Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].C(OC([N:9]1[C@H:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C@H:12]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:11]=[C:10]1[NH:26][CH2:27][C:28]1[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=1)=O)(C)(C)C>CCOC(C)=O>[ClH:1].[C:14]1([C@H:13]2[C@@H:12]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[NH:11][C:10]([NH:26][CH2:27][C:28]3[CH:29]=[CH:30][C:31]([F:34])=[CH:32][CH:33]=3)=[N:9]2)[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CC(C)(C)OC(=O)N1C(NCc2ccc(F)cc2)=N[C@@H](c2ccccc2)[C@H]1c1ccccc1
Agent: Cl
Solvent: CCOC(C)=O
Product: Fc1ccc(CNC2=N[C@@H](c3ccccc3)[C@@H](c3ccccc3)N2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Hydrogen chloride is bubbled into a solution of 85 (0.69 g, 1.58 mmol) in EtOAc (40 mL) for 2 min, and the solution is stirred at RT overnight and then at 45° C. for 3 h. The solvent is removed by rotary evaporation, and the residue crystallized from dichloromethane and Et2O to give 0.52 g of the product 86. 1H NMR (DMSO-d6) δ 9.80-8.40 (m, 3H), 7.60-7.45 (m, 2H), 7.35-7.25 (m, 2H), 7.15-6.95 (m, 6H), 6.95-6.80 (m, 4H), 5.50 (s, 2H), 4.58 (d, 2H); MS: m/z 346 (M++1).
Reaction SMILES: [NH2:1][CH:2]([CH:7]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH3:23])[CH:17]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH3:15])[CH:9]=1)[C:3]([O:5]C)=[O:4].Cl>>[NH2:1][CH:2]([CH:7]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH3:15])[CH:9]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH3:23])[CH:17]=1)[C:3]([OH:5])=[O:4]
Reactant: COC(=O)C(N)C(c1cccc(OC)c1)c1cccc(OC)c1
Agent: Cl
Product: COc1cccc(C(c2cccc(OC)c2)C(N)C(=O)O)c1
Temperature: 0 °C

Procedure:
6.0 g (19.0 mmol) of methyl 2-amino-3,3-di(3-methoxyphenyl)propionate were refluxed in 140 ml of 6 normal hydrochloric acid for 6 hours. The mixture was then cooled to 0° C., and the precipitate was filtered off, washed with water and dried. The solid was then dissolved in 50 ml of ethanol, 20 ml of propene oxide were added and the mixture was refluxed for 30 minutes. After cooling, the precipitate was filtered off, washed with ethanol and dried. 2.20 g (38.4%) of a white powder of melting piont 168-173° C. were obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[CH2:5][NH2:6].[CH3:11][O:12][C:13](=[O:34])[C:14]1[CH:19]=[CH:18][C:17]([C:20]2[N:21]=[C:22](Cl)[C:23]3[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[S:26][C:24]=3[N:25]=2)=[CH:16][CH:15]=1>>[CH3:11][O:12][C:13](=[O:34])[C:14]1[CH:19]=[CH:18][C:17]([C:20]2[N:21]=[C:22]([NH:6][CH2:5][C:4]3[CH:7]=[CH:8][C:9]([Cl:10])=[C:2]([Cl:1])[CH:3]=3)[C:23]3[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[S:26][C:24]=3[N:25]=2)=[CH:16][CH:15]=1
Reactant: COC(=O)c1ccc(-c2nc(Cl)c3cc(C(F)(F)F)sc3n2)cc1
Reactant: NCc1ccc(Cl)c(Cl)c1
Product: COC(=O)c1ccc(-c2nc(NCc3ccc(Cl)c(Cl)c3)c3cc(C(F)(F)F)sc3n2)cc1

