Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([OH:13])=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:14](Cl)(=O)[C:15](Cl)=O>C1C=CC=CC=1>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:10][C:11]([C:15]2[CH:14]=[CH:6][CH:5]=[CH:4][CH:9]=2)=[O:13])=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)Cc1ccc([N+](=O)[O-])cc1
Solvent: c1ccccc1
Product: O=C(Cc1ccc([N+](=O)[O-])cc1)c1ccccc1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To a solution of 4-nitrophenylacetic acid (200 g) in benzene (1.5 L) was added oxalyl chloride (200 mL). The mixture was warmed to 50°-60° C. for 2 hrs, after which time benzene and excess oxalyl chloride were distilled off under vacuum at 50° C. until a final volume of 500 mL was achieved. The residue was diluted with benzene (1 L) and cooled to 0° C. To this was added anhydrous aluminum chloride (160 g) portion-wise over 15 minutes. Thereafter, the mixture was stirred overnight at room temperature. The reaction mixture was poured over a mixture of ice (3 L) and concentrated HCl (1 L). The resulting slurry was filtered through celite and the precipitate washed with ethyl acetate. The combined filtrates were washed with water, saturated sodium bicarbonate and with brine, dried over sodium sulfate and evaporated to give 227 grams of 2-(4-nitrophenyl)-1-phenylethanone.
Reaction SMILES: [CH:1]([N:4]([CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)[C:5](=[O:13])[C:6]1[CH:11]=[CH:10][C:9](Br)=[CH:8][CH:7]=1)([CH3:3])[CH3:2].[CH3:20][O:21][C:22]1[CH:23]=[C:24]([OH:30])[CH:25]=[C:26]([O:28][CH3:29])[CH:27]=1>N1C(C)=CC(C)=CC=1C>[CH:14]1([N:4]([CH:1]([CH3:3])[CH3:2])[C:5](=[O:13])[C:6]2[CH:11]=[CH:10][C:9]([O:30][C:24]3[CH:25]=[C:26]([O:28][CH3:29])[CH:27]=[C:22]([O:21][CH3:20])[CH:23]=3)=[CH:8][CH:7]=2)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: COc1cc(O)cc(OC)c1
Reactant: CC(C)N(C(=O)c1ccc(Br)cc1)C1CCCCC1
Solvent: Cc1cc(C)nc(C)c1
Product: COc1cc(OC)cc(Oc2ccc(C(=O)N(C(C)C)C3CCCCC3)cc2)c1

Procedure:
The reaction and workup were carried out in the same manner as described in Example 1 using p-bromobenzoic acid N-isopropyl-N-cyclohexyl amide (2.353 g, 7.26 mmol), 3,5-dimethoxy phenol (1.061 g, 6.88 mmol) and cuprous oxide (492 mg, 3.44 mmol) in 2,4,6-collidine (15 ml). The crude product was chromatographed on silica gel using mixtures of ethyl acetate and hexane as eluents to give the title compound as a crystalline solid that could be recrystallized from ethyl acetate and hexane, m. pt. 140.12° C. (DSC).
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[C:5]([O:13][C@H:14]1[C@@H:19]2[O:20]S(=O)O[C@@H:18]2[CH:17]=[C:16]([C:24]([O:26][CH3:27])=[O:25])[CH2:15]1)(=[O:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>CN(C=O)C.CCOC(C)=O>[C:5]([O:13][C@H:14]1[C@H:19]([OH:20])[C@@H:18]([N:1]=[N+:2]=[N-:3])[CH:17]=[C:16]([C:24]([O:26][CH3:27])=[O:25])[CH2:15]1)(=[O:12])[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: [N-]=[N+]=[N-]
Reactant: COC(=O)C1=C[C@H]2OS(=O)O[C@H]2[C@H](OC(=O)c2ccccc2)C1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)C1=C[C@H](N=[N+]=[N-])[C@@H](O)[C@H](OC(=O)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 36 %

