Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: NC1C(C)=CC(Cl)=CC=1C(NC)=[O:5].ClCCl.[Cl:17][C:18]1[C:19]([N:25]2[C:29]([C:30](Cl)=[O:31])=[CH:28][C:27]([C:33]([F:36])([F:35])[F:34])=[N:26]2)=[N:20][CH:21]=[C:22]([Cl:24])[CH:23]=1.C(N(CC)CC)C>O>[Cl:17][C:18]1[C:19]([N:25]2[C:29]([C:30]([OH:5])=[O:31])=[CH:28][C:27]([C:33]([F:36])([F:35])[F:34])=[N:26]2)=[N:20][CH:21]=[C:22]([Cl:24])[CH:23]=1
Reactant: CNC(=O)c1cc(Cl)cc(C)c1N
Reactant: O=C(Cl)c1cc(C(F)(F)F)nn1-c1ncc(Cl)cc1Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: O=C(O)c1cc(C(F)(F)F)nn1-c1ncc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 125.7 %

Procedure:
To a 100 mL flask, 2-amino-5-chloro-N,3-dimethylbenzamide (0.24 g, 1.22 mmol), dichloromethane (20 mL), 1-(3,5-dichloropyridin-2-yl)-3-(trifluoromethyl)-1H-pyrazole-5-carbonyl chloride (0.42 g, 1.22 mmol) and triethylamine (0.12 g, 1.22 mmol) were added sequentially. The reaction mixture was stirred for 3 hours at room temperature. The reaction mixture was poured into water (100 mL) and extracted with ethyl acetate (2×100 mL). The organic layer was washed with saturated sodium carbonate solution and saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography to give the compound 3 (0.50 g) as a white solid in 81% yield.
Reaction SMILES: [C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[Cl:16])=[CH:13][CH:12]=[CH:11][C:10]=2[CH3:17])(=[O:5])[CH2:2][CH2:3][CH3:4].[CH3:18][O:19][C:20]1[CH:26]=[C:25]([O:27][CH3:28])[CH:24]=[CH:23][C:21]=1[NH2:22]>O1CCOCC1>[ClH:16].[C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:22][C:21]1[CH:23]=[CH:24][C:25]([O:27][CH3:28])=[CH:26][C:20]=1[O:19][CH3:18])=[CH:13][CH:12]=[CH:11][C:10]=2[CH3:17])(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: COc1ccc(N)c(OC)c1
Reactant: CCCC(=O)c1cnc2c(C)cccc2c1Cl
Solvent: C1COCCO1
Product: CCCC(=O)c1cnc2c(C)cccc2c1Nc1ccc(OC)cc1OC
Product: Cl
Yield: 52.4 %

Procedure:
3-Butyryl-4-chloro-8-methylquinoline (2.48 g, 10 mmol), 2,4-dimethoxyaniline (3.06 g, 20 mmol) and 1,4-dioxan (20 ml) were heated at reflux for 1.5 hours, the solvent evaporated, the residue taken up in dichloromethane, washed with aqueous sodium bicarbonate, dried and evaporated. Chromatography (silica gel, 1% methanol in chloroform), conversion to the hydrochloride salt and recrystallisation from aqueous methanol gave 3-butyryl-4-(2,4-dimethoxyphenylamino)-8-methylquinoline hydrochloride (2.10 g, 57%), m.p. 190°-192°.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[NH:7][C:6]1=[O:14].Cl.[CH3:16][N:17]1[C:21](=[O:22])[C:20]2([CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[N:19]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:18]1.C(=O)([O-])[O-].[Na+].[Na+].CC(C)CC(=O)C>O>[O:14]=[C:6]1[N:5]([CH2:4][CH2:3][CH2:2][N:25]2[CH2:26][CH2:27][C:20]3([N:19]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[CH2:18][N:17]([CH3:16])[C:21]3=[O:22])[CH2:23][CH2:24]2)[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[NH:7]1
Reactant: O=c1[nH]c2ccccc2n1CCCCl
Reactant: CN1CN(c2ccccc2)C2(CCNCC2)C1=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)CC(C)C
Product: CN1CN(c2ccccc2)C2(CCN(CCCn3c(=O)[nH]c4ccccc43)CC2)C1=O
Yield: 50 %