Procedure:
The reaction procedure as above wherein 3,4-dichlorobenzylamine is reacted with 4-(4-chloro-6-trifluoromethyl-thieno-[2,3-d]-pyrimidin-2-yl)-benzoic acid methylester yields 4-[4-(3,4-dichlorobenzylamino)-6-trifluoromethyl-thieno-[2,3-d]-pyrimidin-2-yl]-benzoic acid methylester.
Reaction SMILES: CO.[CH3:3][S:4][C:5]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17]2([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)OCC[O:18]2)[CH:12]=1)([CH3:10])[C:6]([O:8][CH3:9])=[O:7].Cl>O>[CH3:3][S:4][C:5]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17](=[O:18])[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:12]=1)([CH3:10])[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)C(C)(SC)c1cccc(C2(c3ccccc3)OCCO2)c1
Agent: Cl
Solvent: O
Solvent: CO
Product: COC(=O)C(C)(SC)c1cccc(C(=O)c2ccccc2)c1
Yield: 95 %

Procedure:
Methanol (10 ml) and 1 ml of water was added to 2.52 g of methyl α-methylthio-α-[m-(2-phenyl-1,3-dioxa-2-cyclopentyl)phenyl]propionate, and 0.2 ml of conc. hydrochloric acid was added. The mixture was heated for 20 minutes under reflux. After cooling, 20 ml of water was added, and the mixture was extracted with 50 ml and 10 ml respectively of methylene chloride. The extract was washed twice with 10 ml of water, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was chromatographed on a column of silica gel using methylene chloride as an eluent to afford 2.10 g of methyl α-methylthio-α-(m-benzoylphenyl)-propionate as a colorless oil in a yield of 95%.
Reaction SMILES: O.[OH-].[Na+].[CH3:4][C:5]([C:7]1([Cl:10])[CH2:9][CH2:8]1)=[O:6].[Cl:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]=O)=[CH:14][CH:13]=1>C(O)C>[Cl:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]=[CH:4][C:5]([C:7]2([Cl:10])[CH2:9][CH2:8]2)=[O:6])=[CH:14][CH:13]=1
Reactant: CC(=O)C1(Cl)CC1
Reactant: O=Cc1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(C=Cc1ccc(Cl)cc1)C1(Cl)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 90 %

Procedure:
50 ml of water and 10 pellets of solid sodium hydroxide are added at room temperature to a mixture of 0 g (0.5 mol) of 1-chlorocyclopropyl methyl ketone, 70 g (0.5 mol) of 4-chlorobenzaldehyde and 250 ml of ethanol. The mixture is stirred at room temperature for 16 hours. The precipitated solid is then filtered off with suction. In this manner, 108.5 g (89% of theory) of 1-chlorocyclopropyl 4-chlorophenylethenyl ketone are obtained in the form of a solid substance of melting point 92° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:7][C:8]3[C:13]([S:14][C:15]=2[CH:16]=1)=[CH:12][C:11]([O:17][CH3:18])=[CH:10][CH:9]=3.C(=O)([O-])[O-].[K+].[K+].I[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]>C(OCC)(=O)C.CCCCCC>[CH2:26]([N:7]1[C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:16][C:15]=2[S:14][C:13]2[C:8]1=[CH:9][CH:10]=[C:11]([O:17][CH3:18])[CH:12]=2)[CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]
Reactant: CCCCCCI
Reactant: COc1ccc2c(c1)Sc1cc(OC)ccc1N2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCCCCCN1c2ccc(OC)cc2Sc2cc(OC)ccc21

