Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[S:7]([O-:9])=[O:8].[Na+].ClN1C(=O)CCC1=O.S(Cl)(Cl)(=O)=O.[NH2:24][C:25]1[C:26]([F:47])=[C:27]([C:31]2[N:32]=[C:33]([C:43]([CH3:46])([CH3:45])[CH3:44])[S:34][C:35]=2[C:36]2[CH:41]=[CH:40][N:39]=[C:38]([NH2:42])[N:37]=2)[CH:28]=[CH:29][CH:30]=1.N1C=CC=CC=1>ClCCl>[NH2:42][C:38]1[N:37]=[C:36]([C:35]2[S:34][C:33]([C:43]([CH3:45])([CH3:46])[CH3:44])=[N:32][C:31]=2[C:27]2[C:26]([F:47])=[C:25]([NH:24][S:7]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=3)(=[O:9])=[O:8])[CH:30]=[CH:29][CH:28]=2)[CH:41]=[CH:40][N:39]=1
Reactant: O=S([O-])c1ccccn1
Reactant: CC(C)(C)c1nc(-c2cccc(N)c2F)c(-c2ccnc(N)n2)s1
Agent: O=C1CCC(=O)N1Cl
Agent: [Na+]
Solvent: c1ccncc1
Solvent: O=S(=O)(Cl)Cl
Solvent: ClCCl
Product: CC(C)(C)c1nc(-c2cccc(NS(=O)(=O)c3ccccn3)c2F)c(-c2ccnc(N)n2)s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 12.4 %

Procedure:
To a suspension of sodium 2-pyridinesulfinate (48.4 mg, 0.291 mmol) in dichloromethane (3 ml) was added N-chlorosuccinimide (38.9 mg, 0.291 mmol). After 1 hour, the reaction mixture was filtered through a short Celite plug. To the crude sulfonyl chloride solution was added the 4-[4-(3-amino-2-fluorophenyl)-2-(1,1-dimethylethyl)-1,3-thiazol-5-yl]-2-pyrimidinamine (50 mg, 0.146 mmol) and pyridine (0.035 ml, 0.437 mmol), and the mixture was stirred for 3 hours at ambient temperature. After 3 hours, the reaction was quenched with methanol, and the crude reaction mixture was concentrated, redissolved in methanol, and purified via reversed-phase HPLC chromatography, eluting with 30-60% acetonitrile/0.1% aqueous trifluoroacetic acid. The desired fractions were combined, neutralized with aqueous saturated sodium bicarbonate, and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the title compound (8.8 mg, 12%) as tan solid. MS (ESI): 485 [M+H]+.
Reaction SMILES: C(#N)C.Cl[C:5]1[CH:10]=[CH:9][C:8]([S:11]([CH:14]([C:23]2[CH:28]=[CH:27][N:26]=[CH:25][C:24]=2[Cl:29])[C:15]2[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=2[F:22])(=[O:13])=[O:12])=[CH:7][N:6]=1.[F-:30].[K+]>[Br-].C1([P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.ClCCl>[Cl:29][C:24]1[CH:25]=[N:26][CH:27]=[CH:28][C:23]=1[CH:14]([C:15]1[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=1[F:22])[S:11]([C:8]1[CH:9]=[CH:10][C:5]([F:30])=[N:6][CH:7]=1)(=[O:13])=[O:12]
Reactant: [F-]
Reactant: O=S(=O)(c1ccc(Cl)nc1)C(c1cc(F)ccc1F)c1ccncc1Cl
Agent: [Br-]
Agent: [K+]
Agent: c1ccc([P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CC#N
Product: O=S(=O)(c1ccc(F)nc1)C(c1cc(F)ccc1F)c1ccncc1Cl
Temperature: 25 °C
Yield: 6.9 %

Procedure:
To an acetonitrile (2 ml) solution of 2-chloro-5-[(3-chloropyridin-4-yl)(2,5-difluorophenyl)methylsulfonyl]pyridine (66 mg, 0.16 mmol) were added potassium fluoride (94 mg, 1.60 mmol) and tetraphenylphosphonium bromide (134 mg, 0.32 mmol). The resulting mixture was heated under reflux for 16 hours. After the reaction mixture was cooled to room temperature, dichloromethane was added thereto. The resulting mixture was washed with water. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was subjected to flash silica gel column chromatography. The fraction obtained from the hexane:ethyl acetate=17:3 eluate is concentrated under reduced pressure to give the title compound (4.5 mg, 0.011 mmol, 7%) as a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([Mg]Br)=[CH:4][CH:3]=1.[N:10]12[CH2:17][CH2:16][C:13]([C:18]([O:20]CC)=O)([CH2:14][CH2:15]1)[CH2:12][CH2:11]2>C1COCC1>[N:10]12[CH2:11][CH2:12][C:13]([C:18]([C:5]3[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=3)([C:5]3[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=3)[OH:20])([CH2:14][CH2:15]1)[CH2:16][CH2:17]2
Reactant: CCOC(=O)C12CCN(CC1)CC2
Reactant: Cc1ccc([Mg]Br)cc1
Solvent: C1CCOC1
Product: Cc1ccc(C(O)(c2ccc(C)cc2)C23CCN(CC2)CC3)cc1
Temperature: 25 °C
Yield: 86.6 %

Procedure:
A solution of 4-methylphenylmagnesiumbromide (1.0 M in THF, 3.3 mL, 3.3 mmol) was chilled down to 0° C. under Ar. Ethyl 1-azabicyclo[2.2.2]octane-4-carboxylate (0.1509 g, 0.823 mmol) in THF (4 mL) was slowly added to the reaction mixture at 0° C. over 20 min. The reaction was allowed to warm up to room temperature and then heated at 60° C. for 16 h. The reaction was chilled in an ice bath, quenched with saturated NH4Cl, and concentrated under vacuum. The resulting residue was treated with H2O and extracted with EtOAc. The combined organic layers were dried with MgSO4, filtered, and concentrated under vacuum to yield the desired product (0.2291 g, 86.6%). EI-MS m/z 322(M+H+) Rt (1.57 min).
Reaction SMILES: [Br:1][C:2]1([N+]([O-])=O)[CH:7]=[C:6]([C:8]2[C:20]3[C:19]([CH3:21])=[C:18]([CH3:22])[S:17][C:16]=3[C:15]([Br:23])=[C:14]3[C:9]=2[CH:10]=[CH:11][CH:12]=[CH:13]3)[CH:5]=CC1O.[NH2:28]N.[CH2:30]([OH:32])[CH3:31]>>[NH2:28][C:31]1[CH:5]=[C:6]([C:8]2[C:20]3[C:19]([CH3:21])=[C:18]([CH3:22])[S:17][C:16]=3[C:15]([Br:23])=[C:14]3[C:9]=2[CH:10]=[CH:11][CH:12]=[CH:13]3)[CH:7]=[C:2]([Br:1])[C:30]=1[OH:32]
Reactant: NN
Reactant: Cc1sc2c(Br)c3ccccc3c(C3=CC(Br)([N+](=O)[O-])C(O)C=C3)c2c1C
Reactant: CCO
Product: Cc1sc2c(Br)c3ccccc3c(-c3cc(N)c(O)c(Br)c3)c2c1C
Temperature: 85 °C
Yield: 66 %

Procedure:
Using a procedure similar to Tet. Lett. 1990, 1181-1182, Montmorillinite K10 clay (1.4 g) was added to a solution of 2-bromo-4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2-nitro-phenol (1.2 g, 2.37 mmol), anhydrous hydrazine (1 mL) and ethanol (7.2 mL) and the suspension was heated at 85° C. for 1 h. The reaction mixture was cooled to room temperature and concentrated. The residue was twice flash chromatographed (first time, eluent: ether, second time, eluent: 4:1 petrolerum ether ethyl acetate) to provide the title compound as a white solid (0.741 g, 66%): NMR (DMSO-d6); δ8.16 (ddd, J=8, 1, 1 Hz, 1H), 7.65-7.60 (m, 2 H), 7.47 (ddd, J=8, 6, 1 Hz, 1H), 6.65 (d, J=2 Hz, 1H), 6.57 (d, J=2 Hz, 1H), 2.43 (d, J=1 Hz, 3H), 1.73 (d, J=1 Hz, 3H); MS (EI): 2 bromine isotope pattern 475 (50%, M+H), 477 (100%, M+H), 479 (50%, M+H); Anal. Calc. for C20H15Br2NOS: C, 50.34; H, 3.17; N, 2.94. Found: C, 51.35; H, 3.35; N, 2.72.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C@H:9]2[CH2:14][CH2:13][C@H:12]([OH:15])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1)#[N:2].[CH2:16]([C@@H:19]1[CH2:23][C@@H:22]([CH2:24]OS(C)(=O)=O)[N:21]([CH2:30][CH2:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:20]1=[O:39])[CH:17]=[CH2:18].[OH-].[K+].Cl>O>[CH2:16]([C@@H:19]1[CH2:23][C@@H:22]([CH2:24][O:15][C@H:12]2[CH2:13][CH2:14][C@H:9]([C:6]3[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][CH:7]=3)[CH2:10][CH2:11]2)[N:21]([CH2:30][CH2:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:20]1=[O:39])[CH:17]=[CH2:18]