Procedure:
A mixture of 4.8 parts of 1-(3-chloropropyl)-1,3-dihydro-2H-benzimidazol-2-one, 5.6 parts of 3-methyl-1-phenyl-1,3,8-triazaspiro[4,5]decan-4-one hydrochloride, 7.4 parts of sodium carbonate and 200 parts of 4-methyl-2-pentanone is stirred and refluxed overnight with water-separator. The reaction mixture is cooled, water is added and the layers are separated. The 4-methyl-2-pentanone-phase is dried, filtered and evaporated. The residue is purified by column-chromatography over silica gel using a mixture of trichloromethane and 5% of methanol as eluent. The pure fractions are collected and the eluent is evaporated. The residue is triturated in 4-methyl-2-pentanone. The solid product is filtered off and dried, yielding 4.1 parts (50%) of 8-[3-(1,3-di-hydro-2-oxo-2H-benzimidazol-1-yl)propyl]-3-methyl-1-phenyl-1,3,8-triazaspiro[4,5]decan-4-one; mp. 186° C.
Reaction SMILES: [F:1][C:2]([F:23])([CH2:8][CH2:9][C:10]([F:22])([F:21])[C:11]([F:20])([F:19])[C:12]([F:18])([F:17])[C:13]([F:16])([F:15])[F:14])[C:3]([O:5]CC)=[O:4].[OH-].[Na+:25].O.CO>C(OCC)(=O)C>[F:1][C:2]([F:23])([CH2:8][CH2:9][C:10]([F:21])([F:22])[C:11]([F:19])([F:20])[C:12]([F:17])([F:18])[C:13]([F:14])([F:15])[F:16])[C:3]([O-:5])=[O:4].[Na+:25]
Reactant: CCOC(=O)C(F)(F)CCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CO
Product: O=C([O-])C(F)(F)CCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Temperature: 50 °C
Reaction time: 2 h
Yield: 96.7 %

Procedure:
A mixture of ethyl 2,2,5,5,6,6,7,7,8,8,8-undecafluorooctanoate (46.4 g, 0.125 mol), sodium hydroxide (5.11 g, 0.128 mol), water (80 mL) and methanol (80 mL) was stirred at ambient temperature for 2 hr and at 50° C. for 2 hr. After cooling, ethyl acetate was added to extract the product. The organic layer was washed with brine and dried over magnesium sulfate, and then the solvent was removed in vacuo. After drying overnight under high vacuum, 44 g (96% yield) of sodium 2,2,5,5,6,6,7,7,8,8,8-undecafluorooctanoate was obtained as a white solid having a melting point of 155°-157° C.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].CS([C:11]1[N:12]=[C:13]([CH2:37][CH2:38][CH3:39])[C:14]2[N:19]=[C:18]([C:20]3[CH:34]=[C:33]([CH3:35])[C:23]([O:24][CH2:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])=[C:22]([CH3:36])[CH:21]=3)[O:17][C:15]=2[N:16]=1)(=O)=O.[F:40][C:41]1[CH:46]=[CH:45][C:44]([F:47])=[CH:43][C:42]=1[OH:48]>CN1C(=O)CCC1.C(OCC)(=O)C>[F:40][C:41]1[CH:46]=[CH:45][C:44]([F:47])=[CH:43][C:42]=1[O:48][C:11]1[N:12]=[C:13]([CH2:37][CH2:38][CH3:39])[C:14]2[N:19]=[C:18]([C:20]3[CH:34]=[C:33]([CH3:35])[C:23]([O:24][CH2:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])=[C:22]([CH3:36])[CH:21]=3)[O:17][C:15]=2[N:16]=1
Reactant: Oc1cc(F)ccc1F
Reactant: CCCc1nc(S(C)(=O)=O)nc2oc(-c3cc(C)c(OCC(=O)OC(C)(C)C)c(C)c3)nc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: CCCc1nc(Oc2cc(F)ccc2F)nc2oc(-c3cc(C)c(OCC(=O)OC(C)(C)C)c(C)c3)nc12
Temperature: 110 °C
Yield: 38.1 %