Procedure:
A suspension of 15.0 g (57.8 mmol) of 3,7-dimethoxyphenothiazine, 31.9 g (0.231 mmol) of powdered potassium carbonate, 61.29 g (0.289 mol) of 1 -iodohexane and 1.6 g (5.0 mmol) of tris-[2-(2-methoxymethoxy)ethyl]amine was heated to 110° for 64 hours. The working up was effected analogously to that described in Example 4.1.1.b. After chromatography on silica gel with ethyl acetate/hexane (1:4) 18.33 g (91.8%) of 10-hexyl-3,7-dimethoxy-phenothiazine were obtained as a brownish oil.
Reaction SMILES: [F:1][S:2]([F:17])([F:16])([F:15])([F:14])[C:3]1[CH:8]=[CH:7][C:6]([CH:9]=[CH:10][C:11](O)=[O:12])=[CH:5][CH:4]=1.C(Cl)(=O)C(Cl)=O.[NH3:24]>O1CCCC1.CN(C)C=O>[F:1][S:2]([F:17])([F:16])([F:15])([F:14])[C:3]1[CH:8]=[CH:7][C:6]([CH:9]=[CH:10][C:11]([NH2:24])=[O:12])=[CH:5][CH:4]=1
Reactant: N
Reactant: O=C(O)C=Cc1ccc(S(F)(F)(F)(F)F)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: NC(=O)C=Cc1ccc(S(F)(F)(F)(F)F)cc1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a suspension of 5.70 g (20.8 mmol) 3-(4-pentafluorosulfanyl-phenyl)-acrylic acid in 30 ml tetrahydrofuran and 0.21 ml N,N-dimethyl formamide a solution of 3.47 ml (27.4 mmol) oxalyl chloride in 5.0 ml tetrahydrofuran was added dropwise at 0° C. within 10 min. Stirring was continued at 0–5° C. for 30 min. and 3 h at room temperature thereafter. The resulting solution was cooled to 0–5° C. again and then added within 15 min. to mixture of 300 ml ice and 120 ml of a 25% aqueous ammonia solution. The precipitated amide was collected, washed with water and n-heptane and dried at 40° C. in vacuo. Yield 5.17 g (91%) 3-(4-pentafluorosulfanyl-phenyl)-acrylamide.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[C:9]([Br:11])[C:8](=[O:12])[N:7]([C@H:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH3:14])[C:6]=1[CH2:21][N:22]([CH2:33][C:34]([O:36][CH3:37])=[O:35])S(C1C=CC(C)=CC=1)(=O)=O)=O.C[O-].[Na+].Cl>CO>[CH3:37][O:36][C:34]([C:33]1[C:3]([OH:2])=[C:5]2[C:6](=[CH:21][N:22]=1)[N:7]([C@H:13]([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[CH3:14])[C:8](=[O:12])[C:9]([Br:11])=[CH:10]2)=[O:35]
Reactant: COC(=O)CN(Cc1c(C(=O)OC)cc(Br)c(=O)n1[C@@H](C)c1ccccc1)S(=O)(=O)c1ccc(C)cc1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1ncc2c(cc(Br)c(=O)n2[C@@H](C)c2ccccc2)c1O
Temperature: 25 °C
Reaction time: 16 h
Yield: 65.6 %

Procedure:
(S)-5-Bromo-2-{[methoxycarbonylmethyl-(toluene-4-sulfonyl)-amino]-methyl}-6-oxo-1-(1-phenyl-ethyl)-1,6-dihydro-pyridine-3-carboxylic acid methyl ester (2.26 g, 3.82 mmol) was dissolved in 80 mL of MeOH and placed in ice bath. NaOMe solution (2.6 mL, 11.5 mmol, 4.375 M in MeOH) was added and the mixture was stirred for 16 h at r.t. 1 M HCl was added to acidify the mixture, and the resulting suspension was extracted with CH2Cl2. The organic layer was dried over MgSO4 and concentrated. The crude product was purified by silica gel chromatography (30-100% CH2Cl2/hexanes) to give 1.01 g of the title compound as a pale yellow solid. MS: (−) m/z 401.24, 403.19 (M−1, 79/81Br).
Reaction SMILES: [CH2:1]([OH:4])[CH2:2][OH:3].CC1C=CC(S(O)(=O)=O)=CC=1.[OH:16][C@@:17]1([CH3:37])[CH2:22][CH2:21][C@H:20]2[C@H:23]3[C@H:33]([CH2:34][CH2:35][C@:18]12[CH3:19])[C@:31]1([CH3:32])[C@H:26]([CH2:27][C:28](=O)[CH2:29][CH2:30]1)[CH2:25][CH2:24]3>C(Cl)Cl>[CH2:1]1[O:4][C:28]2([CH2:29][CH2:30][C@@:31]3([CH3:32])[C@@H:26]([CH2:25][CH2:24][C@@H:23]4[C@@H:33]3[CH2:34][CH2:35][C@@:18]3([CH3:19])[C@H:20]4[CH2:21][CH2:22][C@@:17]3([OH:16])[CH3:37])[CH2:27]2)[O:3][CH2:2]1
Reactant: OCCO
Reactant: C[C@]12CCC(=O)C[C@@H]1CC[C@@H]1[C@@H]2CC[C@@]2(C)[C@H]1CC[C@]2(C)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Product: C[C@]12CCC3(C[C@@H]1CC[C@@H]1[C@@H]2CC[C@@]2(C)[C@H]1CC[C@]2(C)O)OCCO3

