Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3](NC)[CH:2]=1.ClC(Cl)(Cl)[C:11]([C:13]1[N:22]2[C:16]([CH2:17][N:18]([C:27]([C:29]3[CH:34]=[CH:33][C:32]([C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=4[O:41][CH3:42])=[CH:31][CH:30]=3)=[O:28])[C:19]3[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=3[CH2:21]2)=[CH:15][CH:14]=1)=[O:12].[CH2:45]([N:47](CC)CC)C.CS(C)=O>ClCCl.C(#N)C>[CH3:42][O:41][C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=1[C:32]1[CH:31]=[CH:30][C:29]([C:27]([N:18]2[C:19]3[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=3[CH2:21][N:22]3[C:13]([C:11]([NH:47][CH2:45][C:3]4[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=4)=[O:12])=[CH:14][CH:15]=[C:16]3[CH2:17]2)=[O:28])=[CH:34][CH:33]=1
Reactant: CCN(CC)CC
Reactant: COc1ccccc1-c1ccc(C(=O)N2Cc3ccc(C(=O)C(Cl)(Cl)Cl)n3Cc3ccccc32)cc1
Reactant: CNc1cccnc1
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CC#N
Product: COc1ccccc1-c1ccc(C(=O)N2Cc3ccc(C(=O)NCc4cccnc4)n3Cc3ccccc32)cc1
Yield: 54.2 %

Procedure:
The title compound was prepared according to the procedure of Example 6, Step D, from pyridin-3-yl-methylamine (0.515 mL, 5.057 mmol), 2,2,2-trichloro-1-{10-[(2′-methoxy-1,1′-biphenyl-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}ethanone (1.30 g, 2.41 mmol), triethylamine (0.738 mL, 5.30 mmol), dimethylsulfoxide (0.854 mL, 12.04 mmol) and acetonitrile (15 mL). The crude material was purified by flash column chromatography on silica gel Merck-60 using 4% methanol in dichloromethane as the eluant to give a light yellow solid. The solid was taken up in dichloromethane and precipitated by the addition of diethyl ether and ethyl acetate. The precipitate was collected by filtration and dried under reduced pressure to give the title compound (0.69 g, 54%) of as a white solid, m.p. 123-127° C.
Reaction SMILES: [CH2:1](Br)[C:2]#C.[CH2:5]([NH:8][C:9]1[CH:10]=[C:11]([CH:15]=[C:16]([S:25](=[O:28])(=[O:27])[NH2:26])[C:17]=1[O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:12]([OH:14])=[O:13])[CH:6]=[CH2:7]>>[CH2:1]([O:13][C:12](=[O:14])[C:11]1[CH:15]=[C:16]([S:25](=[O:28])(=[O:27])[NH2:26])[C:17]([O:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[C:9]([NH:8][CH2:5][C:6]#[CH:7])[CH:10]=1)[CH3:2]
Reactant: C#CCBr
Reactant: C=CCNc1cc(C(=O)O)cc(S(N)(=O)=O)c1Oc1ccccc1
Product: C#CCNc1cc(C(=O)OCC)cc(S(N)(=O)=O)c1Oc1ccccc1

Procedure:
By substituting propargyl bromide (4.8 g) for the allyl bromide of Example 58 A and extending the reaction time to 48 hours, ethyl-4-phenoxy-3-propargylamino-5-sulphamyl-benzoate was obtained with a melting point of 189°-190° C.
Reaction SMILES: Cl[C:2]1[S:3][C:4]2[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:5]=2[N:6]=1.[CH3:14][O:15][C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][C:22]=1[O:23][CH3:24])[NH2:19]>>[CH3:14][O:15][C:16]1[CH:17]=[C:18]([NH:19][C:2]2[S:3][C:4]3[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:5]=3[N:6]=2)[CH:20]=[CH:21][C:22]=1[O:23][CH3:24]
Reactant: COc1ccc(N)cc1OC
Reactant: O=[N+]([O-])c1ccc2nc(Cl)sc2c1
Product: COc1ccc(Nc2nc3ccc([N+](=O)[O-])cc3s2)cc1OC

