Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:5]([CH2:14][CH:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)=[CH:6][C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH3:2].N1CC[CH:24]([C:27]([C:29]2[CH:38]=[CH:37][C:36]3[C:31](=CC=C(Cl)C=3)[CH:30]=2)=[O:28])[CH2:23]C1.BrCCC(C1C=CC=CC=1)O.ClCCCC(C1C=CC(F)=CC=1)=O>>[C:29]1([CH:27]([OH:28])[CH2:24][CH2:23][N:18]2[CH2:19][CH2:20][CH:15]([CH2:14][C:5]3[C:4]([O:3][CH2:1][CH3:2])=[CH:13][C:12]4[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=4)[CH:6]=3)[CH2:16][CH2:17]2)[CH:38]=[CH:37][CH:36]=[CH:31][CH:30]=1
Reactant: CCOc1cc2ccccc2cc1CC1CCNCC1
Reactant: O=C(c1ccc2cc(Cl)ccc2c1)C1CCNCC1
Agent: O=C(CCCCl)c1ccc(F)cc1
Agent: OC(CCBr)c1ccccc1
Product: CCOc1cc2ccccc2cc1CC1CCN(CCC(O)c2ccccc2)CC1

Procedure:
When in the procedure of Example 25, 4-[(3-ethoxy-2-naphthyl)methyl]piperidine is substituted for 6-chloro-2-naphthyl 4-piperidyl ketone and 3-bromo-1-phenylpropanol substituted for 4-chloro-1-(4-fluorophenyl)-1-butanone, α-phenyl-4-[(3-ethoxy-2-naphthyl)methyl]-1-piperidinepropanol is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:26])=[C:6]([C:8]2[CH2:12][N:11]([C:13](=[O:18])[C:14]([CH3:17])([CH3:16])[NH2:15])[CH:10]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([OH:25])[CH:20]=3)[CH:9]=2)[CH:7]=1.C(NCC)C>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:26])=[C:6]([C:8]2[CH2:12][N:11]([C:13](=[O:18])[C:14]([CH3:17])([CH3:16])[NH2:15])[C@H:10]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([OH:25])[CH:20]=3)[CH:9]=2)[CH:7]=1
Reactant: CC(C)(N)C(=O)N1CC(c2cc(Cl)ccc2F)=CC1c1cccc(O)c1
Solvent: CCNCC
Solvent: CCO
Product: CC(C)(N)C(=O)N1CC(c2cc(Cl)ccc2F)=C[C@H]1c1cccc(O)c1

Procedure:
Resolution of enantiomers of racemic 4-(5-chloro-2-fluorophenyl)-2-(3-hydroxyphenyl)-1-(2-methylalanyl)-2,5-dihydro-1H-pyrrole (174) by chiral normal-phase HPLC (Chiralcel OD column: 0.1% diethylamine in 10% ethanol in hexanes initially, grading to 30% ethanol in hexanes) provided (2S)-4-(5-chloro-2-fluorophenyl)-2-(3-hydroxyphenyl)-1-(2-methylalanyl)-2,5-dihydro-1H-pyrrole (17-5) as the first eluting, minus (−) enantiomer.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[N:13]1[C:17]([N:18]([CH2:20][CH2:21][OH:22])[CH3:19])=[C:16]([S:23]([C:26]([F:29])([F:28])[F:27])(=[O:25])=[O:24])[C:15]([C:30]#[N:31])=[N:14]1.[H-].[Na+].[C:34]1([CH3:44])[CH:39]=[CH:38][C:37]([S:40](Cl)(=[O:42])=[O:41])=[CH:36][CH:35]=1.[Cl-].[NH4+]>O1CCCC1.C(OCC)(=O)C>[Cl:12][C:4]1[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=[C:2]([Cl:1])[C:3]=1[N:13]1[C:17]([N:18]([CH3:19])[CH2:20][CH2:21][O:22][S:40]([C:37]2[CH:38]=[CH:39][C:34]([CH3:44])=[CH:35][CH:36]=2)(=[O:42])=[O:41])=[C:16]([S:23]([C:26]([F:29])([F:27])[F:28])(=[O:24])=[O:25])[C:15]([C:30]#[N:31])=[N:14]1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CN(CCO)c1c(S(=O)(=O)C(F)(F)F)c(C#N)nn1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)OCCN(C)c2c(S(=O)(=O)C(F)(F)F)c(C#N)nn2-c2c(Cl)cc(C(F)(F)F)cc2Cl)cc1