Procedure:
Ethylene glycol (20 ml.) and p-TSA (5 mg.) is added to 17β-hydroxy-17α-methyl-5α-androstan-3-one (sold by Steraloids, Inc., Wilton, N.H., 3.0 g.) in methylene chloride (20 ml.). The mixture is heated on a steam bath until most of the methylene chloride is removed. The remainder of the methylene chloride is removed on a rotary evaporator. The mixture is cooled and a small amount of a sodium bicarbonate solution and water are added and the mixture filtered. The filtered solids are washed and dried to give the title compound, NMR (CDCl3), 0.83, 0.84, 1.20 and 3.29δ.
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([C:11]([F:14])([F:13])[F:12])=[C:4](Cl)[CH:3]=1.[CH3:16][C:17]1[NH:18][CH:19]=[CH:20][N:21]=1.O>CN(C)C=O>[NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([C:11]([F:14])([F:13])[F:12])=[C:4]([N:18]2[CH:19]=[CH:20][N:21]=[C:17]2[CH3:16])[CH:3]=1
Reactant: Nc1cc(Cl)c(C(F)(F)F)cc1[N+](=O)[O-]
Reactant: Cc1ncc[nH]1
Solvent: CN(C)C=O
Solvent: O
Product: Cc1nccn1-c1cc(N)c([N+](=O)[O-])cc1C(F)(F)F
Reaction time: 30 h
Yield: 61.9 %

Procedure:
To a solution of 20.0 g (~83 mmol) 4-amino-2-chloro-5-nitrobenzotrifluoride in 50 ml dry N,N-dimethylformamide was added 30 g (~370 mmol) 2-methylimidazole, and stirring was continued at 180° C. for 30 h. The reaction mixture was poured into 400 ml water to give the title compound (14.7 g; 62%). M.p. 222°-225° C.
Reaction SMILES: Br[C:2]1[CH:13]=[CH:12][C:5]([CH:6]=[CH:7][C:8]([O:10][CH3:11])=[O:9])=[CH:4][CH:3]=1.[CH:14]#[C:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]>C(N(CC)CC)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:14]([C:2]1[CH:13]=[CH:12][C:5]([CH:6]=[CH:7][C:8]([O:10][CH3:11])=[O:9])=[CH:4][CH:3]=1)#[C:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: C#CCCCCCCCCCCC
Reactant: COC(=O)C=Cc1ccc(Br)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCC#Cc1ccc(C=CC(=O)OC)cc1
Yield: 46 %