Reactant: C=CC[C@@H]1C[C@@H](COS(C)(=O)=O)N(CCCc2ccccc2)C1=O
Reactant: N#Cc1ccc([C@H]2CC[C@H](O)CC2)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: C=CC[C@@H]1C[C@@H](CO[C@H]2CC[C@H](c3ccc(C#N)cc3)CC2)N(CCCc2ccccc2)C1=O

Procedure:
0.73 g of trans-4-(4-cyanophenyl)cyclohexanol, 2.8 g of (3R,5S)-3-allyl-5-[(methanesulphonyl)oxymethyl]-1-(3-phenylpropyl)-2-pyrrolidinone, 2.5 ml of 60% aqueous potassium hydroxide solution and 0.3 g of polyethyleneglycol-750 monomethylether (bound to polystyrene-1% divinylbenzene) are stirred for 24 hours at 45° C. Ice and water are added to the mixture, it is acidified with hydrochloric acid and extracted with ethyl acetate. The organic phase is dried with sodium sulphate, concentrated by evaporation and the residue is chromatographed over a silica gel column with petroleum ether/ethyl acetate (2:1). 0.4 g (24% of theory) of product are obtained. Rf value: 0.61 (silica gel; petroleum ether/ethyl acetate 12:1) Calculated: C 78.91 H 7.95 N 6.14 Found: 78.88 8.13 6.10
Reaction SMILES: [CH:1]1([NH2:4])[CH2:3][CH2:2]1.Cl.Cl[CH2:7][C:8]1[N:9]=[CH:10][S:11][CH:12]=1.CCCCC.C(OCC)(=O)C>C(O)C.C(=O)([O-])O.[Na+]>[S:11]1[CH:12]=[C:8]([CH2:7][NH:4][CH:1]2[CH2:3][CH2:2]2)[N:9]=[CH:10]1
Reactant: NC1CC1
Reactant: ClCc1cscn1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: CCCCC
Product: c1nc(CNC2CC2)cs1
Temperature: 25 °C
Reaction time: 20 h
Yield: 33.5 %

Procedure:
20 ml (0.29 mol) of cyclopropylamine was added to a solution of 4.9 g (29.0 mmol) of 4-(chloromethyl)-thiazole hydrochloride in 45 ml ethanol and 45 ml of saturated aqueous sodium hydrogen carbonate. The reaction mixture was stirred for 20 hrs at ambient temperature and extracted with ethyl acetate (3×100 ml). The combined organic layers were dried over magnesium sulphate and concentrated in vacuum. Column chromatography (gradient n-pentane/ethyl acetate) yielded 1.5 g (32% yield) of N-(1,3-thiazol-4-ylmethyl)cyclopropylamine. At ambient temperature a solution of 0.28 g (1.4 mmol) of 3-(difluoromethyl)-1-methyl-pyrazole-4-carbonyl chloride in 2 ml of tetrahydrofurane was added drop wise to a solution of 0.20 g (1.3 mmol) of N-(1,3-thiazol-4-ylmethyl)-cyclopropylamine and 0.6 ml triethylamine in 4 ml tetrahydrofurane. The reaction mixture was stirred for 16 hrs at ambient temperature and quenched with water. The watery layer was extracted three times with ethyl acetate (3×20 ml), the combined organic layers were dried over magnesium sulphate and concentrated in vacuum. Column chromatography (gradient n-pentane/ethyl acetate) yielded 0.13 mg (51% yield) of N-cyclopropyl-N-(1,3-thiazol-4-yl-methyl)-1-methyl-3-difluoromethyl-pyrazole-4-carboxamide (M+1=313).