Procedure:
68 mg of potassium carbonate were added to a solution of 107 mg of tert-butyl [4-(5-methanesulfonyl-7-propyloxazolo[5,4-d]pyrimidin-2-yl)-2,6-dimethylphenoxy]acetate in 1.1 ml of NMP, and 32 mg of 2,5-difluorophenol were then added. The reaction mixture was heated in a microwave synthesizer to 110° C. for 5 min and then cooled and poured onto ice. The precipitated compound was taken up in ethyl acetate, washed with water until neutral, dried over sodium sulfate, filtered and concentrated. The crude product was chromatographed on silica gel (heptane/ethyl acetate), giving 45 mg (38%) of the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10](=O)[CH2:11]S(C)=O.[C:16]([C:18]1[CH:27]=[CH:26][C:21]([CH:22]=[CH:23][CH:24]=O)=[CH:20][CH:19]=1)#[N:17].COC1C2OC(C=CC3C=CC(C#N)=CC=3)=CC(=O)C=2C=CC=1>>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2]2[O:1][C:24]([CH:23]=[CH:22][C:21]3[CH:20]=[CH:19][C:18]([C:16]#[N:17])=[CH:27][CH:26]=3)=[CH:11][CH2:10][C:3]=2[CH:4]=1
Reactant: COc1ccc(O)c(C(=O)CS(C)=O)c1
Reactant: N#Cc1ccc(C=CC=O)cc1
Agent: COc1cccc2c(=O)cc(C=Cc3ccc(C#N)cc3)oc12
Product: COc1ccc2c(c1)CC=C(C=Cc1ccc(C#N)cc1)O2

Procedure:
This was prepared by reacting 11.4g of 2'-hydroxy-5'-methoxy-2-(methylsulfinyl)acetophenone with 7.85 g of p-cyanocinnamaldehyde in analogous fashion to 4-[2-(8-methoxy-4-oxo-4H-1-benzopyran-2-yl) ethenyl]benzonitrile. The material was recrystallized from toluene. mp 224°-26°; yield 6.5g (43%); λ max mμ (ε) 224 (20,600), 294 (21,900), 332 (43,500); ν max 820 (m), 980 (ms), 1080 (m), 1290 (m), 1580 (m), 1620 (s), 1645 (s), 2240 (m) cm-1.
Reaction SMILES: OC(C(F)(F)F)=O.[CH2:8]1[C:11]2([CH2:15][CH2:14][CH2:13][NH:12]2)[CH2:10][O:9]1.[F:16][CH:17]([F:46])[C:18]1[CH:23]=[CH:22][C:21]([C:24]2[O:28][C:27]([C:29]([N:31]3[CH2:34][CH:33]([O:35][C:36]4[CH:43]=[CH:42][C:39]([CH:40]=O)=[CH:38][C:37]=4[O:44][CH3:45])[CH2:32]3)=[O:30])=[N:26][N:25]=2)=[CH:20][CH:19]=1.C(N(CC)CC)C.[Na].C([O-])(O)=O.[Na+]>ClCCl>[CH2:10]1[C:11]2([CH2:15][CH2:14][CH2:13][N:12]2[CH2:40][C:39]2[CH:42]=[CH:43][C:36]([O:35][CH:33]3[CH2:34][N:31]([C:29]([C:27]4[O:28][C:24]([C:21]5[CH:20]=[CH:19][C:18]([CH:17]([F:46])[F:16])=[CH:23][CH:22]=5)=[N:25][N:26]=4)=[O:30])[CH2:32]3)=[C:37]([O:44][CH3:45])[CH:38]=2)[CH2:8][O:9]1
Reactant: C1CNC2(C1)COC2
Reactant: COc1cc(C=O)ccc1OC1CN(C(=O)c2nnc(-c3ccc(C(F)F)cc3)o2)C1
Agent: O=C([O-])O
Agent: [Na+]
Agent: [Na]
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cc(CN2CCCC23COC3)ccc1OC1CN(C(=O)c2nnc(-c3ccc(C(F)F)cc3)o2)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 62.6 %