Reaction time: 1 h
Yield: 55.6 %

Procedure:
A solution of 1-(2,6-dichloro-4-trifluoromethylphenyl)-3-cyano-5-[N-(2-hydroxyethyl)-N-methylamino]-4-trifluoromethylsulfonylpyrazole (0.100 g, 0.2 mmol) and sodium hydride (0.016 g, 0.4 mmol) in dry tetrahydrofuran was stirred vigorously under an atmosphere of nitrogen for 1 hour at 20° C. 4-Toluenesulfonyl chloride (0.056 g, 0.3 mmol) was then added and stirring continued for 1 hour at 20° C. The mixture was then added to saturated ammonium chloride solution and ethyl acetate; and the organic layer washed with water and brine, dried (sodium sulfate) and evaporated. The residue was purified by flash column chromatography eluting with heptane/ethyl acetate (4:1) to afford the title compound as a fine white powder (0.074 g, Compound 93, yield 55%), 19F-NMR: −64.2, −79.2.
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]=[O:9])=[C:6]([N:10]2[CH:22]=[CH:21][N:13]3[C:14]4[CH2:15][CH2:16][CH2:17][CH2:18][C:19]=4[CH:20]=[C:12]3[C:11]2=[O:23])[N:5]=[CH:4][CH:3]=1.[CH3:24][N:25]1[CH:30]=[C:29](B2OC(C)(C)C(C)(C)O2)[CH:28]=[C:27]([NH:40][C:41]2[CH:50]=[C:44]3[CH2:45][N:46]([CH3:49])[CH2:47][CH2:48][N:43]3[N:42]=2)[C:26]1=[O:51].[O-]P([O-])([O-])=O.[K+].[K+].[K+].C([O-])(=O)C.[Na+]>O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(#N)C>[CH:8]([C:7]1[C:6]([N:10]2[CH:22]=[CH:21][N:13]3[C:14]4[CH2:15][CH2:16][CH2:17][CH2:18][C:19]=4[CH:20]=[C:12]3[C:11]2=[O:23])=[N:5][CH:4]=[CH:3][C:2]=1[C:29]1[CH:28]=[C:27]([NH:40][C:41]2[CH:50]=[C:44]3[CH2:45][N:46]([CH3:49])[CH2:47][CH2:48][N:43]3[N:42]=2)[C:26](=[O:51])[N:25]([CH3:24])[CH:30]=1)=[O:9]
Reactant: O=Cc1c(Cl)ccnc1-n1ccn2c3c(cc2c1=O)CCCC3
Reactant: CN1CCn2nc(Nc3cc(B4OC(C)(C)C(C)(C)O4)cn(C)c3=O)cc2C1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: CC#N
Solvent: O
Product: CN1CCn2nc(Nc3cc(-c4ccnc(-n5ccn6c7c(cc6c5=O)CCCC7)c4C=O)cn(C)c3=O)cc2C1
Temperature: 25 °C
Yield: 54.5 %

Procedure:
A 50-mL single-neck round-bottomed flask equipped with a reflux condenser was charged with 195f (130 mg, 0.40 mmol), 1-methyl-3-(5-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-ylamino)-5-(4,4,5,5-tetra-methyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one 135a (154 mg, 0.40 mmol), Pd(dppf)Cl2 (29 mg, 0.040 mmol), K3PO4 (170 mg, 0.80 mmol), sodium acetate (66 mg, 0.80 mmol), water (6 drops), and acetonitrile (10 mL). After three cycles of vacuum/argon flush, the mixture was heated at reflux for 2 h. It was then cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by silica-gel column chromatography eluting with 30:1 dichloromethane/methanol to afford 195g as yellow solid (120 mg, 54%). MS-ESI: [M+H]+ 551.2