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([NH2:11])[CH:9]=2)[NH:4][N:3]=1.N1C=CC=CC=1.[F:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[C:20]=1[S:26](Cl)(=[O:28])=[O:27]>O1CCCC1>[NH2:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([NH:11][S:26]([C:20]3[C:21]([F:25])=[CH:22][CH:23]=[CH:24][C:19]=3[F:18])(=[O:28])=[O:27])[CH:9]=2)[NH:4][N:3]=1
Reactant: Nc1ccc2[nH]nc(N)c2c1
Reactant: O=S(=O)(Cl)c1c(F)cccc1F
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: Nc1n[nH]c2ccc(NS(=O)(=O)c3c(F)cccc3F)cc12
Yield: 8.4 %

Procedure:
N-(3-Amino-1H-indazol-5-yl)-2,6-difluorobenzenesulfonamide can be obtained as described in Example 39 from 1 g of 3,5-diamino-1H-indazole, 10 ml of pyridine, 10 ml of tetrahydrofuran and 1.4 g of 2,6-difluorobenzenesulfonyl chloride. 179 mg of N-(3-amino-1H-indazol-5-yl)-2,6-difluorobenzenesulfonamide are thus obtained in the form of a gray solid melting at 241° C. (analysis C13H10F2N4O2S % calculated C, 48.15; H, 3.11; F, 11.72; N, 17.28; O, 9.87; S, 9.89. % found C, 47.81; H, 3.18; F, 11.64; N, 17.00; S, 9.67).
Reaction SMILES: C[Si](Br)(C)C.C([O:8][P:9]([CH2:14][CH2:15][C:16]([F:28])([F:27])[C:17]([F:26])([F:25])[C:18]([F:24])([F:23])[C:19]([F:22])([F:21])[F:20])(=[O:13])[O:10]CC)C.O>C(Cl)Cl>[F:28][C:16]([F:27])([C:17]([F:25])([F:26])[C:18]([F:23])([F:24])[C:19]([F:21])([F:22])[F:20])[CH2:15][CH2:14][P:9](=[O:8])([OH:13])[OH:10]
Reactant: CCOP(=O)(CCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)OCC
Agent: C[Si](C)(C)Br
Solvent: ClCCl
Solvent: O
Product: O=P(O)(O)CCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 95 %

Procedure:
Neat 1,1,1,2,2,3,3,4,4-nonafluoro-6-iodohexane (10 mmol) was added to 50 mmol of triethyl phosphate. The reaction mixture was heated at 160° C. overnight to produce diethyl(3,3,4,4,5,5,6,6,6-nonafluorohexyl)phosphonate, which was isolated by fractional distillation (90-95% yield). Neat trimethylsilyl bromide (21 mmol) was added slowly to a solution of diethyl(3,3,4,4,5,5,6,6,6-nonafluorohexyl)phosphonate (7 mmol) in dry CH2Cl2 (25 mL) at 0° C. The reaction mixture was stirred overnight at room temperature, after which time water (30 mmol) was added to the reaction mixture. Volatiles were removed in vacuo leaving (3,3,4,4,5,5,6,6,6-nonafluorohexyl)phosphonic acid as a white crystal (>95% yield). The procedure for producing the phosphonic acid salt was similar as described for Intermediate 1.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:15][C:16]1[CH:25]=[CH:24][CH:23]=[C:22]2[C:17]=1[CH:18]=[CH:19][CH:20]=[C:21]2[OH:26])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[I-].[Na+].[OH2:29]>CN(C)C=O.O1CCCC1>[CH2:3]([O:15][C:16]1[CH:25]=[CH:24][CH:23]=[C:22]2[C:17]=1[CH:18]=[CH:19][CH:20]=[C:21]2[O:26][CH2:17][CH:16]([OH:15])[CH2:25][OH:29])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCCCCCCCCCCOc1cccc2c(O)cccc12