Procedure:
2-Oxa-5-azaspiro[3.4]octane TFA salt (0.1.1 g, ca. 70%, 0.34 mmol) and 4-(1-(5-(4-(difluoromethyl)phenyl)-1,3,4-oxadiazole-2-carbonyl)azetidin-3-yloxy)-3-methoxybenzaldehyde (0.146 g, 0.34 mmol) were mixed in dichloromethane (2 ml). Triethylamine (0.1 ml, 0.72 mmol) was added, followed by sodium triacetoxyhydroborate (0.144 g, 0.68 mmol). The mixture was stirred at ambient temperature overnight (16 h). LC-MS showed some remaining starting material and an additional amount of sodium triacetoxyhydroborate (0.113 g) was added. Stirring continued for 6 h. The reaction mixture was then diluted with dichloromethane (10 ml) and shaken with NaHCO3 (sat. 3 ml). The two phases were separated by the use of a phase separator. Evaporation of the organic phase afforded a residue, which was purified by preparative reverse-phase HPLC at pH 10 to give 0.112 g (62%) of the desired product as a solid.
Reaction SMILES: [C:1]([C:3]1[CH:4]([C:16]2[C:25]3[S:24][C:23]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)=[CH:22][C:21](=O)[C:20]=3[CH:19]=[CH:18][CH:17]=2)[C:5]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:6]([CH3:10])[NH:7][C:8]=1[CH3:9])#[N:2].[BH4-].[Na+].C(O)(C)(C)C>CO>[C:1]([C:3]1[CH:4]([C:16]2[C:25]3[S:24][C:23]([C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=4)=[CH:22][CH2:21][C:20]=3[CH:19]=[CH:18][CH:17]=2)[C:5]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:6]([CH3:10])[NH:7][C:8]=1[CH3:9])#[N:2]
Reactant: CCOC(=O)C1=C(C)NC(C)=C(C#N)C1c1cccc2c(=O)cc(-c3ccccc3)sc12
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: CO
Product: CCOC(=O)C1=C(C)NC(C)=C(C#N)C1c1cccc2c1SC(c1ccccc1)=CC2
Reaction time: 8 h

Procedure:
3 mmol of Ethyl 5-cyano-1,4-dihydro-2,6-dimethyl-4-(4-oxo-2-phenyl-4H-1-benzothiopyran-8-yl)-3-pyridinecarboxylate (DE 33 11 005) and 15 mmol of NaBH4 are initially introduced into 10 ml of t-butanol, 1.8 ml of MeOH are added at 60° C. and the mixture is kept at 65° C. for 8 hours. Customary working up gives the title compound.
Reaction SMILES: [CH:1]([NH:4][C:5](=O)[CH:6]([Cl:8])[Cl:7])([CH3:3])[CH3:2].Cl.P(Cl)(Cl)([Cl:13])=O>P(Cl)(Cl)(Cl)(Cl)Cl>[CH:1]([N:4]=[C:5]([Cl:13])[CH:6]([Cl:8])[Cl:7])([CH3:3])[CH3:2]
Reactant: CC(C)NC(=O)C(Cl)Cl
Reactant: O=P(Cl)(Cl)Cl
Agent: Cl
Agent: ClP(Cl)(Cl)(Cl)Cl
Product: CC(C)N=C(Cl)C(Cl)Cl
Yield: 65 %