Reaction SMILES: [CH2:1]([C@H:3]1[CH2:8][C@H:7]2[C@H:9]3[C@H:18]([CH2:19][CH2:20][C@:5]2([CH3:6])[C@H:4]1[OH:22])[C@@H:17]1[C:12](=[CH:13][C:14](=[O:21])[CH2:15][CH2:16]1)[CH2:11][CH2:10]3)[CH3:2].CN(C)C1C=CC=CC=1.[Br:32][CH2:33][C:34](Br)=[O:35].C(OCC)(=O)C>ClCCl>[CH2:1]([C@H:3]1[CH2:8][C@H:7]2[C@H:9]3[C@H:18]([CH2:19][CH2:20][C@:5]2([CH3:6])[C@H:4]1[O:22][C:34](=[O:35])[CH2:33][Br:32])[C@@H:17]1[C:12](=[CH:13][C:14](=[O:21])[CH2:15][CH2:16]1)[CH2:11][CH2:10]3)[CH3:2]
Reactant: O=C(Br)CBr
Reactant: CC[C@H]1C[C@H]2[C@@H]3CCC4=CC(=O)CC[C@@H]4[C@H]3CC[C@]2(C)[C@H]1O
Solvent: CN(C)c1ccccc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC[C@H]1C[C@H]2[C@@H]3CCC4=CC(=O)CC[C@@H]4[C@H]3CC[C@]2(C)[C@H]1OC(=O)CBr
Temperature: 25 °C
Yield: 74.6 %

Procedure:
In 40 ml of dichloromethane are dissolved 4.5 g of 16β-ethyl-17β-hydroxy-4-estren-3-one and 1.8 g of N,N-dimethylaniline and, with ice-cooling and stirring, a solution of 3.5 g of bromoacetyl bromide in 5 ml of dichloromethane is added dropwise to the above solution. The mixture is stirred with ice-cooling for 30 minutes and at room temperature (15°-25° C.) for 5 hours, and 200 ml of ethyl acetate is added. The mixture is washed with 10% cold sulfuric acid (three times), water and saturated aqueous sodium chloride solution in that order and dried over anhydrous sodium sulfate. The solvent is then distilled off under reduced pressure. The residue is recrystallized from diisopropyl ether-petroleum ether (1:1) to give 4.7 g of the above-identified compound as colorless crystals.
Reaction SMILES: [NH2:1][CH:2]1[C:7]2[CH:8]=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=[CH:11][C:6]=2[O:5][C:4]([CH2:17][F:18])([CH2:15][F:16])[CH:3]1[OH:19].Br[CH2:21][C:22]1[CH:31]=[CH:30][CH:29]=[CH:28][C:23]=1[C:24](OC)=[O:25].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>O.C(#N)C>[F:18][CH2:17][C:4]1([CH2:15][F:16])[C@@H:3]([OH:19])[C@H:2]([N:1]2[CH2:21][C:22]3[C:23](=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:24]2=[O:25])[C:7]2[CH:8]=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=[CH:11][C:6]=2[O:5]1
Reactant: NC1c2cc([N+](=O)[O-])ccc2OC(CF)(CF)C1O
Reactant: COC(=O)c1ccccc1CBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: O=C1c2ccccc2CN1[C@@H]1c2cc([N+](=O)[O-])ccc2OC(CF)(CF)[C@H]1O
Reaction time: 6 h
Yield: 42.2 %

Procedure:
A mixture of 0.25 g of 4-amino-2,2-bisfluoromethyl-3,4-dihydro-6-nitro-2H-1-benzopyran-3-ol, 0.22 g of methyl 2-bromomethylbenzoate, 0.40 g of potassium carbonate, 0.09 g of potassium iodide and 5 ml of acetonitrile was stirred at 75°-85° C. for 6 hours. Water was added thereto and the mixture was extracted with a mixed solvent of ethyl acetate and ether. After the organic layer was washed with 1N hydrochloric acid and dried, the solvent was distilled off. The resultant residue was purified using silica gel column chromatography (developing solution, AcOEt:hexane=1:1) and recrystallized from a mixed solvent of ethyl acetate and hexane to obtain 0.15 g of trans-2,2-bisfluoromethyl-3,4-dihydro-4-(2,3-dihydro-1-oxo-1H-isoindol-2-yl)-6-nitro-2H-1-benzopyran-3-ol represented by the following formula having a melting point of 285°-288° C.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH2:11][NH:12][CH3:13])=[C:3]1[CH3:14].[NH2:15][C:16]1[N:21]=[CH:20][C:19](/[CH:22]=[CH:23]/[C:24]([OH:26])=O)=[CH:18][CH:17]=1.CCN(CC)CC.C1C=CC2N(O)N=NC=2C=1.O.C(Cl)CCl>CN(C=O)C.C(Cl)Cl>[NH2:15][C:16]1[N:21]=[CH:20][C:19](/[CH:22]=[CH:23]/[C:24]([N:12]([CH2:11][C:4]2[C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[N:2]([CH3:1])[C:3]=2[CH3:14])[CH3:13])=[O:26])=[CH:18][CH:17]=1
Reactant: CNCc1c(C)n(C)c2ccccc12
Reactant: Nc1ccc(/C=C/C(=O)O)cn1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: Cc1c(CN(C)C(=O)/C=C/c2ccc(N)nc2)c2ccccc2n1C
Yield: 96.8 %

Procedure:
To a stirred solution of 1,2-dimethyl-3-(methylaminomethyl)-1H-indole (0.8 g, 4.2 mmole) in 1:1 DMF/CH2Cl2 (30 mL) at RT was added (E)-3-(6-aminopyridin-3-yl)acrylic acid (0.7 g, 4.3 mmole), Et3N (0.61 mL, 4.3 mmole), HOBt.H2O (0.58 g, 4.3 mmole) and EDC (0.83 g, 4.3 mmole). After 16 h the reaction was concentrated under vacuum and the residue was taken lip in EtOAc (100 mL). The solution was washed with 1.0 N Na2CO3 (100 mL) then with brine, dried (Na2SO4), and concentrated. Purification by flash chromatography on silica gel (4% MeOH/CHCl3) followed by trituration with 1:1 Et2O/petroleum ether and drying under vacuum gave the title compound (1.36 g, 97%) as an off-white solid: MS (ES) m/e 335.2 (M+H)+.
Reaction SMILES: ClCCCS(NCC(OC1C=CON=1)[CH2:11][O:12][C:13](=O)NCCCCCCCCCCCCCCCCCC)(=O)=O.[CH2:40]([S:56][CH2:57][CH:58](OC)[CH2:59][NH:60][S:61]([CH2:64][CH2:65][CH2:66][I:67])(=[O:63])=[O:62])[CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH3:55]>>[CH2:40]([S:56][CH2:57][CH:58]([CH2:11][O:12][CH3:13])[CH2:59][NH:60][S:61]([CH2:64][CH2:65][CH2:66][I:67])(=[O:62])=[O:63])[CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH3:55]
Reactant: CCCCCCCCCCCCCCCCSCC(CNS(=O)(=O)CCCI)OC
Reactant: CCCCCCCCCCCCCCCCCCNC(=O)OCC(CNS(=O)(=O)CCCCl)Oc1ccon1
Product: CCCCCCCCCCCCCCCCSCC(CNS(=O)(=O)CCCI)COC

Procedure:
3-(3-Chloropropylsulfonylamino)-1-hexadecylthio-2-methoxymethylpropane III k3 is allowed to react and worked up by the same procedure as described in (5). The summary of the experimental condition and the physical data of the product are listed in Table 8.
