Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:13])[CH2:3][CH2:4][CH:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)O.[H-].[Na+].F[C:17]1[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=1.CN(C)C=[O:30]>>[CH3:1][N:2]([CH3:13])[CH2:3][CH2:4][CH2:5][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:30][C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=2)[CH:8]=1
Reactant: Fc1ccc(C(F)(F)F)cc1
Reactant: CN(C)CCC(O)c1ccccc1
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Product: CN(C)CCCc1cccc(Oc2ccc(C(F)(F)F)cc2)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
Sodium borohydride (6.7 g) was slowly added to a solution of 3-dimethylaminopropiophenone (15.5 g) in 2-propanol (125 ml) and methanol (25 ml). After two hrs, the reaction mixture was stirred with water and extracted with ethyl acetate-ether. The organic extract was washed with water and saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and the filtrate was evaporated to give 15.2 g (97%) of 3-dimethylamino-1-phenyl-1-propanol, as an oil. A solution of 3-dimethylamino-1-phenyl-1-propanol (15 g) in dimethylformamide (75 ml) was slowly added to a suspension of sodium hydride (60% oil-dispersion, washed with hexane, 5.5 g) in dimethylformamide (20 ml). A solution of 4-fluorobenzotrifluoride (18 g) in dimethylformamide (20 ml) was added. After two hrs, the reaction mixture was stirred with ice-water and extracted with ether. The ether extract was dried over anhydrous magnesium sulfate, filtered, and the filtrate was evaporated to provide 27 g (100%) of N,N-dimethyl-3-[ 4-(trifluoromethyl)phenoxy]benzenepropanamine.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][N:16]([S:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[N+:36]([O-:38])=[O:37])(=[O:29])=[O:28])[CH:17]2[CH2:26][C:25]3[N:24]=[CH:23][CH:22]=[CH:21][C:20]=3[CH2:19][CH2:18]2)=[CH:11][CH:10]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:7][CH2:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][N:16]([CH:17]2[CH2:26][C:25]3[N:24]=[CH:23][CH:22]=[CH:21][C:20]=3[CH2:19][CH2:18]2)[S:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[N+:36]([O-:38])=[O:37])(=[O:28])=[O:29])=[CH:13][CH:14]=1
Reactant: CC(C)(C)OC(=O)NCc1ccc(CN(C2CCc3cccnc3C2)S(=O)(=O)c2ccccc2[N+](=O)[O-])cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NCc1ccc(CN(C2CCc3cccnc3C2)S(=O)(=O)c2ccccc2[N+](=O)[O-])cc1
Reaction time: 0.33 h
Yield: 57.2 %

Procedure:
To a stirred solution of (4-{[(2-Nitro-benzenesulfonyl)-(5,6,7,8-tetrahydro-quinolin-7-yl)-amino]-methyl}-benzyl)-carbamic acid tert-butyl ester (160 mg, 0.29 mmol) in anhydrous CH2Cl2 (2 mL) was added TFA (2 mL). The resultant solution was stirred at room temperature overnight. The mixture was concentrated in vacuo, dissolved with MeOH, and added NaHCO3. The mixture was stirred for 20 min, diluted with CH2Cl2, filtered through celite. The crude product was purified by flash chromatography on silica gel (1:1:98 CH3OH—NH3 H2O—CH2Cl2) afforded the title compound (75 mg, 57%) as a white foam.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[CH:11][N:10]=[CH:9]2)=[CH:4][CH:3]=1.Br[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]>C1COCC1>[Br-:1].[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N+:8]2[CH:12]=[CH:11][N:10]([CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH3:14])[CH:9]=2)=[CH:6][CH:7]=1
Reactant: Brc1ccc(-n2ccnc2)cc1
Reactant: CCCCCCCCCCCCCCBr
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCn1cc[n+](-c2ccc(Br)cc2)c1
Product: [Br-]