Procedure:
N-isopropyldichloroacetamide, 249.5 grams (2.94 mole), and 210 milliliters of phosphorous pentachloride, 306.5 grams (2.94 mole), was added and the mixture was stirred vigorously and heated at reflux until hydrogen chloride evolution ceased. The phosphorous oxychloride was stripped off at reduced pressure. Distillation at 4.5 millimeters gave 360 grams (65% yield) of N-isopropyldichloroacetimidoyl chloride, b.p. 63°-72° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][CH:21]=1)[O:5][CH2:6][CH2:7][N:8]1[C:16](=[O:17])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]1=[O:18].[CH2:22]([O:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34]OS(C)(=O)=O)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[CH2:22]([O:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][O:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][CH:21]=1)[O:5][CH2:6][CH2:7][N:8]1[C:9](=[O:18])[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:16]1=[O:17])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CS(=O)(=O)OCCCCCOCc1ccccc1
Reactant: O=C1c2ccccc2C(=O)N1CCOc1cccc(O)c1
Product: O=C1c2ccccc2C(=O)N1CCOc1cccc(OCCCCCOCc2ccccc2)c1

Procedure:
Alkylation reaction of phenol 24 with methanesulfonic acid 5-benzyloxypentyl ester gave 2-(2-(3-(5-benzyloxypentoxy)phenoxy)ethyl)isoindoline-1,3-dione as yellow oil. Yield (1.0 g, 62%): 1H NMR (400 MHz, CDCl3) δ 7.84-7.87 (m, 2H), 7.70-7.73 (m, 2H), 7.25-7.40 (m, 5H), 7.09-7.14 (m, 1H), 6.42-6.48 (m, 3H), 4.50 (s, 2H), 4.20 (t, J=5.8 Hz, 2H), 4.10 (t, J=5.6 Hz, 2H), 3.90 (t, J=6.4 Hz, 2H), 3.64 (t, J=6.0 Hz, 2H), 3.48 (t, J=6.0 Hz, 2H), 1.40-1.80 (m, 6H).
Reaction SMILES: [H-].[Na+].[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]([OH:14])=[O:13])=[N:4]1.[C:15]1([CH3:27])[CH:20]=[C:19]([CH3:21])[CH:18]=[C:17]([CH3:22])[C:16]=1[S:23](Cl)(=[O:25])=[O:24]>CN(C=O)C.O1CCCC1>[CH3:27][C:15]1[CH:20]=[C:19]([CH3:21])[CH:18]=[C:17]([CH3:22])[C:16]=1[S:23]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]([OH:14])=[O:13])=[N:4]1)(=[O:24])=[O:25]
Reactant: O=C(O)c1n[nH]c2ccccc12
Reactant: Cc1cc(C)c(S(=O)(=O)Cl)c(C)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Cc1cc(C)c(S(=O)(=O)n2nc(C(=O)O)c3ccccc32)c(C)c1
Temperature: 0 °C

Procedure:
NaH (60% in oil, 40 mmol) is washed under argon with petroleum ether and then suspended in 60 ml of anhydrous DMF. An indazole-3-carboxylic acid solution (3.35 g, 20 mmol) in anhydrous DMF (50 ml) is added dropwise to this suspension kept at 0° C. The reaction mixture becomes clear. When the addition is complete, the medium is allowed to react for 30 min at room temperature and then the reaction mixture is again cooled to 0° C. Mesitylenesulphonyl chloride (4.82 g, 22 mmol) in solution in anhydrous tetrahydrofuran (THF) (50 ml) is added. The ice bath is removed and a suspension appears. The medium is allowed to react for 30 min at room temperature. The solvents are evaporated under vacuum and the residue is taken up in 0.1N NaOH solution. The solution obtained is washed with diethyl ether and then acidified with 6N HCl. The compound which separates is filtered, and taken up in AcOEt. The AcOEt solution is dried over Na2SO4 and then evaporated. The residue (6.18 g) is recrystallized from AcOEt/petroleum ether.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:9]2[N:13]([CH2:14][CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]3)[C:12]3[CH:21]=[C:22]([F:26])[C:23]([F:25])=[CH:24][C:11]=3[N:10]=2)=[C:6]([OH:8])[CH:7]=1.[CH3:27][O:28][C:29](=[O:39])[CH2:30][C:31]1[CH:36]=[CH:35][C:34]([CH2:37]Br)=[CH:33][CH:32]=1>>[CH3:27][O:28][C:29](=[O:39])[CH2:30][C:31]1[CH:32]=[CH:33][C:34]([CH2:37][O:8][C:6]2[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=2[C:9]2[N:13]([CH2:14][CH:15]3[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]3)[C:12]3[CH:21]=[C:22]([F:26])[C:23]([F:25])=[CH:24][C:11]=3[N:10]=2)=[CH:35][CH:36]=1
Reactant: COC(=O)Cc1ccc(CBr)cc1
Reactant: Oc1cc(Cl)ccc1-c1nc2cc(F)c(F)cc2n1CC1CCCCC1
Product: COC(=O)Cc1ccc(COc2cc(Cl)ccc2-c2nc3cc(F)c(F)cc3n2CC2CCCCC2)cc1