Procedure:
To a deaerated solution of methyl 4-bromocinnamate (9.64 g, 40 mmole) in dry triethylamine (120 ml) was added triphenylphosphine (308 mg) followed by 1-tridecyne (8.00 g, 45 mmole) and palladium (II) acetate (92 mg) under nitrogen. The mixture was heated to reflux for 24 hours, the reaction being followed by hplc. After this time the mixture was cooled and the precipitated triethylamine hydrobromide was filtered off and washed with a little triethylamine. The filtrate was evaporated to a red solid which was chromatographed on 220 g of silica eluting with petroleum ether [bp 60-80]-dichloromethane (3:2) to give 6.26 g (47%) of title compound as a pale yellow solid of mp (MeOH) 57°-59° C., υmax (mull) 1710, 1630, 1600, 1315, 1170, 1000, 830 cm-1, δ(CDCl3). 0.85 (3H, distorted t, terminal CH3), 1.28 (18H, m, alkylene chain), 2.38 (2 H, t, J 6.5 Hz, C≡C--CH2), 3.78 (3H, s, ester CH3), 6.37 (1H, d, J 16 Hz, =CHCO2), 7.42 (4H, near s, arom), 7.63 (1H, d, J 16 Hz, ArCH=)
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:13]1[CH:18]=[CH:17][C:16](CO)=[CH:15][CH:14]=1)[CH2:9][C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH:21]N1C(=O)CCC1=O.C1(N=C=NC2CCCCC2)CCCCC1>O1CCCC1.C(#N)C>[C:1]([O:5][C:6]([N:8]([C:13]1[CH:18]=[CH:17][C:16]([OH:21])=[CH:15][CH:14]=1)[CH2:9][C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C1CCC(=O)N1O
Reactant: CC(C)(C)OC(=O)N(CC(=O)O)c1ccc(CO)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1CCOC1
Solvent: CC#N
Product: CC(C)(C)OC(=O)N(CC(=O)O)c1ccc(O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 115.6 %

Procedure:
To a solution of dl-N-t-butoxycarbonyl-p-hydroxymethylphenylglycine (3.0 g, 0.011 mole) and N-hydroxysuccinimide (1.25 g., 0.011 mole) in 10 ml dry tetrahydrofuran and 50 ml dry acetonitrile was added N,N'-dicyclohexylcarbodiimide (2.238 g., 0.011 mole). The mixture was stirred at room temperature overnight. The dicyclohexylurea was filtered off and the filtrate taken to dryness under reduced pressure. The resulting solid was triturated with ether and filtered to give the N-hydroxysuccinimide ester of N-t-butoxycarbonyl-p-hydroxyphenylglycine (3.4 g., 83 percent yield) m.p. 141°-148° dec.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][C:2]1=[O:6].C(N(CC)CC)C.[Cl:14][C:15]1[CH:33]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:31]=[CH:30][C:16]=1[O:17][C:18]1[CH:19]=[C:20]([C:24]([N+:27]([O-:29])=[O:28])=[CH:25][CH:26]=1)[C:21](Cl)=[O:22]>C1(C)C=CC=CC=1>[Cl:14][C:15]1[CH:33]=[C:32]([C:34]([F:35])([F:37])[F:36])[CH:31]=[CH:30][C:16]=1[O:17][C:18]1[CH:19]=[C:20]([C:24]([N+:27]([O-:29])=[O:28])=[CH:25][CH:26]=1)[C:21]([N:1]1[CH2:5][CH2:4][CH2:3][C:2]1=[O:6])=[O:22]
Reactant: O=C1CCCN1
Reactant: O=C(Cl)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: O=C1CCCN1C(=O)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Pyrrolidin-2-one (7.60 grams; 0.02 mol), triethylamine (2.0 grams; 0.02 mol) and toluene (50 mol) were placed in a three-necked, glass reaction flask equipped with stirrer, thermometer, addition funnel and drying tube. 3-(2-Chloro-4-trifluoromethylphenoxy)-6-nitrobenzoylchloride (7.60 grams; 0.02 mol) in toluene (10 ml) was added to the mixture in the flask. The mixture, after being stirred overnight at room temperature, was washed with water, dried over sodium sulfate and evaporated to give a dark oil. The oil was chromatographed using silica gel into two fractions, the first using toluene as eluant and the second fraction using an equal mixture of toluene and ethyl acetate gave the desired product as a brown oil which solidified upon standing. Trituration with isopropyl ether resulted in white crystals, melting point 88° C. This product analyzed as follows:
Reaction SMILES: Cl.O1CCCCC1[O:8][CH2:9][CH2:10][N:11]1[CH2:16][CH:15]=[C:14]([C:17]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[NH:19][CH:18]=2)[CH2:13][CH2:12]1.C(O)C.[OH-].[Na+]>O>[NH:19]1[C:20]2[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:17]([C:14]2[CH2:15][CH2:16][N:11]([CH2:10][CH2:9][OH:8])[CH2:12][CH:13]=2)=[CH:18]1
Reactant: C1=C(c2c[nH]c3ccccc23)CCN(CCOC2CCCCO2)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: OCCN1CC=C(c2c[nH]c3ccccc23)CC1
Reaction time: 2 h