Procedure:
According to the general synthesis procedure, 4.5 mmol (1.00 g) 1-(4-bromophenyl)imidazole and 5.4 mmol (1.50 g, 1.47 ml) 1-bromotetradecane are dissolved in 5 ml THF and heated for 69 h to 90° C. After the reaction the product is precipitated with diethylether from the reaction solution.
Reaction SMILES: [CH:1]([C:4]1[N:8]=[C:7]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]3[C:16]4[S:23][CH:22]=[C:21]([C:24]5[CH:29]=[CH:28][C:27]([NH2:30])=[CH:26][CH:25]=5)[C:17]=4[N:18]=[CH:19][N:20]=3)[CH2:11][CH2:10]2)[O:6][N:5]=1)([CH3:3])[CH3:2].[CH2:31](OC(OCC)OCC)C.[N-:41]=[N+:42]=[N-:43].[Na+]>C(O)(=O)C>[N:30]1([C:27]2[CH:26]=[CH:25][C:24]([C:21]3[C:17]4[N:18]=[CH:19][N:20]=[C:15]([N:12]5[CH2:11][CH2:10][CH:9]([C:7]6[O:6][N:5]=[C:4]([CH:1]([CH3:3])[CH3:2])[N:8]=6)[CH2:14][CH2:13]5)[C:16]=4[S:23][CH:22]=3)=[CH:29][CH:28]=2)[CH:31]=[N:43][N:42]=[N:41]1
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)c1noc(C2CCN(c3ncnc4c(-c5ccc(N)cc5)csc34)CC2)n1
Reactant: CCOC(OCC)OCC
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(C)c1noc(C2CCN(c3ncnc4c(-c5ccc(-n6cnnn6)cc5)csc34)CC2)n1
Temperature: 100 °C
Reaction time: 12 h

Procedure:
4-(4-(4-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-1-yl)thieno[3,2-d]pyrimidin-7-yl)benzenamine was dissolved in acetic acid, and triethylorthoformate and sodium azide were added thereto followed by stirring at 100° C. for 12 hr. When the reaction is terminated, the resulting mixture was distilled under a reduced pressure to remove acetic acid, and ethyl acetate was added thereto, followed by washing with satuated sodium bicarbonate and water. Subsequently, the resultant was dried over anhydrous sodium sulfate, filtered and distilled under a reduced pressure to obtain the title compound.
Reaction SMILES: [SH:1][C@@H:2]([CH2:6][CH:7]([CH3:9])[CH3:8])[C:3]([OH:5])=[O:4].[C:10]1(C)C=CC(S(O)(=O)=O)=C[CH:11]=1.O>C(O)C.C(Cl)(Cl)Cl>[SH:1][C@@H:2]([CH2:6][CH:7]([CH3:9])[CH3:8])[C:3]([O:5][CH2:10][CH3:11])=[O:4]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CC(C)C[C@H](S)C(=O)O
Solvent: ClC(Cl)Cl
Solvent: CCO
Solvent: O
Product: CCOC(=O)[C@@H](S)CC(C)C
Reaction time: 4 h
Yield: 3077.9 %

Procedure:
A solution of 7.2 g (48.6 mmole) of (S)-2-mercapto-4 methylpentanoic acid [J. A. Yankeelov, Jr., K. F. Fok, and D. J. Carothers, J. Org Chem., 43, 1623 (1978)] and 219 mg of p-toluenesulfonic acid in 12 ml of absolute ethanol and 12 ml of CHCl3 was stirred under reflux with collection of liberated H2O in a Dean-Stark trap pre-filled with CHCl3. After 4 hours, the solution was cooled, diluted with an equal volume of CHCl3, and washed successively with H2O, saturated aqueous NaHCO3 solution, and H2O. The organic phase was dried over MgSO4, filtered, and concentrated to give 6.90 g (81%) of an oil, [α]20D -19.0° (c 2, ether), TLC in 9:1 hexane-ethyl acetate. The structure was verified by 200 MHz NMR (CDCl3).
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[CH:3]([OH:8])[C:4]([F:7])([F:6])[F:5].Cl[C:12](Cl)([O:14]C(=O)OC(Cl)(Cl)Cl)Cl.C(N(CC)C(C)C)(C)C.[Cl:32][C:33]1[CH:38]=[CH:37][C:36]([CH:39]([C:47]2[CH:52]=[CH:51][C:50]([Cl:53])=[CH:49][CH:48]=2)[N:40]2[CH2:45][CH2:44][NH:43][CH2:42][CH:41]2[CH3:46])=[CH:35][CH:34]=1>O.C(#N)C>[Cl:53][C:50]1[CH:49]=[CH:48][C:47]([CH:39]([C:36]2[CH:35]=[CH:34][C:33]([Cl:32])=[CH:38][CH:37]=2)[N:40]2[CH2:45][CH2:44][N:43]([C:12]([O:8][CH:3]([C:4]([F:7])([F:6])[F:5])[C:2]([F:10])([F:9])[F:1])=[O:14])[CH2:42][CH:41]2[CH3:46])=[CH:52][CH:51]=1
Reactant: OC(C(F)(F)F)C(F)(F)F
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CC1CNCCN1C(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Solvent: CC#N
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CC1CN(C(=O)OC(C(F)(F)F)C(F)(F)F)CCN1C(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 15.9 %

