred solution of 13.11 g (50 mmol) Ph3P, 6.99 g (47.5 mmol) phthalimide and 17.77 g (50 mmol) N6-benzoyl-2′-deoxyadenosine in 400 mL dry THF was added 9.84 mL (50 mmol) of diisopropyl azodicarboxylate under a nitrogen atmosphere. The resulting mixture was stirred for 2 h in an ice water bath and then 4 h at room temperature. After most of the THF was evaporated under reduced pressure, the oily residue was added 100 ml of dichloromethane. The precipitate, which was formed after the addition of dichloromethane, was filtered and washed with small amounts of THF/dichloromethane mixture (1:1). The filtrate was concentrated and purified with a silica gel column chromatography (dichloromethane/THF=2:1 then dichloromethane/methanol=19:1) to give 7.1 g of compound 2.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[C:15]([O-])([O-])=O.[K+].[K+].IC>CC(C)=O>[CH3:15][O:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:9][CH2:10][C:11](=[O:14])[CH2:12][CH2:13]2)=[CH:6][CH:7]=1
Reactant: O=C1CCC(c2ccc(O)cc2)CC1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: COc1ccc(C2CCC(=O)CC2)cc1
Temperature: 65 °C
Yield: 99.4 %

Procedure:
A solution of 4-(4-hydroxyphenyl)cyclohexanone (5.0 g, 26.3 mmol) in acetone (100 mL) was treated with K2CO3 (14.5 g, 105 mmol, 4 equiv) and iodomethane (4.9 mL, 11.2 g, 78.6 mmol, 3 equiv.). The reaction was heated at 65° C. overnight. After the solvent was removed, the residue was treated with H2O and extracted with EtOAc. The organic extracts were combined and washed with brine, dried over Na2SO4 and concentrated in vacuum to give the spectroscopically pure 4-(4-methoxyphenyl)-cyclohexanone (5.34 g, 100%). 1H NMR(CDCl3) 7.16 (dt, 2H), 6.87 (dt, 2H), 3.78 (s, 3H), 2.99 (tt, 1H), 2.47-2.53 (m, 4H), 2.20 (m, 2H) and 1.83-1.98 (m, 2H); MS (electrospray) m/e, 205 (M+1)+, Calcd for C13H16O2, 204. Step 2:
Reaction SMILES: C([O:3][C:4](=[O:32])[CH2:5][S:6][C:7]1[S:11][C:10]([NH:12][C:13]([N:15]([C:23]2[CH:31]=[CH:30][C:26]3[O:27][CH2:28][O:29][C:25]=3[CH:24]=2)CC2CCCCC2)=[O:14])=[N:9][CH:8]=1)C.C1(CN([C:52]2[CH:57]=[CH:56][C:55](S(C)(=O)=O)=[CH:54][CH:53]=2)C(=O)NC2SC=C(CC(O)=O)N=2)CCCC1.O1C2C=CC(NCC3CCCCC3)=CC=2O[CH2:63]1.C(OC(=O)CSC1SC(N)=NC=1)C>>[O:27]1[C:26]2[CH:30]=[CH:31][C:23]([N:15]([CH:52]3[CH2:57][CH2:56][CH2:55][CH2:54][CH2:53]3)[C:13](=[O:14])[N:12]([CH3:63])[C:10]3[S:11][C:7]([S:6][CH2:5][C:4]([OH:3])=[O:32])=[CH:8][N:9]=3)=[CH:24][C:25]=2[O:29][CH2:28]1
Reactant: CS(=O)(=O)c1ccc(N(CC2CCCC2)C(=O)Nc2nc(CC(=O)O)cs2)cc1
Reactant: c1cc2c(cc1NCC1CCCCC1)OCO2
Reactant: CCOC(=O)CSc1cnc(NC(=O)N(CC2CCCCC2)c2ccc3c(c2)OCO3)s1
Agent: CCOC(=O)CSc1cnc(N)s1
Product: CN(C(=O)N(c1ccc2c(c1)OCO2)C1CCCCC1)c1ncc(SCC(=O)O)s1