Procedure:
The title compound was prepared in analogy to Example 5, intermediate a, from 5-chloro-2-(1-cyclohexylmethyl-5,6-difluoro-1H-benzoimidazol-2-yl)-phenol (Example 19, intermediate a) and (4-bromomethyl-phenyl)-acetic acid methyl ester (7398-42-7). Brown solid (45%). MS (Turbo Spray): m/z=539.3 (M+H).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([I:16])=[CH:12][C:11]=2[F:17])[C:5]([NH2:18])=[CH:4][CH:3]=1.Cl[S:20]([C:23]1[N:27]([CH3:28])[C:26]([C:29]([O:31][CH3:32])=[O:30])=[CH:25][CH:24]=1)(=[O:22])=[O:21]>>[F:8][C:7]1[C:6]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([I:16])=[CH:12][C:11]=2[F:17])=[C:5]([NH:18][S:20]([C:23]2[N:27]([CH3:28])[C:26]([C:29]([O:31][CH3:32])=[O:30])=[CH:25][CH:24]=2)(=[O:21])=[O:22])[CH:4]=[CH:3][C:2]=1[F:1]
Reactant: COC(=O)c1ccc(S(=O)(=O)Cl)n1C
Reactant: Nc1ccc(F)c(F)c1Nc1ccc(I)cc1F
Product: COC(=O)c1ccc(S(=O)(=O)Nc2ccc(F)c(F)c2Nc2ccc(I)cc2F)n1C