Procedure:
A 50 mL round-bottom flask was charged with 1,1,1,3,3,3-hexafluoropropan-2-ol (336 mg, 2.00 mmol, 1.00 equiv), acetonitrile (20 mL), triphosgene (198 mg, 0.670 mmol, 0.330 equiv). N,N-diisopropylethylamine (942 mg, 7.29 mmol, 3.65 equiv) was added dropwise. The mixture was stirred for 2 hours at room temperature. Then 1-[bis(4-chlorophenyl)methyl]-2-methylpiperazine (670 mg, 2.00 mmol, 1.00 equiv) was added. The resulting solution was stirred for 2 hours at room temperature and diluted with H2O (20 mL). The resulting solution was extracted with dichloromethane (3×20 mL) and the organic layers were combined, washed with water (3×20 mL) and dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was chromatographed on a silica gel column with ethyl acetate/petroleum ether (1/5). The product (218 mg) was purified by preparative HPLC using the following gradient conditions: 20% CH3CN/80% phase A increasing to 80% CH3CN over 10 min, then to 100% CH3CN over 0.1 min, holding at 100% CH3CN for 1.9 min, then reducing to 20% over 0.1 min, and holding at 20% for 1.9 min, on a waters 2767-5 chromatograph. Column: X-bridge Prep C18, 19*150 mm Sum; Mobile phase: Phase A: aqueous NH4HCO3 (0.05%); Phase B: CH3CN; Detector, UV220 & 254 nm. Purification resulted in 56.4 mg (5% yield) of 1,1,1,3,3,3-hexafluoropropan-2-yl 4-[bis(4-chlorophenyl)methyl]-3-methylpiperazine-1-carboxylate as a light yellow solid. 1H NMR 300 MHz (CDCl3) δ 7.26-7.36 (m, 8H), 5.69-5.77 (m, 1H), 4.56-4.62 (m, 1H), 3.81-3.93 (m, 1H), 3.67-3.75 (m, 1H), 3.34-3.38 (m, 1H), 3.11-3.28 (m, 1H), 2.97 (br, 1H), 2.39-2.58 (m, 2H), 0.95-0.99 (m, 3H). LCMS: (ESI, m/z): 528 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:13]=[CH:12][C:5]([O:6][CH2:7][C@@H:8]([OH:11])[C:9]#[CH:10])=[CH:4][CH:3]=1.[Br:14]N1C(=O)CCC1=O>CC(C)=O.[N+]([O-])([O-])=O.[Ag+]>[Br:14][C:10]#[C:9][C@H:8]([OH:11])[CH2:7][O:6][C:5]1[CH:12]=[CH:13][C:2]([F:1])=[CH:3][CH:4]=1
Reactant: C#C[C@H](O)COc1ccc(F)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Solvent: CC(C)=O
Product: O[C@@H](C#CBr)COc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of (3S)-4-(4-fluorophenoxy)-3-hydroxy-1-butyne (2.5 g, 14 mmol), N-bromosuccinimide (NBS) (2.74 g, 15.4 mmol) and AgNO3 (0.12 g, 0.7 mmol) in acetone (70 mL) was stirred at ambient temperature. The pale solution became cloudy over 30 minutes. The mixture was concentrated under vacuum and the resulting residue was filtered through a plug of silica gel (1×5 cm) eluted with 1:4 ethyl acetate:hexane to obtain (3S)-1-bromo-4-(4-fluorophenoxy)-3-hydroxy-1-butyne, a compound of formula (CC), as a pale yellow oil containing some ethyl acetate, 4.75 g (quant.); 1H NMR (CDCl3) δ 3.95-4.15 (m, 2H), 4.75 (m, 1H), 6.86 (m, 2H), 6.97 (m, 2H) ppm.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[S:11][C:10]([C:12]([OH:14])=O)=[CH:9][CH:8]=1.S(Cl)([Cl:17])=O>>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[S:11][C:10]([C:12]([Cl:17])=[O:14])=[CH:9][CH:8]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1ccc(-c2ccccn2)s1
Product: O=C(Cl)c1ccc(-c2ccccn2)s1