Procedure:
The title compound was prepared via [2-(3-benzo[1,3]dioxol-5-yl-3-cyclohexylmethyl-ureido)-thiazol-5-ylsulfanyl]-acetic acid ethyl ester in a similar manner as described for the synthesis of {2-[3-cyclopentylmethyl-3-(4-methanesulfonyl-phenyl)-ureido]-thiazol-4-yl}-acetic acid, using benzo[1,3]dioxol-5-yl-cyclohexylmethyl-amine and (2-amino-thiazol-5-ylsulfanyl)acetic acid ethyl ester
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])=[N:10][C:9]=2[C:17]2[C:18]([F:33])=[C:19]([NH:23][S:24]([C:27]3[CH:31]=[CH:30][N:29]([CH3:32])[CH:28]=3)(=[O:26])=[O:25])[CH:20]=[CH:21][CH:22]=2)[CH:5]=[CH:4][N:3]=1.[OH-].[NH4+:35]>>[ClH:1].[NH2:35][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])=[N:10][C:9]=2[C:17]2[C:18]([F:33])=[C:19]([NH:23][S:24]([C:27]3[CH:31]=[CH:30][N:29]([CH3:32])[CH:28]=3)(=[O:26])=[O:25])[CH:20]=[CH:21][CH:22]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Cn1ccc(S(=O)(=O)Nc2cccc(-c3nc(C(C)(C)C)sc3-c3ccnc(Cl)n3)c2F)c1
Reactant: [NH4+]
Agent: [OH-]
Product: Cl
Product: Cn1ccc(S(=O)(=O)Nc2cccc(-c3nc(C(C)(C)C)sc3-c3ccnc(N)n3)c2F)c1

Procedure:
Following a procedure analogous to the procedure described in Example 282 using N-{3-[5-(2-chloro-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-1-methyl-1H-pyrrole-3-sulfonamide (230 mg, 0.45 mmol) and ammonium hydroxide (5 ml), the title compound was obtained as a white solid (130 mg, 54.8%). 1HNMR (DMSO-d6): δ ppm 9.80 (s, 1H), 8.13-8.15 (d, J=5.6 Hz, 1H), 7.87 (brs, 2H), 7.47-7.51 (dd, J1=7.6 Hz, J2=2.0 Hz, 1H), 7.23-7.29 (m, 3H), 6.80-6.82 (t, J=2.4 Hz, 1H), 6.23-6.24 (dd, J1=2.0H, J2=2.8 Hz, 1H), 6.13-6.14 (d, J=6.0 Hz, 1H), 3.61 (s, 3H), 1.42 (s, 9H); MS: 487.1 [M+H]+.
Reaction SMILES: [P:1](=[O:5])([OH:4])([OH:3])[OH:2].[Nb:6]>O>[P:1]([O-:5])([O-:4])([O-:3])=[O:2].[Nb+5:6].[P:1]([O-:5])([O-:4])([O-:3])=[O:2].[P:1]([O-:5])([O-:4])([O-:3])=[O:2].[P:1]([O-:5])([O-:4])([O-:3])=[O:2].[P:1]([O-:5])([O-:4])([O-:3])=[O:2].[Nb+5:6].[Nb+5:6]
Reactant: O=P(O)(O)O
Reactant: [Nb]
Solvent: O
Product: O=P([O-])([O-])[O-]
Product: [Nb+5]

Procedure:
Phosphoric acid (11.82 g; 85 wt. %) is diluted to 30 ml total volume with water. The aqueous phosphoric acid solution is poured over niobic acid (10.0 g; Niobium Products Corp., CBMM number AD222), and the mixture is stirred and dried according to the general procedure of Examples 4(a-d) to yield a niobium phosphate having a P/Nb mole ratio of 1.41.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[C:5](=[C:10]([OH:14])[CH:11]=[CH:12][CH:13]=1)[C:6]([O:8][CH3:9])=[O:7].C(=O)([O-])[O-].[K+].[K+].Br[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([O:30][CH3:31])[CH:25]=1>CC(C)=O>[CH3:1][O:2][C:3](=[O:15])[C:4]1[C:5](=[C:10]([O:14][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([O:30][CH3:31])[CH:25]=2)[CH:11]=[CH:12][CH:13]=1)[C:6]([O:8][CH3:9])=[O:7]
Reactant: COc1cccc(CBr)c1
Reactant: COC(=O)c1cccc(O)c1C(=O)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)c1cccc(OCc2cccc(OC)c2)c1C(=O)OC
Yield: 122.3 %