Procedure:
Sodium azide (2.3 g, 36.0 mmol) was added to a solution of Example 13F in DMF (30 mL). After stirring at room temperature overnight, the reaction mixture was diluted with EtOAc, washed with brine, dried (MgSO4), filtered and concentrated. The concentrate was purified by flash chromatography using hexanes/ethyl acetate (3/2) to afford 1.36 g (36%) of the desired product as a colorless oil.
Reaction SMILES: [N+:1]([C:4]1[CH:18]=[CH:17][CH:16]=[CH:15][C:5]=1[C:6]([N:8]1[CH:12]=[CH:11][CH:10]=[C:9]1[CH:13]=O)=[O:7])([O-])=O>C(OCC)(=O)C.Cl.[Pd]>[CH:10]1[CH:11]=[CH:12][N:8]2[C:6](=[O:7])[C:5]3[CH:15]=[CH:16][CH:17]=[CH:18][C:4]=3[NH:1][CH2:13][C:9]=12
Reactant: O=Cc1cccn1C(=O)c1ccccc1[N+](=O)[O-]
Agent: [Pd]
Agent: Cl
Solvent: CCOC(C)=O
Product: O=C1c2ccccc2NCc2cccn21
Reaction time: 1.75 h
Yield: 82.1 %

Procedure:
A mixture of 1.5 g of N-(2-nitrobenzoyl)pyrrole-2-carboxaldehyde in 50 ml of ethyl acetate, 2 drops of concentrated HCl and 0.3 g of 10% Pd/C is shaken in a Parr apparatus under hydrogen pressure for 1.75 hours. The mixture is filtered, 0.4 g of 10% Pd/C added and the mixture shaken in a Parr apparatus under hydrogen pressure for 2 hours. The reaction mixture is filtered through diatomaceous earth and the filtrate concentrated in vacuo to give 1.0 g of a yellow oil. The residue is purified on thick layer chromatography plates by elution with 4:1 ethyl acetate:hexane to give 107 mg of the desired product as an oily solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([CH2:9][CH2:10][OH:11])[C:3]=1[OH:12].C([O-])([O-])=O.[K+].[K+].Br[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.O>CC(C)=O>[CH2:20]([O:12][C:3]1[C:2]([F:1])=[CH:7][C:6]([F:8])=[CH:5][C:4]=1[CH2:9][CH2:10][OH:11])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: BrCc1ccccc1
Reactant: OCCc1cc(F)cc(F)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: OCCc1cc(F)cc(F)c1OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 79.2 %