Reactant: O
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCOc1cccc2c(OCC(O)CO)cccc12
Reaction time: 8 h

Procedure:
To a suspension of 2.19 g of 50% sodium hydride in 80 ml of dimethylformamide, under argon, was added with stirring a solution of 12 g of 5-(dodecyloxy)-1-naphthalenol in 60 ml of tetrahydrofuran over 1/2 hour. A 2 g portion of sodium iodide and 9.77 g of solketal mesylate were added and the mixture was stirred overnight. The mixture was diluted with water and extracted with ether. The ether extract was washed with dilute sodium hydroxide, then brine, dried, filtered through silica gel and the solvent removed. The residue was refluxed in a mixture of 100 ml of methanol, 16 ml of water and 1 ml of concentrated sulfuric acid for one hour, then cooled and the solid collected. This solid was dissolved in boiling chloroform containing magnesium sulfate and activated carbon and filtered through diatomaceous earth. The filtrate was evaporated and the residue recyrstallized from carbon tetrachloride, giving 8 g of the desired compound as an off-white solid, mp 143°-144° C.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([S:11]([CH2:14][S:15]([C:18]2[CH:23]=[CH:22][C:21]([O:24][C:25](=[O:27])[CH3:26])=[CH:20][CH:19]=2)(=[O:17])=[O:16])(=[O:13])=[O:12])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].C1(C)C=CC(S([N:37]=[N+:38]=[N-])(=O)=O)=CC=1.C1CCN2C(=NCCC2)CC1.Cl>ClCCl>[C:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([S:11]([C:14]([S:15]([C:18]2[CH:19]=[CH:20][C:21]([O:24][C:25](=[O:27])[CH3:26])=[CH:22][CH:23]=2)(=[O:17])=[O:16])=[N+:37]=[N-:38])(=[O:13])=[O:12])=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1ccc(S(=O)(=O)CS(=O)(=O)c2ccc(OC(C)=O)cc2)cc1
Reactant: Cc1ccc(S(=O)(=O)N=[N+]=[N-])cc1
Agent: Cl
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: CC(=O)Oc1ccc(S(=O)(=O)C(=[N+]=[N-])S(=O)(=O)c2ccc(OC(C)=O)cc2)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 31 %

Procedure:
The bis(4-acetyloxyphenylsulfonyl)methane in Synthesis Example 3, 4.5 g (0.011 mol), was dispersed in 49 g of dichloromethane. To the dispersion was added 2.5 g (0.016 mol) of p-toluenesulfonylazide which had been separately prepared. With stirring at room temperature, 3.0 g (0.015 mol) of 1,8-diazabicyclo[5.4.0]-7-undecene (DBU) was added to the dispersion, and after 5 minutes, 50 g of a 0.2N aqueous hydrochloric acid was added to stop reaction. The organic layer was separated and washed with 50 g of water. The organic layer was concentrated and 8 g of the residue was purified by silica gel column chromatography using dichloromethane as an elute. The thus obtained oily product was combined with 10 g of hexane for crystallization, followed by filtration and vacuum drying. There was obtained 1.5 g (yield 31%) of fine yellow crystals.