Reaction SMILES: [CH2:1]([O:7][C:8]1[CH:34]=[CH:33][C:11]([C:12]([OH:32])([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][CH:22]=[CH:23][CH:24]=[CH2:25])=[CH:15][CH:14]=2)=[CH:10][CH:9]=1)[CH2:2][CH:3]=[CH:4][CH:5]=[CH2:6].C(Cl)(=O)C.[C@@H:39]1([N:47]2[CH:55]=[C:53]([CH3:54])[C:51](=[O:52])[NH:50][C:48]2=[O:49])[O:46][C@H:43]([CH2:44]O)[C@@H:41]([OH:42])[CH2:40]1.CN(C1N=CC=CN=1)C>C1(C)C=CC=CC=1.N1C=CC=CC=1>[CH2:1]([O:7][C:8]1[CH:34]=[CH:33][C:11]([C:12]([O:32][CH2:44][C@H:43]2[O:46][C@@H:39]([N:47]3[CH:55]=[C:53]([CH3:54])[C:51](=[O:52])[NH:50][C:48]3=[O:49])[CH2:40][C@@H:41]2[OH:42])([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][CH:22]=[CH:23][CH:24]=[CH2:25])=[CH:15][CH:14]=2)=[CH:10][CH:9]=1)[CH2:2][CH:3]=[CH:4][CH:5]=[CH2:6]
Reactant: C=CC=CCCOc1ccc(C(O)(c2ccccc2)c2ccc(OCCC=CC=C)cc2)cc1
Reactant: Cc1cn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]c1=O
Agent: CN(C)c1ncccn1
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Solvent: CC(=O)Cl
Product: C=CC=CCCOc1ccc(C(OC[C@H]2O[C@@H](n3cc(C)c(=O)[nH]c3=O)C[C@@H]2O)(c2ccccc2)c2ccc(OCCC=CC=C)cc2)cc1
Yield: 84.4 %

Procedure:
Compound 30 (3.5 grams, 7.73 mmol) was coevaporated with toluene (2×) and then dissolved in anhydrous toluene (85 mL). Acetyl chloride (33 mL, 464 mmol) was added to the solution and the reaction mixture was heated to reflux and stirred under argon. After 4 hours the reaction mixture was concentrated in vacuo and the crude product was coevaporated with pyridine and then dissolved in anhydrous pyridine (42 mL). Thymidine (1.5 grams, 6.18 mmol), which had been coevaporated with pyridine and dissolved in anhydrous pyridine (42 mL), was then added to the solution containing the crude product. A catalytic amount of dimethylaminopyrimidine (DMAP) was added and the reaction mixture was stirred under argon overnight and the solvent was evaporated. The residue was redissolved in dichloromethane and washed with a 5% aqueous solution of sodium bicarbonate followed by water. The organic phase was dried (MgSO4), evaporated and purified by column chromatography (silica gel; EtOAc/hexane, 1/1) to afford 3.53 grams (84%) of compound 31 as an off-white solid. 1H NMR (300 MHz, CDCl3) δ 1.47 (s, 3H), 2.22-2.46 (m, 2H), 2.50-2.63 (m, 4H), 3.35-3.58 (m, 2H), 3.85-4.09 (m, 5H), 4.51-4.60 (m, 1H), 5.02 (dd, J=1.5, 10.4 Hz, 2H), 5.14 (dd, J=1.5, 17.3 Hz, 2H), 5.68-5.83 (m, 2H), 6.12-6.45 (m, 5H), 6.82 (d, J=9.0 Hz, 4H), 7.18-7.46 (m, 9H), 7.58 (s, 1H), 8.44 (s, 1H); Anal. Calcd for C41H44N2O7.2H2O (712.8384): C, 69.08; H, 6.79; H, 3.93. Found: C, 69.34; H, 6.44; N, 3.91.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:6][N:5]([C:7]2[CH:8]=[N:9][C:10]([Cl:14])=[C:11]([Cl:13])[CH:12]=2)[CH2:4][C@@H:3]1[CH2:15]O.S(Cl)(Cl)=O.O>COCCOC.CN1CCCC1=O>[Cl:13][C:11]1[CH:12]=[C:7]([N:5]2[CH2:6][C@@H:2]3[C@@H:3]([CH2:15][NH:1]3)[CH2:4]2)[CH:8]=[N:9][C:10]=1[Cl:14]