Procedure:
To a solution of 2,4-difluoro-6-(2-hydroxyethyl)phenol (450 mg, 2.58 mmol) in Acetone (10 mL) was added K2CO3 (714 mg, 5.17 mmol) followed by (bromomethyl)benzene (0.461 mL, 3.88 mmol) and the resulting mixture was stirred at room temp for 16 h. Water was then added and the mixture was extracted with ethyl acetate, dried (Na2SO4), filtered and concentrated. The residue was then purified by Biotage (5-30% EtOAc/hexane) to afford 2-(2-(benzyloxy)-3,5-difluorophenyl)ethanol (540 mg, 2.043 mmol, 79% yield) as viscous oil. 1H NMR (400 MHz, CDCl3) δ 7.48-7.36 (m, 5H), 6.84-6.72 (m, 2H), 5.07 (s, 2H), 3.78 (q, J=6.3 Hz, 2H), 2.84 (t, J=6.4 Hz, 2H), 1.53 (t, J=5.5 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([O:9][CH3:10])[CH:5]=[CH:4][C:3]=1[C:11](=[O:15])[CH:12]([CH3:14])[CH3:13].[Br:16]Br.S(=O)(O)[O-].[Na+]>C(O)(=O)C>[Br:16][C:12]([CH3:13])([CH3:14])[C:11]([C:3]1[CH:4]=[CH:5][C:6]([O:9][CH3:10])=[C:7]([Cl:8])[C:2]=1[Cl:1])=[O:15]
Reactant: COc1ccc(C(=O)C(C)C)c(Cl)c1Cl
Reactant: BrBr
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: COc1ccc(C(=O)C(C)(C)Br)c(Cl)c1Cl
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A stirred solution of 2',3'-dichloro-4'methoxyisobutyrophenone (45 g., 0.183 mole) in acetic acid (150 ml.) is treated during 1/2 hour with bromine (30 g., 0.187 mole). The reaction mixture is stirred 10 minutes, then poured into ice water (600 ml.) containing sodium bisulfite (2 g.). The 2-bromo-2'-3'-dichloro-4'-methoxyisobutyrophenone which separates (48 g.) melts at 72°-73° C. after recrystallization from hexane.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH2:12][N:13]([CH3:15])[CH3:14])=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[CH:6]2.CN(C=O)C.[CH3:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([S:29](Cl)(=[O:31])=[O:30])=[CH:25][CH:24]=1>>[CH3:1][O:2][C:3]1[C:4]([CH2:12][N:13]([CH3:14])[CH3:15])=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([S:29]([C:26]1[CH:25]=[CH:24][C:23]([O:22][CH3:21])=[CH:28][CH:27]=1)(=[O:31])=[O:30])[CH:7]=[CH:6]2
Reactant: COc1ccc2[nH]ccc2c1CN(C)C
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Solvent: CN(C)C=O
Product: COc1ccc(S(=O)(=O)n2ccc3c(CN(C)C)c(OC)ccc32)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 7.6 %

Procedure:
To a solution of 1-(5-methoxy-1H-indol-4-yl)-N,N-dimethylmethanamine (15 mg, 0.07 mmol; Intermediate 97) in DMF (1 mL) NaH (4 mg, 0.15 mmol) was added at rt. The reaction mixture was stirred at rt for 15 min and 4-methoxybenzene-1-sulfonyl chloride (23 mg, 0.11 mmol) was added. The reaction mixture was allowed to stir at rt over night. The reaction was quenched by addition of water. Purification using preparative HPLC/UV (System B) afforded the title product (2 mg, 6%) as a white solid. MS (ESI+) for C19H22N2O4S m/z 375 (M+H)+.
Reaction SMILES: [NH2:1][C@@:2]1([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=2[F:22])[CH2:7][O:6][C@@H:5]([CH:8]2[CH2:10][CH2:9]2)[CH2:4][C@H:3]1[C@@H:11]([OH:14])[CH2:12][F:13].C1([C@@H]2OC[C@@](N[C:41]([NH:43][C:44](=[O:51])[C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)=[S:42])(C3C=CC(F)=CC=3F)[C@H]([C@@H](O)C)C2)CC1>>[CH:8]1([C@@H:5]2[O:6][CH2:7][C@@:2]([NH:1][C:41]([NH:43][C:44](=[O:51])[C:45]3[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=3)=[S:42])([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=3[F:22])[C@H:3]([C@@H:11]([OH:14])[CH2:12][F:13])[CH2:4]2)[CH2:10][CH2:9]1
Reactant: C[C@H](O)[C@@H]1C[C@H](C2CC2)OC[C@@]1(NC(=S)NC(=O)c1ccccc1)c1ccc(F)cc1F
Reactant: N[C@@]1(c2ccc(F)cc2F)CO[C@@H](C2CC2)C[C@H]1[C@@H](O)CF
Product: O=C(NC(=S)N[C@@]1(c2ccc(F)cc2F)CO[C@@H](C2CC2)C[C@H]1[C@@H](O)CF)c1ccccc1