Procedure:
To a stirred suspension of 3-hydroxyphthalic acid dimethyl ester (1 g, 5.2 mmol) in acetone (45 mL) and potassium carbonate (2.2 g, 15.7 mmol) was added 1-bromomethyl-3-methoxy-benzene (0.77 mL, 5.5 mmol) and refluxed for three hours. The solvent was evaporated and the residue was partitioned between water (50 mL) and ethyl acetate (80 mL) and washed with water (2×50 mL). The combined organic phases was dried, concentrated and purified by flash column chromatography (EtOAc/Hexane) to give 3-(3-methoxy-benzyloxy)-phthalic acid dimethyl ester (2.1 g, 118% crude yield). The product was used in the next step without further purification.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([N:17]=[C:18]=[O:19])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:20][NH:21][CH3:22].O.Cl>C1COCC1>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([NH:17][C:18]([N:21]([CH3:22])[CH3:20])=[O:19])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CNC
Reactant: O=C=NC1CCN(C(=O)OCc2ccccc2)CC1
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: CN(C)C(=O)NC1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 97.2 %

Procedure:
To 0.83 g (3.2 mmol) of (1-benzyloxycarbonylpiperidin-4-yl)isocyanate from Procedure 1, Step A in 10 mL was added 16 mL (32 mmol) of 2 M dimethylamine in THF. The reaction was stirred under nitrogen at rt for 24 h and then poured into water containing 20 mL of 2 N hydrochloric acid and was extracted twice with ethyl acetate. The organic layers were each washed with a portion of brine, dried over sodium sulfate, combined and concentrated to give 0.95 g of the crude title compound which can be used directly in subsequent reactions.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:24])[CH2:22]Cl)=[CH:16][CH:15]=1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O.O>[Cl:13][C:14]1[CH:15]=[CH:16][C:17]([NH:20][C:21](=[O:24])[CH2:22][N:10]2[CH2:9][CH2:8][N:7]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=3)[CH2:12][CH2:11]2)=[CH:18][CH:19]=1
Reactant: c1ccc(N2CCNCC2)nc1
Reactant: O=C(CCl)Nc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(CN1CCN(c2ccccn2)CC1)Nc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 84.6 %

Procedure:
A mixture of 1-pyridin-2-ylpiperazine (24 mg, 0.15 mmol, Aldrich), N-(4-chlorophenyl)-2-chloroacetamide (41 mg, 0.20 mmol, Maybridge) and sodium carbonate (50 mg) in N,N-dimethylformamide/water (2:1, 2 mL) was shaken at room temperature for 18 hours. The resulting mixture was decanted, concentrated under reduced pressure and the residue purified by preparative HPLC to provide 42 mg (85%) of the desired product. 1H NMR (500 MHz, DMSO-d6) δ b2.60 (t, J=4 Hz, 4H), 3.21 (s, 2H), 3.58 (t, J=4 Hz, 4H), 6.63 (t, J=5 Hz, 1H), 6.83 (d, J=6 Hz, 1H), 7.38 (d, J=6 Hz, 2H), 7.54 (t, J=6 Hz, 1H), 7.70 (d, J=6 Hz, 2H), 8.12 (d, J=5 Hz, 1H), 9.90 (s, 1H); MS (ESI/APCI+) m/e 331 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[C:16]2[CH2:15][CH2:14][N:13]([C@H:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH3:18])[C@@H:12]([CH2:25][NH2:26])[C:11]=2[S:10][C:9]=1[NH2:27])=[O:7])([CH3:4])([CH3:3])[CH3:2].[O:28]([C:35]1[CH:40]=[CH:39][C:38]([N:41]=[C:42]=[O:43])=[CH:37][CH:36]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>ClCCl>[C:1]([O:5][C:6]([C:8]1[C:16]2[CH2:15][CH2:14][N:13]([C@H:17]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH3:18])[C@@H:12]([CH2:25][NH:26][C:42]([NH:41][C:38]3[CH:39]=[CH:40][C:35]([O:28][C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=4)=[CH:36][CH:37]=3)=[O:43])[C:11]=2[S:10][C:9]=1[NH2:27])=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: C[C@@H](c1ccccc1)N1CCc2c(sc(N)c2C(=O)OC(C)(C)C)[C@@H]1CN
Reactant: O=C=Nc1ccc(Oc2ccccc2)cc1
Solvent: ClCCl
Product: C[C@@H](c1ccccc1)N1CCc2c(sc(N)c2C(=O)OC(C)(C)C)[C@@H]1CNC(=O)Nc1ccc(Oc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 99.9 %