Reactant: N[C@@H]1CN(c2cnc(Cl)c(Cl)c2)C[C@@H]1CO
Solvent: O=S(Cl)Cl
Solvent: CN1CCCC1=O
Solvent: O
Product: Clc1cc(N2C[C@@H]3CN[C@@H]3C2)cnc1Cl
Temperature: 50 °C
Reaction time: 3 h

Procedure:
(3S,4S)-[4-Amino-1-(5,6-dichloro-pyridin-3-yl)-pyrrolidin-3-yl]-methanol (10 g) was suspended in 1,2-dimethoxyethane (100 mL) and N-methylpyrrolidinone (15 mL). The mixture was heated to 50° C. and then a solution of thionyl chloride (7.9 g) in 1,2-dimethoxyethane (35 mL) was slowly added, while maintaining the temperature below 60° C. The reaction mixture was stirred at 50° C. for about 3 hours and then cooled to room temperature. After adding water (100 mL), the 1,1-dimethoxyethane was removed by distillation. Ethanol (100 mL) and water (100 mL) were added and the pH adjusted to 11-12 with 50% aqueous sodium hydroxide. The resulting mixture was heated at 60° C. for at least 12 hours and then cooled to room temperature. After filtering through a bed of Hy-Flo, the ethanol was removed by vacuum distillation. The pH was adjusted to >12 with 50% aqueous sodium hydroxide and then extracted with isopropyl acetate (2×80 mL). The combined organic extracts were concentrated, and then suspended in isopropyl acetate (˜50 mL). After heating to 80° C., the solution was cooled to room temperature while stirring rapidly. The suspension was cooled to 0° C., filtered, washed with isopropyl acetate and dried in the vacuum oven. 1H NMR (MeOH-d4, 300 MHz) δ 3.04 (dd, J=10.9, 4.8 Hz, 1H), 3.11 (dd, J=10.2, 6.8 Hz, 1H), 3.26 (dd, J=8.8, 4.4 Hz, 1H), 3.38 (m, 1H), 3.73 (t, J=11.2 Hz, 2H), 3.84 (t, J=8.1 Hz, 1H), 4.55 (dd, J=6.8, 4.8 Hz, 1H), 7.37 (d, J=3.1 Hz, 1H), 7.84 (d, J=2.7 Hz, 1H): MS (DCl/NH3) m/z 244/246/248 (M+H)+.
Reaction SMILES: [CH2:1]([S:3][C:4]1[N:9]=[N:8][C:7]([C:10]([OH:12])=O)=[CH:6][CH:5]=1)[CH3:2].C1N=CN(C(N2C=NC=C2)=O)C=1.Cl.[NH2:26][CH2:27][C:28]1[CH:29]=[C:30]2[C:34](=[CH:35][CH:36]=1)[C:33](=[O:37])[N:32]([C:38]1([CH3:46])[CH2:43][CH2:42][C:41](=[O:44])[NH:40][C:39]1=[O:45])[C:31]2=[O:47].O>CN(C)C=O>[CH3:46][C:38]1([N:32]2[C:31](=[O:47])[C:30]3[C:34](=[CH:35][CH:36]=[C:28]([CH2:27][NH:26][C:10]([C:7]4[N:8]=[N:9][C:4]([S:3][CH2:1][CH3:2])=[CH:5][CH:6]=4)=[O:12])[CH:29]=3)[C:33]2=[O:37])[CH2:43][CH2:42][C:41](=[O:44])[NH:40][C:39]1=[O:45]
Reactant: CC1(N2C(=O)c3ccc(CN)cc3C2=O)CCC(=O)NC1=O
Reactant: CCSc1ccc(C(=O)O)nn1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: CN(C)C=O
Product: CCSc1ccc(C(=O)NCc2ccc3c(c2)C(=O)N(C2(C)CCC(=O)NC2=O)C3=O)nn1