Procedure:
According to the general procedure B, 5,6-difluoro-N1-(2-fluoro-4-iodophenyl)benzene 1,2-diamine was reacted with methyl 5-(chlorosulfonyl)-1-methyl-1H-pyrrole-2-carboxylate to obtain the title compound. 1H NMR (300 MHz, CDCl3): δ 7.37 (dd, J=1.8 & 10.5 Hz, 1H), 7.29 (m, 2H), 7.12-6.94 (m, 4H), 5.87 (dt, J=1.8, 8.4 & 17.4 Hz, 1H), 5.56 (br s, 1H), 3.65 (s, 3H), 3.75 (s, 3H).
Reaction SMILES: [NH:1]1[CH2:6][CH:5]=[C:4]([C:7]2[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[CH:9][C:8]=2[N:17]2[CH2:22][CH2:21][O:20][C:19]3[CH:23]=[C:24]([S:27]([NH:30][C:31]4[S:32][CH:33]=[CH:34][N:35]=4)(=[O:29])=[O:28])[CH:25]=[CH:26][C:18]2=3)[CH2:3][CH2:2]1.O.[C:37](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>CCOC(C)=O>[CH3:37][N:1]1[CH2:2][CH:3]=[C:4]([C:7]2[CH:12]=[C:11]([C:13]([F:14])([F:16])[F:15])[CH:10]=[CH:9][C:8]=2[N:17]2[CH2:22][CH2:21][O:20][C:19]3[CH:23]=[C:24]([S:27]([NH:30][C:31]4[S:32][CH:33]=[CH:34][N:35]=4)(=[O:28])=[O:29])[CH:25]=[CH:26][C:18]2=3)[CH2:5][CH2:6]1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: O=S(=O)(Nc1nccs1)c1ccc2c(c1)OCCN2c1ccc(C(F)(F)F)cc1C1=CCNCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: CN1CC=C(c2cc(C(F)(F)F)ccc2N2CCOc3cc(S(=O)(=O)Nc4nccs4)ccc32)CC1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
EXAMPLE 44 was prepared by charging a 10-mL round bottomed flask with 4-(2-(1,2,3,6-tetrahydropyridin-4-yl)-4-(trifluoromethyl)phenyl)-N-(thiazol-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide, (EXAMPLE 38, 0.040 g, 0.077 mmol). The reaction vessel was then flushed with N2 gas and the solid starting materials were dissolved in methanol (0.4 mL). To the resulting solution, formaldehyde 37% wt in water (0.085 mL, 1.148 mmol) was added and the mixture was stirred for 5 min at room temperature. Sodium triacetoxyborohydride (0.243 g, 1.148 mmol) was added portion wise and the resulting solution was stirred for 10 min. The reaction mixture was poured into a sep. funnel containing sat. NaHCO3 and EtOAc. The aqueous layer was washed with EtOAc (3×25 mL), the organic layers were combined and dried over Na2SO4. The organic layer was filtered and concentrated to give pure 4-(2-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-4-(trifluoromethyl)phenyl)-N-(thiazol-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide (0.030 g, 0.056 mmol) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.18 (d, J=5.58 Hz, 3 H) 2.41 (br. s., 2 H) 2.91 (br. s., 2 H) 3.57 (br. s., 3 H) 4.25 (br. s., 2 H) 5.22 (s, 1 H) 5.80 (br. s., 1 H) 6.40 (t, J=8.61 Hz, 1 H) 6.60 (d, J=3.62 Hz, 1 H) 6.85 (d, J=4.70 Hz, 1 H) 7.03-7.12 (m, 1 H) 7.13-7.22 (m, 1 H) 7.35 (d, J=4.50 Hz, 1 H) 7.46-7.63 (m, 2 H) 7.64-7.78 (m, 1 H).
Reaction SMILES: C(OC([NH:11][C:12]1[C:17](=[O:18])[N:16]([CH2:19][C:20]([NH:22][CH:23]([CH:40]([CH3:42])[CH3:41])[C:24](=[O:39])[C:25]([F:38])([F:37])[C:26](=[O:36])[NH:27][CH2:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])=[O:21])[C:15]([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)=[N:14][CH:13]=1)=O)C1C=CC=CC=1>C(O)C.O1CCCC1.[Pd]>[NH2:11][C:12]1[C:17](=[O:18])[N:16]([CH2:19][C:20]([NH:22][CH:23]([CH:40]([CH3:42])[CH3:41])[C:24](=[O:39])[C:25]([F:38])([F:37])[C:26](=[O:36])[NH:27][CH2:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])=[O:21])[C:15]([C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=2)=[N:14][CH:13]=1
Reactant: CC(C)C(NC(=O)Cn1c(-c2ccccc2)ncc(NC(=O)OCc2ccccc2)c1=O)C(=O)C(F)(F)C(=O)NCC(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: CC(C)C(NC(=O)Cn1c(-c2ccccc2)ncc(N)c1=O)C(=O)C(F)(F)C(=O)NCC(=O)OC(C)(C)C
Reaction time: 2.5 h
Yield: 80 %

Procedure:
To a solution of 2-(5-benzyloxycarbonylamino-6-oxo-2-phenyl-1,6-dihydro-pyrimidin-1-yl)-N-[3,3-difluoro-1-isopropyl-2-oxo-3-[N-(tert-butoxycarbonylmethyl)carbamoyl]propyl]acetamide (0.20 g) in ethanol (1 mL) and tetrahydrofuran (2 mL) was added 10% (v/v) palladium on carbon (0.075 g), and the mixture was shaken under a hydrogen atmosphere (3 bar) for 2.5 hours. The mixture was filtered through diatomaceous earth and evaporated. Chromatography, with chloroform:methanol (96:4) as the eluent, gave material which was precipitated from dichloromethane and hexane to yield the title compound as a white solid (0.128 g); TLC: Rf =0.35, chloroform:methanol (96:4); MS: m/z=498(M+1). Analysis for C24H31F2N5O6.0.3 H2O: Calculated: C, 55.51; H, 5.89; N, 12.95; Found: C, 55.65; H, 5.73; N, 12.60.
Reaction SMILES: CC(C)=O.[CH3:5][NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(=O)([O-])[O-].[K+].[K+].Cl[C:20]([O:22][C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([C:30]([CH3:33])([CH3:32])[CH3:31])[CH:24]=1)=[S:21]>O>[CH3:5][N:6]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:20](=[S:21])[O:22][C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([C:30]([CH3:32])([CH3:31])[CH3:33])[CH:24]=1
Reactant: CC(C)(C)c1cc(OC(=S)Cl)ccc1Cl
Reactant: CNc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: CN(C(=S)Oc1ccc(Cl)c(C(C)(C)C)c1)c1ccccc1
Temperature: 25 °C
Yield: 79.2 %