Procedure:
A solution of 2-amino-7-(S)-aminomethyl-6-(1-(S)-phenyl-ethyl)-4,5,6,7-tetrahydrothieno-[2,3-c]pyridine-3-carboxylic acid tert-butyl ester (250 mg, 0.645 mmol) in dichloromethane (10 ml) was added 4-phenoxyphenyl isocyanate (136 mg, 0.645 mmol) and the reaction mixture was stirred 16 hours at room temperature, before the solvent was removed in vacuo which afforded 386 mg (100%) of 2-amino-7-(S)-(3-(4-phenoxy-phenyl)-ureidomethyl)-6-(1-(S)-phenyl-ethyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid tert-butyl ester as an oil.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)[C:11]([O:13]CC)=[O:12])=[CH:6][CH:5]=1.[CH3:23]I>CN(C=O)C.CCOC(C)=O>[Cl:22][C:19]1[CH:18]=[CH:17][C:16]([C:10]([C:7]2[CH:8]=[CH:9][C:4]([Cl:3])=[CH:5][CH:6]=2)([CH3:23])[C:11]([OH:13])=[O:12])=[CH:21][CH:20]=1
Reactant: CCOC(=O)C(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C(=O)O)(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 57.4 %

Procedure:
A solution of NaH (60% dispersion in mineral oil) (2.1 g, 53 mmol) in DMF (100 mL) in a 500 mL round bottom flask was cooled 0° C. A solution of ethyl 2,2-bis(4-chlorophenyl)acetate (5.47 g, 18 mmol) and MeI (3.3 mL, 53 mmol) in DMF (50 mL) was added dropwise over 15 minutes. The mixture was stirred at 0° C. for 15 minutes and then allowed to warm to room temperature and stirred for 20 hours. A mixture of products was observed by LC/MS. The solution was diluted with EtOAc (200 mL), and then washed with 10% HCl(aq) (200 mL), with deionized water (200 mL), and then with brine (100 mL). The organic layer was dried over MgSO4, concentrated, and dried in vacuo to give 10.11 g crude product which was purified by flash column chromatography (silica, 0-100%, hexane/EtOAc) to give 2,2-bis(4-chlorophenyl)propanoic acid (3.05 g).
Reaction SMILES: [O:1]=[C:2]([C:9]1[S:10][CH:11]=[CH:12][CH:13]=1)[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].N1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1.[C:20](O)(=O)[CH3:21]>C1C=CC=CC=1>[C:20]1([CH:21]=[C:3]([C:2]([C:9]2[S:10][CH:11]=[CH:12][CH:13]=2)=[O:1])[C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: C1CCNCC1
Reactant: CC(=O)O
Reactant: CCOC(=O)CC(=O)c1cccs1
Solvent: c1ccccc1
Product: CCOC(=O)C(=Cc1ccccc1)C(=O)c1cccs1
Yield: 938.5 %