Procedure:
15.6 ml of 6 N hydrochloric acid were added to a mixture of the product of Step A and 156 ml of 95% ethanol and the mixture was stirred for 31/2 hours under an inert atmosphere and was then poured into one liter of water. 10 ml of sodium hydroxide were added to the mixture which was then filtered. The recovered crystals were washed with water and dried under reduced pressure to obtain 4.068 g of 4-(1H-indol-3-yl)-3,6-dihydro-1-(2H)-pyridine-ethanol melting at 164°-165° C.
Reaction SMILES: [O:1]=[S:2]1(=[O:18])[N:6]2[CH2:7][CH2:8][N:9](C(OC(C)(C)C)=O)[CH2:10][C@@H:5]2[CH2:4][CH2:3]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[S:2]1(=[O:1])(=[O:18])[N:6]2[CH2:7][CH2:8][NH:9][CH2:10][C@@H:5]2[CH2:4][CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CCN2[C@@H](CCS2(=O)=O)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=S1(=O)CC[C@H]2CNCCN21
Temperature: 25 °C
Yield: 83.6 %

Procedure:
To a solution of tert-butyl (3aS)-1,1-dioxo-2,3,3a,4,6,7-hexahydroisothiazolo[2,3-a]pyrazine-5-carboxylate (360 mg, 1.303 mmol) in DCM (5 mL) at 0° C. was added TFA (1.25 mL, 16.22 mmol) dropwise and the reaction was stirred and warmed slowly to ambient temperature over 45 mins. The reaction mixture was concentrated in vacuo and the residue was adsorbed onto a pre-wetted (methanol/DCM (1:1), 10 mL) SCX-2 cartridge (10 g) and flushed with DCM/methanol (1:1, 50 mL) and then the basic components eluted with 2 M ammonia in methanol (50 mL). The basic eluent was evaporated to dryness to afford (S)-hexahydro-2H-isothiazolo[2,3-a]pyrazine 1,1-dioxide as a colourless oil (192 mg, 84%).
Reaction SMILES: [H-].[Na+].[C:3]([O:6][C:7]1[CH:8]=[C:9]([CH:30]([O:33][CH3:34])[O:31][CH3:32])[CH:10]=[C:11]2[C:19]=1[CH:18]([CH2:20][O:21][C:22](=[O:24])[NH2:23])[C:17]1([O:26][C:27](=[O:29])[CH3:28])[O:25][N:12]2[CH2:13][CH:14]2[CH:16]1[NH:15]2)(=[O:5])[CH3:4].CI.[C:37](O)(=O)C>O1CCCC1>[C:3]([O:6][C:7]1[CH:8]=[C:9]([CH:30]([O:31][CH3:32])[O:33][CH3:34])[CH:10]=[C:11]2[C:19]=1[CH:18]([CH2:20][O:21][C:22](=[O:24])[NH2:23])[C:17]1([O:26][C:27](=[O:29])[CH3:28])[O:25][N:12]2[CH2:13][CH:14]2[CH:16]1[N:15]2[CH3:37])(=[O:5])[CH3:4]
Reactant: CC(=O)O
Reactant: COC(OC)c1cc(OC(C)=O)c2c(c1)N1CC3NC3C(OC(C)=O)(O1)C2COC(N)=O
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: C1CCOC1
Product: COC(OC)c1cc(OC(C)=O)c2c(c1)N1CC3C(N3C)C(OC(C)=O)(O1)C2COC(N)=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a suspension of sodium hydride (60% in oil, 4 mg) in tetrahydrofuran (0.5 ml) was added a solution of B-isomer of 8-carbamoyloxymethyl-4-dimethoxymethyl-14-oxa-1,11-diazatetracyclo[7.4.1.02,7.010,12 ]tetradeca-2,4,6-trien-6,9-diyl diacetate (20 mg) in tetrahydrofuran (2.0 mg) in an ice-water bath. To this solution was added methyl iodide (0.4 ml) in an ice-water bath. After stirring for 3 hours at ambient temperature, acetic acid (0.1 ml) was added to the reaction mixture in an ice-water bath. The resultant mixture was evaporated in vacuo and the residual oil was subjected to preparative thin layer chromatography, which was developed with a mixture of chloroform and methanol (8:1, v/v) to afford 8-carbamoyloxymethyl-4-dimethoxymethyl-11-methyl-14-oxa-1,11-diazatetracyclo[7.4.1.02,7.010,12 ]tetradeca-2,4,6-trien-6,9-diyl diacetate (11 mg).
Reaction SMILES: [F:1][C:2]([F:14])([CH3:13])[CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[CH:11]=[C:10]([NH2:12])[CH:9]=[N:8]1.[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[O:27][CH:26]=[N:25][C:24]=2[C:28](O)=[O:29])=[CH:19][CH:18]=1>>[F:14][C:2]([F:1])([CH3:13])[CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[CH:11]=[C:10]([NH:12][C:28]([C:24]2[N:25]=[CH:26][O:27][C:23]=2[C:20]2[CH:21]=[CH:22][C:17]([O:16][CH3:15])=[CH:18][CH:19]=2)=[O:29])[CH:9]=[N:8]1
Reactant: COc1ccc(-c2ocnc2C(=O)O)cc1
Reactant: CC(F)(F)CCCCn1cc(N)cn1
Product: COc1ccc(-c2ocnc2C(=O)Nc2cnn(CCCCC(C)(F)F)c2)cc1