Procedure:
Conversion of rel-(1R)-1-[(2R,4R,5S)-5-amino-2-cyclopropyl-5-(2,4-difluorophenyl)tetrahydro-2H-pyran-4-yl]-2-fluoroethanol (C45) to the product was carried out according to the method described for synthesis of N-({(3S,4R,6R)-6-cyclopropyl-3-(2,4-difluorophenyl)-4-[(1S)-1-hydroxyethyl]tetrahydro-2H-pyran-3-yl}carbamothioyl)benzamide (C30) in Example 3. The product was obtained as a solid. Yield: 155 mg, 0.324 mmol, 60%. LCMS m/z 479.2 [M+H+].
Reaction SMILES: S(Cl)(Cl)=O.[O:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[CH:7]=[C:6]1[C:14]([OH:16])=[O:15].[CH3:17]O>>[O:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[CH:7]=[C:6]1[C:14]([O:16][CH3:17])=[O:15]
Reactant: CO
Reactant: O=C(O)c1cc2ccccc2o1
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cc2ccccc2o1
Temperature: 25 °C
Reaction time: 19 h

Procedure:
After adding thionyl chloride (3.80 ml) to a solution of 2-benzofurancarboxylic acid (2.00 g) in MeOH (60 ml) at −40° C., the mixture was stirred for 19 hours while the temperature gradually increased to room temperature. The reaction solution was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (n-hexane/AcOEt=6/1) to obtain methyl 2-benzofurancarboxylate.
Reaction SMILES: [NH2:1][C@:2]12[CH2:37][CH2:36][C@@H:35]([C:38]([CH3:40])=[CH2:39])[C@@H:3]1[C@@H:4]1[C@@:17]([CH3:20])([CH2:18][CH2:19]2)[C@@:16]2([CH3:21])[C@@H:7]([C@:8]3([CH3:34])[C@@H:13]([CH2:14][CH2:15]2)[C:12]([CH3:23])([CH3:22])[C:11]([C:24]2[CH:33]=[CH:32][C:27]([C:28]([O:30]C)=[O:29])=[CH:26][CH:25]=2)=[CH:10][CH2:9]3)[CH2:6][CH2:5]1.CN(C)CCC(N[C@]12CC[C@@H](C(C)=C)[C@@H]1[C@@H]1[C@@](C)(CC2)[C@@]2(C)[C@@H]([C@]3(C)[C@@H](CC2)C(C)(C)C(C2C=CC(C(O)=O)=CC=2)=CC3)CC1)=O.[N:87]1([CH2:92][C:93]([OH:95])=O)[CH:91]=[N:90][N:89]=[N:88]1>>[N:87]1([CH2:92][C:93]([NH:1][C@:2]23[CH2:37][CH2:36][C@@H:35]([C:38]([CH3:40])=[CH2:39])[C@@H:3]2[C@@H:4]2[C@@:17]([CH3:20])([CH2:18][CH2:19]3)[C@@:16]3([CH3:21])[C@@H:7]([C@:8]4([CH3:34])[C@@H:13]([CH2:14][CH2:15]3)[C:12]([CH3:23])([CH3:22])[C:11]([C:24]3[CH:25]=[CH:26][C:27]([C:28]([OH:30])=[O:29])=[CH:32][CH:33]=3)=[CH:10][CH2:9]4)[CH2:6][CH2:5]2)=[O:95])[CH:91]=[N:90][N:89]=[N:88]1
Reactant: C=C(C)[C@@H]1CC[C@]2(N)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Reactant: O=C(O)Cn1cnnn1
Agent: C=C(C)[C@@H]1CC[C@]2(NC(=O)CCN(C)C)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Product: C=C(C)[C@@H]1CC[C@]2(NC(=O)Cn3cnnn3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Yield: 33 %