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][O:8][C:9]1[N:14]=[C:13]([NH:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[C:19]([NH:25][CH3:26])[CH:18]=2)[C:12]([C:27]([C:29]2[CH:34]=[C:33]([O:35][CH3:36])[C:32]([O:37][CH3:38])=[C:31]([O:39][CH3:40])[CH:30]=2)=[O:28])=[CH:11][N:10]=1.[S:41](Cl)([CH3:44])(=[O:43])=[O:42].C(N(CC)CC)C.C(=O)([O-])O.[Na+]>C(Cl)Cl.C(OCC)(=O)C>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][O:8][C:9]1[N:14]=[C:13]([NH:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[C:19]([N:25]([S:41]([CH3:44])(=[O:43])=[O:42])[CH3:26])[CH:18]=2)[C:12]([C:27]([C:29]2[CH:30]=[C:31]([O:39][CH3:40])[C:32]([O:37][CH3:38])=[C:33]([O:35][CH3:36])[CH:34]=2)=[O:28])=[CH:11][N:10]=1
Reactant: CNc1cc(CNc2nc(OCc3ccccn3)ncc2C(=O)c2cc(OC)c(OC)c(OC)c2)ccc1OC
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COc1ccc(CNc2nc(OCc3ccccn3)ncc2C(=O)c2cc(OC)c(OC)c(OC)c2)cc1N(C)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2-(2-pyridylmethoxy)-5-(3,4,5-trimethoxyphenyl-carbonyl)-4-(3-metylamino-4-methoxybenzylamino)pyrimidine (prepared in Example 48) 42 mg in methylene chloride 3 ml are added mesyl chloride 48 mg and triethylamine 69 mg, for three times at one hour intervals. The reaction mixture is stirred for 1 hour at room temperature. Ethyl acetate and an aqueous saturated sodium hydrogen carbonate solution is added thereto. The organic layer is separated, washed with brine and dried over anhydrous sodium sulfate. After filtration of sodium sulfate the filtrate is concentrated in vacuo and the residue is purified by preparative thin-layer chromatograph (2 plates, solvent: ethyl acetate) to give 2-(2-pyridylmethoxy)-5-(3,4,5-trimethoxyphenylcarbonyl)-4-[4-methoxy-3-(N-methylmethansulfonylamino)benzylamino]pyrimidine as a colorless amorphous 20 mg.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]1([C:25]3=[CH:26][C:27]4[O:31][CH2:30][O:29][C:28]=4[CH:32]=[C:24]3[O:23][CH2:22]1)[C:5](=[O:21])[N:6]2[CH2:11][C:12]1[O:13][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:15][CH:16]=1.BrC1C=CC=[C:39]2[C:35]=1[C:36]1([C:52]3=[CH:53][C:54]4OCO[C:55]=4[CH:59]=[C:51]3OC1)C(=O)[N:38]2CCCCC.N1C2C(=CC=CC=2)C=C(B(O)O)C=1.CN(C)C1N=CC(B(O)O)=CC=1>>[N:38]1[C:53]2[C:52](=[CH:51][CH:59]=[CH:55][CH:54]=2)[CH:36]=[C:35]([C:2]2[CH:10]=[CH:9][CH:8]=[C:7]3[C:3]=2[C:4]2([C:25]4=[CH:26][C:27]5[O:31][CH2:30][O:29][C:28]=5[CH:32]=[C:24]4[O:23][CH2:22]2)[C:5](=[O:21])[N:6]3[CH2:11][C:12]2[O:13][C:14]([C:17]([F:19])([F:20])[F:18])=[CH:15][CH:16]=2)[CH:39]=1
Reactant: CCCCCN1C(=O)C2(COc3cc4c(cc32)OCO4)c2c(Br)cccc21
Reactant: O=C1N(Cc2ccc(C(F)(F)F)o2)c2cccc(Br)c2C12COc1cc3c(cc12)OCO3
Agent: CN(C)c1ccc(B(O)O)cn1
Agent: OB(O)c1cnc2ccccc2c1
Product: O=C1N(Cc2ccc(C(F)(F)F)o2)c2cccc(-c3cnc4ccccc4c3)c2C12COc1cc3c(cc12)OCO3

Procedure:
Following the procedure as described in EXAMPLE 4, and making non-critical variations using 4′-bromo-1′-{[5-(trifluoromethyl)-2-furyl]methyl}spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one to replace 4′-bromo-1′-pentylspiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one, quinolin-3-ylboronic acid to replace [6-(dimethylamino)pyridin-3-yl]boronic acid, the title compound was obtained (50%) as a colorless solid: 1H NMR (300 MHz, CDCl3) δ 8.52 (d, 1H), 8.09 (d, 1H), 7.74-7.68 (m, 1H), 7.56-7.50 (m, 1H), 7.42-7.39 (m, 2H), 7.32 (s, 1H), 7.09 (d, 1H), 7.01 (d, 1H), 6.78-6.77 (m, 1H), 6.45 (d, 1H), 6.26 (s, 1H), 5.94 (d, 1H), 5.91 (s, 1H), 5.89 (d, 1H), 5.03 (ABq, 2H), 4.52 (ABq, 2H); 13C NMR (75 MHz, CDCl3) δ 177.4, 156.0, 151.8, 150.0, 149.3, 147.0, 142.4, 141.8, 136.8, 135.8, 131.1, 130.2, 129.9, 129.3, 129.0, 128.8, 128.0, 127.1, 127.0, 126.4, 126.0, 120.4, 112.7, 109.5, 108.8, 102.5, 101.7, 93.7, 78.3, 58.5, 37.1; MS (ES+) m/z 557.4 (M+1).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[O:9][CH3:10].[Br:11][C:12]1[CH:13]=[CH:14][C:15]([OH:21])=[C:16]([CH:20]=1)[C:17]([OH:19])=[O:18].[C:22](=[O:25])([O-])[O-].[Cs+].[Cs+]>CC(C)=O>[Br:11][C:12]1[CH:13]=[CH:14][C:15]([O:21][CH2:2][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[O:25][CH3:22])=[C:16]([CH:20]=1)[C:17]([O:19][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[O:9][CH3:10])=[O:18]
Reactant: O=C(O)c1cc(Br)ccc1O
Reactant: COc1ccccc1CCl
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: COc1ccccc1COC(=O)c1cc(Br)ccc1OCc1ccccc1OC
Temperature: 55 °C
Reaction time: 16 h

Procedure:
Neat 1-(chloromethyl)-2-methoxybenzene (397 mg, 2.53 mmol) was added in one charge to a stirred suspension of 5-bromo-2-hydroxybenzoic acid (250 mg, 1.15 mmol) and cesium carbonate (751 mg, 2.30 mmol) in acetone (40 ml) under nitrogen at 20° C. The reaction mixture was stirred at 55° C. for 16 h. The organic phase was evaporated and the residue was washed with water (25 ml), extracted with ethyl acetate (3×30 ml) and evaporated in vacuo to yield the title compound as a light yellow liquid. 420 mg.
Reaction SMILES: Br[CH:2](Br)C.[CH3:5][O:6][C:7]([C:9]1[S:10][C:11]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[CH:12][C:13]=1[N:14]([C:22]([CH:24]1[CH2:29][CH2:28][CH:27]([CH3:30])[CH2:26][CH2:25]1)=[O:23])[CH:15]1[CH2:20][CH2:19][C:18](=O)[CH2:17][CH2:16]1)=[O:8].C(=O)(O)[O-].[Na+]>O1CCCC1.ClCCl.[Zn]>[CH3:5][O:6][C:7]([C:9]1[S:10][C:11]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[CH:12][C:13]=1[N:14]([C:22]([CH:24]1[CH2:25][CH2:26][CH:27]([CH3:30])[CH2:28][CH2:29]1)=[O:23])[CH:15]1[CH2:20][CH2:19][C:18](=[CH2:2])[CH2:17][CH2:16]1)=[O:8]
Reactant: CC(Br)Br
Reactant: COC(=O)c1sc(-c2ccccc2)cc1N(C(=O)C1CCC(C)CC1)C1CCC(=O)CC1
Agent: O=C([O-])O
Agent: [Na+]
Agent: [Zn]
Solvent: ClCCl