Procedure:
Following general procedure B, starting from 1-(5,5-difluoro-hexyl)-1H-pyrazol-4-ylamine and 5-(4-methoxy-phenyl)-oxazole-4-carboxylic acid. LC-MS-conditions 05b: tR=1.12 min; [M+H]+=405.20.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][NH:7][CH2:8][C:9]1[CH:10]=[CH:11][C:12]2[N:16]=[C:15]([CH2:17][CH2:18][CH2:19][CH2:20][N:21]([CH2:25][CH2:26][CH3:27])[CH2:22][CH2:23][CH3:24])[N:14]([CH2:28][CH2:29][CH3:30])[C:13]=2[CH:31]=1.C(O)(=O)C.C[N:37]1[CH:41]=[CH:40][N:39]=[C:38]1[CH:42]=O.C([BH3-])#N.[Na+]>CO>[NH:3]1[CH:4]=[CH:5][N:1]=[C:2]1[CH2:6][N:7]([CH2:8][C:9]1[CH:10]=[CH:11][C:12]2[N:16]=[C:15]([CH2:17][CH2:18][CH2:19][CH2:20][N:21]([CH2:22][CH2:23][CH3:24])[CH2:25][CH2:26][CH3:27])[N:14]([CH2:28][CH2:29][CH3:30])[C:13]=2[CH:31]=1)[CH2:42][C:38]1[NH:37][CH:41]=[CH:40][N:39]=1
Reactant: CCCN(CCC)CCCCc1nc2ccc(CNCc3ncc[nH]3)cc2n1CCC
Reactant: Cn1ccnc1C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CCCN(CCC)CCCCc1nc2ccc(CN(Cc3ncc[nH]3)Cc3ncc[nH]3)cc2n1CCC
Temperature: 0 °C
Reaction time: 48 h