Procedure:
The title compound was prepared in 33% yield from methyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-amino-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate following the same procedure as described for the preparation of 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(3-(dimethylamino)propanamido)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoic acid, except 1-H-tetrazole-1-acetic acid was used instead of 3-(dimethylamino)propionic acid hydrochloride in Step 1. LCMS: m/e 638.7 (M−H)−, 1.98 min (method 6). 1H NMR (500 MHz, 1:1 CDCl3:MeOD) δ=9.10 (s, 1H), 7.93 (d, J=8.2 Hz, 2H), 7.39 (s, 1H), 7.21 (d, J=8.2 Hz, 2H), 5.30 (dd, J=1.5, 6.1 Hz, 1H), 5.27 (d, J=1.5 Hz, 2H), 4.78 (d, J=1.2 Hz, 1H), 4.65 (s, 1H), 2.71 (dt, J=5.2, 11.1 Hz, 1H), 2.64-2.56 (m, 1H), 2.34 (dd, J=8.1, 12.7 Hz, 1H), 2.13 (dd, J=6.4, 17.1 Hz, 1H), 2.00-1.86 (m, 2H), 1.80 (d, J=11.0 Hz, 1H), 1.74 (br. s., 1H), 1.72 (s, 3H), 1.71-1.66 (m, 1H), 1.62-1.30 (m, 11H), 1.29-1.22 (m, 1H), 1.20-1.14 (m, 1H), 1.12 (s, 3H), 1.10 (d, J=4.3 Hz, 1H), 1.03 (s, 6H), 0.95 (s, 3H), 0.94 (s, 3H).
Reaction SMILES: P(Cl)(Cl)(Cl)(Cl)Cl.S[C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][C:11]=2[N:12]=1.[CH3:18][N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>C1(C)C=CC=CC=1>[CH3:18][N:19]1[CH2:24][CH2:23][N:22]([C:8]2[O:9][C:10]3[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][C:11]=3[N:12]=2)[CH2:21][CH2:20]1
Reactant: CN1CCNCC1
Reactant: Cc1ccc2oc(S)nc2c1
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: Cc1ccc2oc(N3CCN(C)CC3)nc2c1
Temperature: 100 °C

Procedure:
Phosphorus pentachloride (227 mg) was dissolved in anhydrous toluene (3 ml), the resulting solution was mixed with 2-mercapto-5-methylbenzoxazole (150 mg) which has been obtained in the same manner as described in Reference Example 1, and the mixture was then stirred with heating at 100° C. for 2 hours. With cooling in an ice bath, to this was added dropwise N-methylpiperazine (1 ml). After 20 minutes of stirring, the thus obtained mixture was extracted with ethyl acetate, and the organic layer was washed with saturated sodium bicarbonate aqueous solution and saturated brine in that order. After drying with magnesium sulfate, the solvent was evaporated under a reduced pressure, and the resulting residue was purified by a silica gel column chromatography (methylene chloride:methanol=10:1) to obtain the title compound 2-(4-methyl-1-piperazinyl)-5-methylbenzoxazole (188 mg).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[CH:4][C:3]=1[C:12]([F:15])([F:14])[F:13].[N:16]1[CH:21]=[CH:20][N:19]=[CH:18][C:17]=1[C:22]1[CH:23]=[CH:24][C:25]([NH2:28])=[N:26][CH:27]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.C(OCC)(=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH:28][C:25]2[CH:24]=[CH:23][C:22]([C:17]3[CH:18]=[N:19][CH:20]=[CH:21][N:16]=3)=[CH:27][N:26]=2)=[O:11])=[CH:4][C:3]=1[C:12]([F:15])([F:14])[F:13]
Reactant: O=C(O)Cc1ccc(Br)c(C(F)(F)F)c1
Reactant: Nc1ccc(-c2cnccn2)cn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(Cc1ccc(Br)c(C(F)(F)F)c1)Nc1ccc(-c2cnccn2)cn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of 2-(4-bromo-3-(trifluoromethyl)phenyl)acetic acid 46-6 (128 mg, 0.5 mmol), 5-(pyrazin-2-yl)pyridin-2-amine 86-3 (95 mg, 0.55 mmol) and o-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU, 214 mg, 0.55 mmol) in DMF (2 mL) was added diispropylethyl amine (DIEA, 250 μL, 1.5 mmol) at room temperature. The mixture was stirred at room temperature for 2 hours. The mixture was diluted with ethyl acetate (50 mL), washed with saturated NaHCO3 aqueous solution, water and brine, dried over Na2SO4, and concentrated by rotary evaporation. The crude product was purified by silica gel flash chromatography, eluted with 5% methanol in dichloromethane to give 2-(4-bromo-3-(trifluoromethyl)phenyl)-N-(5-(pyrazin-2-yl)pyridin-2-yl)acetamide 118-1 as pale orange solid. MS m/z 438.2 (M+1)
Reaction SMILES: C([O:4][C:5]1[CH:13]=[C:12]2[C:8]([CH2:9][CH2:10][C@H:11]2[CH2:14][CH2:15][NH:16][C:17](=[O:20])[CH2:18][CH3:19])=[CH:7][C:6]=1[Br:21])C=C.O.Cl.C(OCC)(=O)C.C(N(CC)[C:33]1[CH:38]=CC=C[CH:34]=1)C>>[CH2:38]([C:13]1[C:5]([OH:4])=[C:6]([Br:21])[CH:7]=[C:8]2[C:12]=1[C@H:11]([CH2:14][CH2:15][NH:16][C:17](=[O:20])[CH2:18][CH3:19])[CH2:10][CH2:9]2)[CH:33]=[CH2:34]
Reactant: C=CCOc1cc2c(cc1Br)CC[C@H]2CCNC(=O)CC
Reactant: CCN(CC)c1ccccc1
Agent: Cl
Solvent: O
Solvent: CCOC(C)=O
Product: C=CCc1c(O)c(Br)cc2c1[C@H](CCNC(=O)CC)CC2
Temperature: 202.5 °C
Reaction time: 2.5 h
Yield: 80 %