Solvent: C1CCOC1
Product: C=C1CCC(N(C(=O)C2CCC(C)CC2)c2cc(-c3ccccc3)sc2C(=O)OC)CC1
Temperature: -40 °C
Yield: 80.5 %

Procedure:
To a suspension of zinc dust (2.87 g, 44.0 mmol) and dibromoethane (1.00 mL, 14.4 mmol) in tetrahydrofuran (20 mL) stirred under a nitrogen atmosphere at −40° C. was added titane tetrachloride (10 mL of a solution 1M in dichloromethane, 10 mmol). The mixture was then allowed to warm to room temperature and was stirred for two days at this temperature. This methylation reagent (2.5 eq) was added to a solution of 3-[(4-Methyl-cyclohexanecarbonyl)-(4-oxo-cyclohexyl)-amino]-5-phenyl-thiophene-2-carboxylic acid methyl ester (0.200 g, 0.440 mmol, 1 eq) in dichloromethane (2 mL) and the resulting mixture was stirred 3 h at room temperature. A saturated solution of sodium bicarbonate was then added and reaction mixture was extracted with dichloromethane (3×30 mL). Organic phases were combined, dried over sodium sulfate and concentrated. The crude was purified by chromatography (30% ethyl acetate/hexanes) to give 160 mg (81%) of 3-[(4-Methyl-cyclohexanecarbonyl)-(4-methylene-cyclohexyl)-amino]-5-phenyl-thiophene-2-carboxylic acid methyl ester as a white solid. NMR 1H (CDCl3, 400 MHz): 7.63 ppm (d, 2H); 7.40 ppm (m, 3H); 6.98 ppm (s, 1H); 4.82 ppm (tt, 1H); 4.78 ppm (d, 2H); 3.85 ppm (s, 3H); 2.20 ppm (m, 4H); 2.05 ppm (m, 2H); 1.90 ppm (d, 1H); 1.65 ppm (m, 4H); 1.42 ppm (m, 1H); 1.30 ppm (m, 2H); 1.00 ppm (m, 2H); 0.78 ppm (d, 3H); 0.64 ppm (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]2[N:6]3[C:10]([CH2:11][NH:12][CH2:13][C:4]=2[CH:3]=1)=[N:9][N:8]=[C:7]3[C@H:14]1[CH2:19][CH2:18][C@H:17]([C:20]2[CH:24]=[C:23]([CH3:25])[O:22][N:21]=2)[CH2:16][CH2:15]1.[CH2:28]([N:30]([CH2:33]C)CC)C.[S:35](Cl)(=[O:38])(=[O:37])N>ClCCl>[CH3:28][N:30]([CH3:33])[S:35]([N:12]1[CH2:11][C:10]2[N:6]([C:7]([C@H:14]3[CH2:15][CH2:16][C@H:17]([C:20]4[CH:24]=[C:23]([CH3:25])[O:22][N:21]=4)[CH2:18][CH2:19]3)=[N:8][N:9]=2)[C:5]2[CH:26]=[CH:27][C:2]([Cl:1])=[CH:3][C:4]=2[CH2:13]1)(=[O:38])=[O:37]
Reactant: Cc1cc([C@H]2CC[C@H](c3nnc4n3-c3ccc(Cl)cc3CNC4)CC2)no1
Reactant: NS(=O)(=O)Cl
Reactant: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc([C@H]2CC[C@H](c3nnc4n3-c3ccc(Cl)cc3CN(S(=O)(=O)N(C)C)C4)CC2)no1
Reaction time: 20 h

Procedure:
To a solution of trans-8-chloro-1-[4-(5-methyl-isoxazol-3-yl)-cyclohexyl]-5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo[e]azulene (50 mg, 0.13 mmol) and triethylamine (0.036 ml, 0.26 mmol) in dichloromethane (1.3 ml) was added sulfamoyl chloride (0.028 ml, 0.26 mmol) at room temperature. Stirring for 20 h was followed by quenching with methanol (0.5 ml). The mixture was concentrated in vacuo. Preparative RP-HPLC with water (0.05% formic acid)/methanol as eluent gave the title compound (42 mg, 66%) as white solid. MS m/e: 491 ([M+H]+).