Procedure:
The compound (64.0 mg) obtained in Example 126-1 was dissolved in methanol (1.3 ml) and added with acetic acid (0.065 ml) and 1-methyl-2-imidazole carboxaldehyde (16.6 mg), followed by cooling to 0° C. Then, the solution was added with sodium cyanoborohydride (14.2 mg) and stirred at room temperature for 2 days. After completion of the reaction, the solvent was distilled off under reduced pressure and the residue was then dissolved in chloroform. After washing with a 1 mol/l sodium hydroxide aqueous solution, the solution was subjected to extraction with chloroform. The organic layer was washed with saturated saline solution and dried with anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure. Subsequently, the residue was purified through silica gel column chromatography (chloroform/methanol) and treated with hydrochloric acid, thereby obtaining hydrochloride (30.0 mg) of the subject compound as a white solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]([C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)O)[CH:2]=1.S(Cl)([Cl:17])=O>C(Cl)Cl>[Cl:17][CH:7]([C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1)[C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1
Reactant: O=S(Cl)Cl
Reactant: OC(c1cccnc1)c1cccnc1
Solvent: ClCCl
Product: ClC(c1cccnc1)c1cccnc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 63 %

Procedure:
A round bottom flask was charged with di(pyridin-3-yl)methanol (600 mg, 3.22 mmol) and CH2Cl2 (50 mL). Thionyl chloride (353 μl, 4.83 mmol) was added and the reaction was stirred for 18 h at room temperature. The solution was concentrated under reduced pressure. The residue was chromatographed on a silica gel column (100% CH2Cl2 to 5% 2M NH3 in MeOH) and yielded 3,3′-(chloromethylene)dipyridine (415 mg, 64%). 1H NMR 400 MHz (CDCl3) δ 8.66 (d, J=2.4 Hz, 2H), 8.59 (dd, J=4.7, 1.6 Hz, 2H), 7.76 (m, 2H), 7.34 (m, 2H), 6.17 (s, 1H).
Reaction SMILES: [F:1][C:2]1[C:7]2[CH2:8][CH2:9][CH:10]([N:19]3[CH:23]=[C:22]([CH:24]4[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]4)[N:21]=[N:20]3)[C:11](=[O:18])[N:12]([CH2:13][C:14]([F:17])([F:16])[F:15])[C:6]=2[CH:5]=[CH:4][CH:3]=1.Cl.Cl[C:32]1[CH:37]=[CH:36][N:35]=[CH:34][N:33]=1.CCN(C(C)C)C(C)C>CC(O)C>[F:1][C:2]1[C:7]2[CH2:8][CH2:9][CH:10]([N:19]3[CH:23]=[C:22]([CH:24]4[CH2:29][CH2:28][N:27]([C:32]5[CH:37]=[CH:36][N:35]=[CH:34][N:33]=5)[CH2:26][CH2:25]4)[N:21]=[N:20]3)[C:11](=[O:18])[N:12]([CH2:13][C:14]([F:16])([F:17])[F:15])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: Clc1ccncn1
Reactant: O=C1C(n2cc(C3CCNCC3)nn2)CCc2c(F)cccc2N1CC(F)(F)F
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: O=C1C(n2cc(C3CCN(c4ccncn4)CC3)nn2)CCc2c(F)cccc2N1CC(F)(F)F
Temperature: 25 °C
Yield: 77 %

Procedure:
In a sealed tube, 6-fluoro-3-[4-(piperidin-4-yl)-1H-1,2,3-triazol-1-yl]-1-(2,2,2-trifluoroethyl)-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one (50 mg, 0.122 mmol), 4-chloropyrimidine hydrochloride (27.5 mg, 0.182 mmol) and DIEA (212 uL, 1.215 mmol) in 2-propanol (1.2 mL) was heated at 140° C. for 1 h. After cooling to ambient temperature and solvent removal under reduced pressure, the residue was purified by column chromatography on silica gel to afford 46 mg title compound.