Procedure:
A suspension of (S)-N-[2-(6-allyloxy-5-bromoindan-1-yl)ethyl]propionamide (50.75 g, 144 mmol.) in N,N-diethylaniline (150 mL) was stirred for 2.5 hours at 200-205° C. under argon atmosphere. The reaction mixture was cooled, followed by distilling off N,N-diethylaniline under reduced pressure to leave an oily residue. To the residue were added water (50 mL), 2N HCl (50 mL) and ethyl acetate (100 mL). The mixture was subjected to extraction twice to extract the organic matter. The extract solution was washed with a saturated aqueous saline solution and water, which was then dried over anhydrous magnesium sulfate, followed by distilling off the solvent under reduced pressure. The residue was purified by means of silica gel column chromatography (ethyl acetate:hexane=7:3) to afford the title compound (yield 40.6 g, 80%).
Reaction SMILES: [Br:1][CH:2]([CH3:12])[C:3]([NH:5][C:6]([CH3:11])([CH3:10])[C:7]([OH:9])=[O:8])=O.C(N(CC)CC)C.ClC(OCC)=O>CC(C)=O>[Br:1][CH:2]([C:3]1[O:8][C:7](=[O:9])[C:6]([CH3:11])([CH3:10])[N:5]=1)[CH3:12]
Reactant: CC(Br)C(=O)NC(C)(C)C(=O)O
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: CC(Br)C1=NC(C)(C)C(=O)O1
Temperature: 25 °C
Reaction time: 2 h
Yield: 75.2 %