Procedure:
A mixture of 1.0 g of 5-(2-pyridinyl)thiophene-2-carboxylic acid and 5 ml of thionyl chloride is refluxed for 2.5 hours. The mixture is concentrated to dryness under vacuum. Toluene is added (2 times) and the solvent removed under vacuum to give the product as a glass.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])=[O:10])=[N:6][CH:7]=1.[C:15](=[O:18])([O-])[O-].[Na+].[Na+].[CH2:21]1[CH2:25]O[CH2:23][CH2:22]1>C(OCC)(=O)C.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:7][N:6]1[C@H:5]2[C@@:21]([CH3:25])([C:21]3[CH:25]=[CH:12][C:11]([C:2]4[CH:3]=[CH:4][C:5]([NH:8][C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])=[O:10])=[N:6][CH:7]=4)=[CH:9][C:22]=3[CH2:23][CH2:4]2)[CH2:22][CH2:23][C:15]1=[O:18]
Reactant: O=C([O-])[O-]
Reactant: C1CCOC1
Reactant: CC(C)(C)C(=O)Nc1ccc(Br)cn1
Agent: [Pd]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Product: CN1C(=O)CC[C@]2(C)c3ccc(-c4ccc(NC(=O)C(C)(C)C)nc4)cc3CC[C@@H]12
Yield: 32 %

Procedure:
A 15 mL round bottom flask was charged with (+)-(4aR)-(10bR)-4-methyl-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one-8-boronic acid 178 mg, 0.65 mmol), tetrakis (triphenylphosphine) palladium (0) (23 mg, 0.02 mmol), 5-bromo-2-(t-butylcarbonylamino)pyridine 167 mg, 0.65 mmol), 0.65 mL of 2M aqueous sodium carbonate and mL of THF, fitted with a reflux condenser, and the stirred mixture was heated at 80°, under nitrogen, for 24 h. The mixture was cooled, diluted with ethyl acetate (75 mL) and washed with brine (2×25 mL). The combined organic extracts were dried over sodium sulfate, concentrated, and purified by silica gel chromatography (ethyl acetate eluent) to give 84 mg (32%) of the title compound as a brown solid. mp 248°-250°. FDMS: m/e=405. α[D]589 =+70.74 (c=0.45, chloroform).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH2:10][CH2:11][CH2:12][CH3:13])=[C:7]([C:14](=[O:34])[C:15]3[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH2:23][CH2:24][N:25]([CH2:30][CH2:31][CH2:32][CH3:33])[CH2:26][CH2:27][CH2:28][CH3:29])=[CH:17][CH:16]=3)[C:6]=2[CH:35]=1.[CH3:36][S:37]([Cl:40])(=[O:39])=[O:38]>ClCCl>[CH3:13][CH2:12][CH2:11][CH2:10][C:8]1[O:9][C:5]2[CH:4]=[CH:3][C:2]([NH:1][S:37]([CH3:36])(=[O:39])=[O:38])=[CH:35][C:6]=2[C:7]=1[C:14]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH2:23][CH2:24][N:25]([CH2:26][CH2:27][CH2:28][CH3:29])[CH2:30][CH2:31][CH2:32][CH3:33])=[CH:17][CH:16]=1)=[O:34].[ClH:40]
Reactant: CS(=O)(=O)Cl
Reactant: CCCCc1oc2ccc(N)cc2c1C(=O)c1ccc(OCCCN(CCCC)CCCC)cc1
Solvent: ClCCl
Product: CCCCc1oc2ccc(NS(C)(=O)=O)cc2c1C(=O)c1ccc(OCCCN(CCCC)CCCC)cc1
Product: Cl