Procedure:
A solution of ethyl 3-oxo-3-(thiophen-2-yl)propanoate (4.10 g, 20.7 mmol), benaldehyde (2.32 ml, 22.8 mmol), piperidine (0.205 ml, 2.07 mmol) and acetic acid (0.593 ml, 10.4 mmol) in benzene (80 ml) was heated at 85° C. for 5 hours using a Dean-Stark trap for removal of the water formed. The reaction solution was concentrated. The resulting residue was purified via flash chromatography (silica gel cartridge with eluent of 0-5% ethyl acetate/hexane) to give ethyl 3-phenyl-2-(thiophene-2-carbonyl)acrylate as a white solid (5.563 g, 94% yield). LCMS m/z 309.1 (M+23); HPLC: Rt 3.15 min.
Reaction SMILES: [CH:1]1([N:6]2[CH2:11][CH2:10][N:9]([C:12]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[NH:19][C:18]([C:23](O)=[O:24])=[CH:17]4)=[O:13])[CH2:8][CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[CH:49]([CH:52]1[CH2:56][CH2:55][CH2:54][NH:53]1)([CH3:51])[CH3:50].C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH:1]1([N:6]2[CH2:7][CH2:8][N:9]([C:12]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[NH:19][C:18]([C:23]([N:53]3[CH2:54][CH2:55][CH2:56][CH:52]3[CH:49]([CH3:51])[CH3:50])=[O:24])=[CH:17]4)=[O:13])[CH2:10][CH2:11]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)C1CCCN1
Reactant: O=C(O)c1cc2cc(C(=O)N3CCN(C4CCCC4)CC3)ccc2[nH]1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)C1CCCN1C(=O)c1cc2cc(C(=O)N3CCN(C4CCCC4)CC3)ccc2[nH]1

Procedure:
The title compound was synthesized in analogy to example 1, from 5-(4-cyclopentyl-piperazine-1-carbonyl)-1H-indole-2-carboxylic acid 1:1 hydrochloride, O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (commercially available), 2-isopropylpyrrolidine (commercially available) and N,N-diisopropylethylamine in N,N-dimethylformamide to give the desired product after purification by preparative HPLC on reversed phase eluting with a gradient formed from acetonitrile/water/formic acid.
Reaction SMILES: [C:1]1([C:7]([CH3:9])=[CH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:10]N1C(=O)CCC1=O.BrC1C=CC=CC=1>>[Br:10][CH2:8][C:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[CH2:9]
Reactant: C=C(C)c1ccccc1
Reactant: O=C1CCC(=O)N1Br
Solvent: Brc1ccccc1
Product: C=C(CBr)c1ccccc1
Temperature: 25 °C
Yield: 46.2 %

Procedure:
A mixture of 2-phenylpropene (22.4 g, 190 mmoles), N-bromosuccinimide (23.7 g, 133 mmoles) and bromobenzene (76 ml) was heated in a 160° C. oil bath until the N-bromosuccinimide dissolved. The reaction mixture was allowed to cool to room temperature. The precipitate was subsequently removed using filtration and was washed using chloroform. The filtrate was distilled under reduced pressure to purify it (b.p. 80° C. to 85° C./3 mmHg), and 3-bromo-2-phenylpropene (12.1 g) was obtained. 1H NMR (CDCl3) δ ═4.39 (s, 2H), 5.49 (s, 1H), 5.56 (s, 1H), 7.33-7.51 (m, 5H); 13C NMR (CDCl3) δ=34.2, 117.2, 126.1, 128.3, 128.5, 137.6, 144.2.
Reaction SMILES: ClCC[N:4]([CH2:27][CH2:28]Cl)C1C=C(Cl)C2OC3C(C)=CC(C(O)=O)=CC=3S(=O)(=O)CC=2C=1.[CH3:30][O:31][C:32]([C:34]1[CH:35]=[C:36]([CH3:59])[C:37]2[O:43][C:42]3[C:44]([Cl:55])=[CH:45][C:46]([N:48]([CH2:52][CH2:53]Cl)[CH2:49][CH2:50]Cl)=[CH:47][C:41]=3[CH2:40][S:39](=[O:57])(=[O:56])[C:38]=2[CH:58]=1)=[O:33].NC([OH:63])C>CO>[CH3:30][O:31][C:32]([C:34]1[CH:35]=[C:36]([CH3:59])[C:37]2[O:43][C:42]3[C:44]([Cl:55])=[CH:45][C:46]([N:48]4[CH2:49][CH2:50][N:4]([CH2:27][CH2:28][OH:63])[CH2:53][CH2:52]4)=[CH:47][C:41]=3[CH2:40][S:39](=[O:57])(=[O:56])[C:38]=2[CH:58]=1)=[O:33]
Reactant: Cc1cc(C(=O)O)cc2c1Oc1c(Cl)cc(N(CCCl)CCCl)cc1CS2(=O)=O
Reactant: COC(=O)c1cc(C)c2c(c1)S(=O)(=O)Cc1cc(N(CCCl)CCCl)cc(Cl)c1O2
Reactant: CC(N)O
Solvent: CO
Product: COC(=O)c1cc(C)c2c(c1)S(=O)(=O)Cc1cc(N3CCN(CCO)CC3)cc(Cl)c1O2
Temperature: 120 °C