Procedure:
To a stirring mixture of 2-(2-bromo-propionylamino)-2-methyl-propionic acid (50.0 g; 0.21 mol), triethylamine (23.37 g; 0.23 mol) and 150 mL acetone, cooled with an ice bath, was added a solution of ethyl chloroformate (25.07 g; 0.23 mol) in 40 mL acetone over a period of 10 minutes. The reaction mixture was then allowed to warm to room temperature and was stirred for 2 hours. The mixture was then filtered, and the solid was washed with 150 mL ether. The combined filtrate was concentrated under vacuum. Ether (100 mL) was added to the residue, and the mixture was filtered. After removal of the solvent under vacuum, the filtrate residue was distilled under reduced pressure (63-64° C.; 1 mmHg) to give 34.73 g (75%) of a colorless oil.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]2[CH2:7][CH2:8][CH2:9][CH2:10][C:4]=2[C:3]=1[C:11]([OH:13])=O.S(Cl)(Cl)=O.[NH2:18][C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=1[OH:26]>>[Br:1][C:2]1[S:6][C:5]2[CH2:7][CH2:8][CH2:9][CH2:10][C:4]=2[C:3]=1[C:11]([NH:18][C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=1[OH:26])=[O:13]
Reactant: Nc1ccc(F)cc1O
Reactant: O=C(O)c1c(Br)sc2c1CCCC2
Solvent: O=S(Cl)Cl
Product: O=C(Nc1ccc(F)cc1O)c1c(Br)sc2c1CCCC2

Procedure:
In the same manner as in Starting Material Synthesis Example 60 and using 2-bromo-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylic acid, thionyl chloride and 2-amino-5-fluorophenol, 2-bromo-4,5,6,7-tetrahydro-N-(4-fluoro-2-hydroxyphenyl)-benzo[b]thiophene-3-carboxamide is obtained.
Reaction SMILES: Br[CH:2]([C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:29])[CH2:11][N:12]2[C:17](=[O:18])[CH:16]=[C:15]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][N:22]=3)[CH:14]=[N:13]2)=[C:6]([CH3:30])[CH:5]=1)[CH3:3].[CH3:31][NH:32][CH3:33]>C(Cl)Cl>[CH3:31][N:32]([CH3:33])[CH:2]([C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:29])[CH2:11][N:12]2[C:17](=[O:18])[CH:16]=[C:15]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][N:22]=3)[CH:14]=[N:13]2)=[C:6]([CH3:30])[CH:5]=1)[CH3:3]
Reactant: COc1ccc(COc2cnn(CC(=O)c3ccc(C(C)Br)cc3C)c(=O)c2)nc1
Reactant: CNC
Solvent: ClCCl
Product: COc1ccc(COc2cnn(CC(=O)c3ccc(C(C)N(C)C)cc3C)c(=O)c2)nc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-{2-[4-(1-Bromo-ethyl)-2-methyl-phenyl]-2-oxo-ethyl}-5-(5-methoxy-pyridin-2-ylmethoxy)-2H-pyridazin-3-one (preparation 10d, 1.55 g, 3.28 mmol) in CH2Cl2 (5 mL) is added a solution of dimethylamine (2 M in THF, 4.9 mL, 9.8 mmol). The reaction mixture is stirred overnight at room temperature. After dilution with CH2Cl2, the mixture is washed with aqueous NaHCO3 solution. The organic layer is dried over MgSO4 and evaporated under reduced pressure. The crude product is purified via reverse phase HPLC chromatography (Phenomenex Gemini C18, gradient 30%→95% methanol in water+0.1% NH4OH, 120 mL/min).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[CH:5][C:6]=1[C:7]([NH2:9])=[O:8].CCN(CC)CC.[C:17](Cl)(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[N:20][CH:19]=1>C1COCC1>[C:7]([C:6]1[CH:5]=[CH:4][S:3][C:2]=1[NH:1][C:17](=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[N:20][CH:19]=1)(=[O:8])[NH2:9]
Reactant: NC(=O)c1ccsc1N
Reactant: O=C(Cl)c1cccnc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: NC(=O)c1ccsc1NC(=O)c1cccnc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 107.7 %