Procedure:
Under a temperature range from room temperature to reflux temperature, preferably reflux temperature, 5-amino-2-butyl-3-(4-[3-(dibutylamino)propoxy]benzoyl)benzofuran is reacted with methanesulfonyl chloride in dichloromethane solvent to provide a crude dronedarone hydrochloride, wherein an amount of dichloromethane used is in the range of 0 to 30 parts by volume, preferably 10 to 25 parts by volume, more preferably 15 to 20 parts by volume based on 1 part by weight of the compound A, and an amount of methanesulfonyl chloride used is in the range of 1 to 15 equivalents, and preferably 5 to 10 equivalents, and more preferably 6 to 9 equivalents relative to the compound A to obtain a reaction mixture. When the reaction is terminated, the reaction mixture is treated with alkaline reagent such as alkali metal hydroxides (such as sodium hydroxide), alkali metal carbonate or alkali metal bicarbonate such as sodium bicarbonate, preferably sodium bicarbonate. Then the obtained dronedarone is salified in the presence of hydrochloric acid in acetone solvent. Subsequently, the crude dronedarone hydrochloride is quickly crystallized. If desired, the crude dronedarone hydrochloride is purified to obtain highly pure dronedarone hydrochloride. Then the obtained dronedarone hydrochloride can be converted to highly pure dronedarone via alkaline solvent, or if desired, further converted to other pharmaceutically acceptable salts of dronedarone.
Reaction SMILES: [C:1]([CH:3]1[CH2:6][N:5]([C:7](=[O:33])[C@H:8]([NH:12][C:13]([C:15]2[C:23]3[C:18](=[N:19][CH:20]=[C:21](Br)[N:22]=3)[N:17]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30])[CH:16]=2)=[O:14])[CH:9]2[CH2:11][CH2:10]2)[CH2:4]1)#[N:2].[Cl:34][C:35]1[CH:40]=[CH:39][N:38]=[C:37]2[CH:41]=[C:42]([Sn](CCCC)(CCCC)CCCC)[S:43][C:36]=12.CCOC(C)=O>CN(C=O)C.[Cu]I.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([CH:3]1[CH2:6][N:5]([C:7](=[O:33])[C@H:8]([NH:12][C:13]([C:15]2[C:23]3[C:18](=[N:19][CH:20]=[C:21]([C:42]4[S:43][C:36]5[C:37](=[N:38][CH:39]=[CH:40][C:35]=5[Cl:34])[CH:41]=4)[N:22]=3)[N:17]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30])[CH:16]=2)=[O:14])[CH:9]2[CH2:11][CH2:10]2)[CH2:4]1)#[N:2]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cc2nccc(Cl)c2s1
Reactant: C[Si](C)(C)CCOCn1cc(C(=O)N[C@@H](C(=O)N2CC(C#N)C2)C2CC2)c2nc(Br)cnc21
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C[Si](C)(C)CCOCn1cc(C(=O)N[C@@H](C(=O)N2CC(C#N)C2)C2CC2)c2nc(-c3cc4nccc(Cl)c4s3)cnc21
Temperature: 90 °C
Reaction time: 16 h
Yield: 85.1 %