Temperature: 40 °C
Reaction time: 1 h
Yield: 81.3 %

Procedure:
A stirred mixture of 6-ethylsulfanyl-pyridazine-3-carboxylic acid (0.37 g, 2.00 mmol) and CDI (0.36 g, 2.20 mmol) in N,N-dimethylformamide (20 mL) was heated to 40° C. under nitrogen. After 1 h, 5-Aminomethyl-2-(3-methyl-2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione hydrochloride (0.68 g, 2.00 mmol) was added and the mixture was heated at 40° C. for 1.5 h. The mixture was cooled to rt and water (40 mL) was added. After 3 h, the product was isolated by filtration, washed with water (10 mL) and dried in vacuo to give 6-ethylsulfanyl-pyridazine-3-carboxylic acid [2-(3-methyl-2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-ylmethyl]amide as a white solid (0.76 g, 81% yield): HPLC: Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 40/60 CH3CN/0.1% H3PO4, 5.24 min (95.32%); mp: 160-162° C.; 1H NMR (DMSO-d6) δ 1.38 (t, J=7.3 Hz, 3H, CH3), 1.88 (s, 3H, CH3), 1.95-2.14 (m, 1H, CHH), 2.52-2.61 (m, 2H, CHH, CHH), 2.61-2.79 (m, 1H, CHH), 3.24-3.43 (m, 2H, CH2), 4.66 (d, J=6.2 Hz, 2H, CH2), 7.74-7.87 (m, 4H, Ar), 7.96 (d, J=8.9 Hz, 1H, Ar), 9.97 (t, J=6.2 Hz, 1H, NH), 11.02 (s, 1H, NH); 13C NMR (DMSO-d6) δ 12.67, 19.51, 22.51, 27.07, 27.60, 40.92, 57.25, 120.31, 121.67, 123.40, 125.41, 128.17, 129.87, 132.06, 145.52, 148.23, 161.45, 163.51, 166.22, 166.37, 170.65, 170.71; LCMS: MH=468; Anal Calcd for C22H21N5O5S+0.2H2O: C, 56.09; H, 4.58; N, 14.87. Found: C, 55.86; H, 4.59; N, 14.72.
Reaction SMILES: II.[C:3]([C:6]1[C:23]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]=2[CH:9]=[CH:8][CH:7]=1)(=[O:5])[CH3:4].[OH-:24].[Na+].[CH3:26][CH2:27][OH:28]>N1C=CC=CC=1.O>[CH:12]1[C:11]2[C:10]3[C:23](=[CH:6][CH:7]=[CH:8][CH:9]=3)[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16]=2[CH:15]=[CH:14][C:26]=1[C:27]([OH:24])=[O:28].[C:3]([C:6]1[C:23]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]=2[CH:9]=[CH:8][CH:7]=1)(=[O:5])[CH3:4]
Reactant: CCO
Reactant: [OH-]
Agent: CC(=O)c1cccc2c3ccccc3c3ccccc3c12
Agent: II
Agent: [Na+]
Solvent: c1ccncc1
Solvent: O
Product: O=C(O)c1ccc2c3ccccc3c3ccccc3c2c1

Procedure:
The reaction product obtained in step a) is admixed with 2.2 equivalents of I2 (based on the crude yield of acetyltriphenylene) in pyridine solvent at room temperature. Thereafter, the mixture is kept at reflux for 45 min, and then a further portion of I2 (1.0 equivalent) is added. After reflux for a further hour, NaOH, EtOH and water are added and the reaction mixture is heated to reflux for 2 h. 2-triphenylenecarboxylic acid is obtained in 76% yield (based on crude yield of acetyltriphenylene, or 74% based on triphenylene).