Procedure:
To 20 ml of acetone were added 1.07 g of N-methylaniline and 1.38 g of anhydrous potassium carbonate, and a solution obtained by dissolving 2.63 g of O-3-tert-butyl-4-chlorophenyl chlorothioformate into 20 ml of acetone was added thereto with stirring at room temperature. After stirring for 30 minutes as it is, the mixture was subjected to refluxing with heating for 2 hours. The reaction mixture was cooled down to room temperature and then poured into cold water. The product was extracted with benzene. The benzene solution was washed with water and a saturated aqueous solution of sodium chloride in this order, and dried over anhydrous magnesium sulfate. Thereafter, benzene was distilled off. The residue was purified through a column chromatography (employing silica gel as carrier, and benzene/hexane=1/1 (V/V) as developing solvent) and further recrystallized form ethanol to give 2.64 g of O-3-tert-butyl-4-chlorophenyl N-methyl-N-phenylthiocarbamate, having melting point of 65°-67° C.
Reaction SMILES: [C:1]([OH:9])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.[NH2:10][CH2:11][CH2:12][O:13][C:14]1[C:24]2[CH2:23][CH2:22][N:21](C(=O)C(F)(F)F)[CH2:20][CH2:19][C:18]=2[CH:17]=[CH:16][C:15]=1[Cl:31]>>[ClH:31].[Cl:31][C:15]1[CH:16]=[CH:17][C:18]2[CH2:19][CH2:20][NH:21][CH2:22][CH2:23][C:24]=2[C:14]=1[O:13][CH2:12][CH2:11][NH:10][C:1]([C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1)=[O:9]
Reactant: NCCOc1c(Cl)ccc2c1CCN(C(=O)C(F)(F)F)CC2
Reactant: O=C(O)c1cccnc1
Product: Cl
Product: O=C(NCCOc1c(Cl)ccc2c1CCNCC2)c1cccnc1
Yield: 185 %

Procedure:
Use a method similar to Example 42, using nicotinic acid (40 mg, 0.327 mmol) and 6-(2-amino-ethoxy)-7-chloro-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (100 mg, 0.297 mmol) to give the title compound as a solid (105 mg, 93%). MS (ES+) m/z: 346 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:6][CH:7]=1.C1([O:20][C:21]([O:23][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])=O)C=CC=CC=1>>[Cl:1][C:2]1[N:3]=[N:4][C:5]([N:8]2[CH2:9][CH2:10][N:11]([C:21]([O:23][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])=[O:20])[CH2:12][CH2:13]2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)COC(=O)Oc1ccccc1
Reactant: Clc1ccc(N2CCNCC2)nn1
Product: CCOC(=O)COC(=O)N1CCN(c2ccc(Cl)nn2)CC1

Procedure:
The process is performed as described in Example 1 (step 1.2.). Starting with 1.60 g (8.05 mmol) of 3-chloro-6-(1-piperazinyl)pyridazine (J. Med. Chem., 18, 2002, 4011-4017) and 1.99 g (8.86 mmol) of ethyl [(phenyloxy-carbonyl)oxy]acetate, prepared in step 1.1. of Example 1, and after chromatography on silica gel, eluting with a 98/2 mixture of dichloromethane and methanol, 1.70 g of product are obtained in the form of a white solid.