Procedure:
To a solution of 2-bromo-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(3-cyano-azetidin-1-yl)-1-cyclopropyl-2-oxo-ethyl]-amide (180 mg, 0.34 mmol) and 7-chloro-2-tributylstannanyl-thieno[3,2-b]pyridine (162 mg, 0.35 mmol) in DMF (3 mL) were added copper(I) iodide (13.5 mg, 0.071 mmol) and tetrakis(triphenylphosphine)palladium(0) (20.4 mg, 0.018 mmol) under argon atmosphere. The reaction mixture was stirred for 16 h at 90° C. then poured into EtOAc (25 mL) and washed with water (4×30 mL). The organic extracts were dried over Na2SO4 and evaporated under vacuum. The crude residue was purified by column chromatography (SiO2, 11 g, CH2Cl2 100% to CH2Cl2:EtOAc 4:6 in 25 min) to afford 180 mg (82%) of 2-(7-chloro-thieno[3,2-b]pyridin-2-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(3-cyano-azetidin-1-yl)-1-cyclopropyl-2-oxo-ethyl]-amide.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:7]([C:9]1[C:13]([N+:14]([O-:16])=[O:15])=[C:12]([C:17]([NH2:19])=[O:18])[NH:11][N:10]=1)[CH3:8].Cl[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=1.O>C(#N)C>[CH2:7]([C:9]1[C:13]([N+:14]([O-:16])=[O:15])=[C:12]([C:17]([NH2:19])=[O:18])[N:11]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=2)[N:10]=1)[CH3:8]
Reactant: ClCc1ccccn1
Reactant: CCc1n[nH]c(C(N)=O)c1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: O
Product: CCc1nn(Cc2ccccn2)c(C(N)=O)c1[N+](=O)[O-]
Temperature: 60 °C
Yield: 30.7 %

Procedure:
Caesium carbonate (1.414 kg, 4.34 mol) was added to a suspension of the title compound of example (4d) (800 g, 4.34 mol) in acetonitrile (51) and the mixture warmed to 60° C. 2-Chloromethylpyridine (664.7 g, 5.23 mol) was added and the reaction heated at 70° C. for 7 hours, then water (9.5 l) added and the reaction mixture cooled to 10° C. Granulation of this mixture gave a precipitate which was filtered and dried to afford 3-ethyl-4-nitro-1-(pyridin-2-yl)methyl-pyrazole-5-carboxamide (367 g). Sodium chloride (1.58 kg) was added to the filtrate and the solution extracted with ethyl acetate (4×1.75 l). The combined organic extracts were distilled to remove approximately 10 l of solvent, toluene (5.6 l) added over 35 minutes to the hot (69-76° C.) solution and the mixture allowed to cool. The resulting suspension was granulated at <10° C. for 30 minutes, filtered, the solid washed with ethyl acetate:toluene (50:50) 600 ml) and dried (60° C.) to afford the title compound (624 g 52%) as a light brown solid. δ (DMSOd6): 1.08 (3H,t), 3.02 (2H,q), 5.53 (2H,s), 7.34 (2H,m), 7.65 (1H,s), 7.82 (1H,m), 7.93 (1H,s), 8.52 (1H,d). LRMS: m/z 276 (M+1)+.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=1)=[O:6].[C:14]([NH:22][CH:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+].O>Cl.CCOCC>[C:14]([NH:22][CH:23]1[CH2:28][CH2:27][N:26]([CH2:2][CH2:3][CH2:4][C:5]([C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=2)=[O:6])[CH2:25][CH2:24]1)(=[O:21])[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1.[ClH:1]
Reactant: O=C(NC1CCNCC1)c1ccccc1
Reactant: O=C(CCCCl)c1ccc(Cl)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOCC
Product: O=C(CCCN1CCC(NC(=O)c2ccccc2)CC1)c1ccc(Cl)cc1
Temperature: 100 °C

Procedure:
4-Chloro-4'-chlorobutyrophenone (2.17 g.) was added to a well-ground mixtue of 4-benzamidopiperidine (2.04 g.) and anhydrous potassium carbonate (1.38 g.) and the mixture heated to 100° C. for 1 hour. The solid residue was slurried with hot water (100 ml.) for 3 hours, filtered, washed with ether and dried to give a cream coloured solid. This solid was dissolved in ethanolic hydrogen chloride, treated with ether and then cooled to 0° C. to give the title compound as its hydrochloride (1.9 g.) m.p. 242°-243° C. (Found: C, 62.8; H, 6.2; N, 6.55. C22H25ClN2O2. HCl requires C, 62.7; H, 6.0; N, 6.65%).
Reaction SMILES: [Cl:1][C:2]1[C:9]([Cl:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.C([O-])(=O)C.[NH4+].[N+:16]([CH3:19])([O-:18])=[O:17].C(O)(=O)C>C(Cl)(Cl)Cl>[Cl:1][C:2]1[C:9]([Cl:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[CH:19][N+:16]([O-:18])=[O:17]
Reactant: O=Cc1cccc(Cl)c1Cl
Reactant: C[N+](=O)[O-]
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: O=[N+]([O-])C=Cc1cccc(Cl)c1Cl
Reaction time: 0.5 h