Procedure:
To a solution of 2-[bis-(2-chloroethyl)amino]-4-chloro-6-methyl10,10-dioxo-10,11-dihydro-5-oxa-10lambda*6*-thia-dibenzo[a,d]-cycloheptene-8-carboxylic acid [prepared by hydrolysis of compound of Example 12, 0.5 g, 1.044 mmol], in methanol (8 mL), aminoethanol (0.25 mL, 4.17 mmol) was added and heated to 120° C. in a sealed reactor for 4 h. The reaction mixture was cooled and the solvent was removed under reduced pressure. To the residue, methanolic HCl (20 mL) was added and refluxed for 3 h. Solvent was removed and the reaction mixture was basified to pH 8 using sodium carbonate solution and extracted using ethyl acetate (3×25 mL). The organic layer was washed with water and brine solution, concentrated and the crude product was purified by column chromatography (silica gel, 1% methanol in chloroform) to obtain the title compound. Yield: 0.317 g, (67.13%); 1H NMR (DMSO-d6, 300 MHz): δ 2.4 (t, 2H, CH2), 2.48 (s, 4H, 2CH2), 2.63 (s, 3H, CH3), 3.17 (s, 4H, 2CH2), 3.41 (t, 2H, CH2), 3.86 (s, 3H, OCH3), 4.44 (t, 1H, OH), 5.15 (s, 2H, CH2), 7.04 (s, 1H, Ar), 7.12 (s, 1H, Ar), 8.08 (s, 1H, Ar), 8.15 (s, 1H, Ar); MS: m/e (ES+) 481 (M+1); analysis: C22H25ClN2O6S requires C, 54.94; H, 5.24; N, 5.82; Cl, 7.37; S, 6.67. found: C, 54.78; H, 5.34; N, 5.7; Cl, 7.87; S, 6.88%.
Reaction SMILES: [CH2:1]([CH:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C-:15]#[N:16].[K+].[ClH:18].[CH3:19][NH:20][CH3:21].CO>CNC>[ClH:18].[CH2:1]([CH:8]1[CH2:13][CH2:12][C:11]([C:15]#[N:16])([N:20]([CH3:21])[CH3:19])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCC(Cc2ccccc2)CC1
Reactant: CNC
Reactant: [C-]#N
Agent: Cl
Agent: [K+]
Solvent: CO
Product: CN(C)C1(C#N)CCC(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 61 %

Procedure:
A mixture of 4-benzylcyclohexanone (4.40 g, 0.023 mole), 3.67 g of potassium cyanide, 5.50 g of dimethylamine hydrochloride and 3 ml of methanol in 30 ml of saturated aqueous dimethylamine was stirred at room temperature for 3 days. The mixture was then extracted thoroughly with CH2Cl2, and the organic layer was concentrated in vacuo. The residue was dissolved in diethyl ether, and the basic material was precipitated with 2 N HCl in diethyl ether. This solid was recrystallized from methylene chloride:ethyl acetate to give 3.91 g (61%) of 4-benzyl-1-cyano-1-(dimethylamino)cyclohexane hydrochloride, m.p. 150°-154° C.