Procedure:
To a solution of 2-aminothiophene-3-carboxamide (800 mg, 5.63 mmol, 1.0 eq.) in THF (15 mL) and Et3N (626 mg, 6.19 mmol, 1.1 eq.) was added nicotinoyl chloride (795 mg, 5.63 mmol, 1.0 eq.) in anhydrous THF (15 mL) dropwise. The resulted mixture was stirred at room temperature overnight. After the reaction was completed, the volatiles were evaporated. The residue was washed with CH2Cl2 (20 mL). The resulting solid was collected and dried in vacuo to give 1.50 g of N-(3-carbamoylthiophen-2-yl)nicotinamide as a brown solid (quantitative yield). LCMS m/z=248.1 (M+1) (Method B) (retention time=1.34 min).
Reaction SMILES: CC(O)=O.C[O:6][CH:7](OC)[CH2:8][CH:9]1[C:13](=[O:14])[CH2:12][CH2:11][CH:10]1[CH2:15][C:16]([O:18][CH3:19])=[O:17]>O>[O:14]=[C:13]1[CH2:12][CH2:11][CH:10]([CH2:15][C:16]([O:18][CH3:19])=[O:17])[CH:9]1[CH2:8][CH:7]=[O:6]
Reactant: COC(=O)CC1CCC(=O)C1CC(OC)OC
Solvent: O
Solvent: CC(=O)O
Product: COC(=O)CC1CCC(=O)C1CC=O
Temperature: 45 °C
Yield: 89 %

Procedure:
In a 4 liter jacketed reactor, a mixture of 1,236 liter of AcOH and 1,236 liter of water was heated to 45° C. Then to this mixture were added 494 g of methyl [2-(2,2-dimethoxyethyl)-3-oxocyclopentyl]acetate. The resulting reaction medium was stirred at 46-49° C. until completion of the conversion of the acetal to aldehyde. Distillation under vacuum allowed for the direct isolation of the purified title compound with a yield of 89% (overall yield from Example 1: 66%).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]3[NH:14][C:13]4[CH2:15][CH2:16][NH:17][CH2:18][C:12]=4[C:7]=3[CH:8]=[N:9]2)=[CH:4][CH:3]=1.F[C:20]1[CH:30]=[CH:29][C:23]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:22][CH:21]=1.C[N+]1([O-])CCOCC1.C([O-])([O-])=O.[Cs+].[Cs+]>O.CS(C)=O>[CH2:27]([O:26][C:24](=[O:25])[C:23]1[CH:29]=[CH:30][C:20]([N:17]2[CH2:16][CH2:15][C:13]3[NH:14][C:6]4[C:5]5[C:10](=[CH:11][C:2]([Cl:1])=[CH:3][CH:4]=5)[N:9]=[CH:8][C:7]=4[C:12]=3[CH2:18]2)=[CH:21][CH:22]=1)[CH3:28]
Reactant: Clc1ccc2c(c1)ncc1c3c([nH]c12)CCNC3
Reactant: CCOC(=O)c1ccc(F)cc1
Agent: C[N+]1([O-])CCOCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: O
Product: CCOC(=O)c1ccc(N2CCc3[nH]c4c(cnc5cc(Cl)ccc54)c3C2)cc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 2.3 %

Procedure:
A mixture of 1.5 g (5.8 mmol) of 3-chloro-8,9,10,11-tetrahydro-7H-pyrido[3',4':4,5]pyrrolo[3,2-c]quinoline, 0.979 g (5.8 mmol) of ethyl 4-fluorobenzoate, 0.68 g (5.8 mmol) of 4-methylmorpholine N-oxide, 3.78 g (11.6 mmol) of Cs2CO3 and 10 ml of dimethylsulfoxide is stirred overnight at 80° C. The reaction mixture is allowed to cool and is diluted with water to yield a brown precipitate which is collected by filtration and dried. The crude product is purified by flash column chromatography (5% methanol in chloroform) to yield 0.055 g (2%) of the title compound as a yellow solid: m.p. 241°-243° C.; m/e 405.