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.C([O:13][C:14](=O)/[CH:15]=[C:16](/[C:23]1[CH:28]=[CH:27][C:26]([C:29]#[C:30][CH2:31][N:32]([CH3:34])[CH3:33])=[CH:25][CH:24]=1)\[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)C.[Cl-].[NH4+].ClCCl>O1CCCC1>[CH3:34][N:32]([CH3:33])[CH2:31][C:30]#[C:29][C:26]1[CH:27]=[CH:28][C:23](/[C:16](/[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[CH:15]/[CH2:14][OH:13])=[CH:24][CH:25]=1
Reactant: CCOC(=O)/C=C(\c1ccccc1)c1ccc(C#CCN(C)C)cc1
Agent: CC(C)C[Al+]CC(C)C
Agent: [Cl-]
Agent: [H-]
Solvent: C1CCOC1
Solvent: ClCCl
Product: CN(C)CC#Cc1ccc(/C(=C/CO)c2ccccc2)cc1
Reaction time: 4 h

Procedure:
A 1 M solution of diisobutylaluminum hydride in tetrahydrofuran (6 ml) was added drop wise to a cooled (0° C.) solution of the above ester (0.600 g; 1.80 mmol) in dry tetrahydrofuran (50 ml). The reaction stirred at the temperature for 4 hours and then added saturated ammoniumchloride (30 ml). After stirring 30 min dichloromethane (150 ml) and hyflo super cell medium (15 g) were added. The mixture was stirred at ambient temperature 2 hours, filtered and evaporated in vacuo. The crude product was taken up in dichloromethane (150 ml) and washed with water (2×50 ml), dried with anhydrous magnesium sulfate and subsequently evaporated in vacuo giving (E)-3-[4-(3-dimethylamino-prop-1-ynyl)-phenyl]-3-phenylprop-2-en-1-ol.
Reaction SMILES: [F:1][C:2]1[CH:7]=[N:6][C:5]([C:8]2[CH:12]=[CH:11][NH:10][N:9]=2)=[C:4]2[NH:13][CH:14]=[C:15]([C:16](=[O:36])[C:17]([N:19]3[CH2:24][CH2:23][N:22]([C:25]4[N:29]([C:30]5[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=5)[N:28]=[N:27][N:26]=4)[CH2:21][CH2:20]3)=[O:18])[C:3]=12.[H-].[Na+].[CH3:39]I>CN(C=O)C>[F:1][C:2]1[CH:7]=[N:6][C:5]([C:8]2[CH:12]=[CH:11][N:10]([CH3:39])[N:9]=2)=[C:4]2[NH:13][CH:14]=[C:15]([C:16](=[O:36])[C:17]([N:19]3[CH2:24][CH2:23][N:22]([C:25]4[N:29]([C:30]5[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=5)[N:28]=[N:27][N:26]=4)[CH2:21][CH2:20]3)=[O:18])[C:3]=12
Reactant: CI
Reactant: O=C(C(=O)N1CCN(c2nnnn2-c2ccccc2)CC1)c1c[nH]c2c(-c3cc[nH]n3)ncc(F)c12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1ccc(-c2ncc(F)c3c(C(=O)C(=O)N4CCN(c5nnnn5-c5ccccc5)CC4)c[nH]c23)n1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 66.6 %

Procedure:
1-(4-fluoro-7-(1H-pyrazol-3-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-(4-(1-phenyl-1H-tetrazol-5-yl)piperazin-1-yl)ethane-1,2-dione (30 mg, 0.06 mmol) in DMF (1 mL) was treated with sodium hydride (60% in oil, 31.2 mg, 0.78 mmol) and stirred at room temperature for 5 min. Methyl iodide (56 uL, 0.9 mmol)was added and the mixture was stirred at rt for 1 h. Reaction was quenched with H2O and concentrated under reduced pressure. The residue was dissolved in DMF and purified using reverse phase prep HPLC to afford the title compound as a white solid (20 mg, 67%). 1H NMR (500 MHz, DMSO-D6) δ ppm 3.15 (s, 2H) 3.32 (s, 2H) 3.47 (s, 2H) 3.71 (s, 2H) 4.05 (s, 3H) 6.92 (s, 1H) 7.58-7.65 (m, 3H) 7.69 (s, 2H) 7.91 (s, 1H) 8.30 (d, J=12.83 Hz, 2H) 12.30 (s, 1H). LCMS: m/e 501 (M+H)+, ret time 1.37 min (method 3).