Procedure:
28.0 g of 2,3-dichlorobenzaldehyde, 13.9 g of ammonium acetate, 13.9 ml of nitromethane and 120 ml of glacial acetic acid are refluxed for 2 hours. After cooling, the reaction mixture is poured onto ice and stirred for 30 minutes. The formed precipitate is then filtered off, washed with water and dried in vacuo to thus obtain the product in the form of slightly yellowish crystals, m.p. 89°-91° C. IR (CHCl3) in cm-1 : 1650 (C=C); 1530 and 1350 (NO2). NMR (CDCl3) in ppm: 7.2-7.7 (m, 4H); 8.50 (d,J=15 Hz, 1H).
Reaction SMILES: [H-].[Na+].[C:3]1([CH:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[NH:12][C:11](=[O:19])[CH2:10]2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:20]1(C2C3C(=CC=CC=3)NC(=O)C2)C=CC=CC=1.CI>C1COCC1>[CH3:20][N:12]1[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:9]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:10][C:11]1=[O:19]
Reactant: O=C1CC(c2ccccc2)c2ccccc2N1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CI
Product: CN1C(=O)CC(c2ccccc2)c2ccccc21
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a suspension of NaH (1.2 eq., 0.537 g of 60% dispersion in mineral oil) in THF (50 mL) under N2 at 0° C. was added the product from Step A (1.0 eq., 2.50 g) in THF (50 mL) via cannula over a period of 5 minutes. The resulting pale yellow mixture was stirred at 0° C. for 10 minutes, then MeI (2.0 eq., 1.39 mL) was added. The opaque yellow mixture was allowed to slowly (ice bath not removed) warm to ambient temperature with stirring for 15 hours. 1M Aq. HCl (50 mL) and EtOAc (250 mL) were added and the phases partitioned. The organic phase was washed with dilute NaHCO3 (1×100 mL), brine (1×100 mL), then dried over MgSO4, filtered, concentrated, and the residue purified by flash chromatography eluting with CH2Cl2/EtOAc (19:1 gradient to 15:1) to provide 1-methyl-4-phenyl-3,4-dihydrocarbostyril.
Reaction SMILES: [OH:1][CH:2]1[CH:6]2[O:7][C:8](=[O:15])[CH:9]3[CH:10]([C:11]([O:13][CH3:14])=[O:12])[CH:3]1[CH2:4][CH:5]23.[Cl:16][CH2:17][C:18](Cl)=[O:19].N1C=CC=CC=1.C(=O)([O-])O.[Na+]>O1CCCC1>[Cl:16][CH2:17][C:18]([O:1][CH:2]1[CH:6]2[O:7][C:8](=[O:15])[CH:9]3[CH:10]([C:11]([O:13][CH3:14])=[O:12])[CH:3]1[CH2:4][CH:5]23)=[O:19]
Reactant: COC(=O)C1C2CC3C(OC(=O)C31)C2O
Reactant: O=C(Cl)CCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: COC(=O)C1C2CC3C(OC(=O)C31)C2OC(=O)CCl
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.6 %

Procedure:
In 180 ml of tetrahydrofuran were dissolved 25.0 g of methyl 6-hydroxy-2-oxohexahydro-3,5-methano-2H-cyclopenta-[b]furan-7-carboxylate and 16.0 g of 2-chloroacetic acid chloride. To the solution below 20° C., 10.7 g of pyridine was added dropwise. The solution was stirred at room temperature for 1 hour and combined with 40 g of a 5% aqueous solution of sodium hydrogen carbonate, followed by ordinary post-treatment. Recrystallization from isopropyl ether gave 31.5 g of the target compound (yield 93%).