Procedure:
The title compound was synthesised from 2-Chloro-6-nitro-benzothiazole (commercially available) and 3,4-dimethoxyaniline (commercially available) according to the procedure described for Example 1a) above. MS (m/e): 332.2 (MH+, 100%).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[CH2:11]([SH:15])[CH2:12][CH2:13][CH3:14].[CH3:16][C:17]1[CH:18]=[C:19]([C:34]2[S:38][C:37]([N:39]3[CH2:45][CH2:44][CH2:43][NH:42][C:41](=[O:46])[CH2:40]3)=[N:36][CH:35]=2)[CH:20]=[C:21]([NH:23][C:24]2[N:29]=[C:28](S(C)(=O)=O)[CH:27]=[CH:26][N:25]=2)[CH:22]=1>CN(C=O)C.C(OCC)(=O)C>[CH2:11]([S:15][C:26]1[CH:27]=[CH:28][N:29]=[C:24]([NH:23][C:21]2[CH:20]=[C:19]([C:34]3[S:38][C:37]([N:39]4[CH2:45][CH2:44][CH2:43][NH:42][C:41](=[O:46])[CH2:40]4)=[N:36][CH:35]=3)[CH:18]=[C:17]([CH3:16])[CH:22]=2)[N:25]=1)[CH2:12][CH2:13][CH3:14]
Reactant: CCCCS
Reactant: Cc1cc(Nc2nccc(S(C)(=O)=O)n2)cc(-c2cnc(N3CCCNC(=O)C3)s2)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCCSc1ccnc(Nc2cc(C)cc(-c3cnc(N4CCCNC(=O)C4)s3)c2)n1
Reaction time: 0.25 h
Yield: 47.7 %

Procedure:
Sodium bis(trimethylsilyl)amide (164 μL, 1.0 M, 0.164 mmol) was added to a solution of 1-butanethiol (28.1 μL, 0.262 mmol) stirring in DMF (327 μL) at room temperature in an oven-dried vial. Stirred for 15 minutes, then added 4-[5-(3-methyl-5-{[4-(methylsulfonyl)-2-pyrimidinyl]amino}phenyl)-1,3-thiazol-2-yl]-1,4-diazepan-2-one (30 mg, 0.065 mmol). Stirred at room temperature for 30 minutes, diluted with ethyl acetate (10 mL), and washed with 1:1 water:brine (10 mL). The organic extracts were dried (Na2SO4), filtered, and concentrated in vacuo. Purified by CombiFlash (100:0 to 0:20 dichloromethane:methanol) to afford 4-[5-(3-{[4-(butylsulfanyl)pyrimidin-2-yl]amino}-5-methylphenyl)-1,3-thiazol-2-yl]-1,4-diazepan-2-one (14.6 mg, 0.031 mmol, 48% yield) as a white solid. MS APCI: [M+H]+ m/z 469.2. 1H NMR (500 MHz, DMSO) δ 9.52 (s, 1H), 8.13 (d, J=5.3 Hz, 1H), 7.60 (dd, J=4.9 Hz, 10.3 Hz, 2H), 7.45 (s, 1H), 7.43 (s, 1H), 6.92 (s, 1H), 6.72 (d, J=5.3 Hz, 1H), 4.16 (s, 2H), 3.84-3.73 (m, 2H), 3.25-3.12 (m, 4H), 2.26 (s, 3H), 1.78 (m, 2H), 1.59 (m, 2H), 1.35 (dd, J=7.4 Hz, 14.9 Hz, 2H), 0.83 (t, J=7.4 Hz, 3H).
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([CH2:31][C:32]1[CH:37]=[C:36]([F:38])[C:35]([F:39])=[CH:34][C:33]=1[F:40])[CH2:9][C:10]([N:12]1[CH2:17][CH2:16][N:15]2[C:18]([C:27]([F:30])([F:29])[F:28])=[N:19][C:20]([C:21](=[O:26])[NH:22][CH2:23][C:24]#[N:25])=[C:14]2[CH2:13]1)=[O:11])(C)(C)C.FC(F)(F)C(O)=O.[Cl:49]CCl>>[ClH:49].[C:24]([CH2:23][NH:22][C:21]([C:20]1[N:19]=[C:18]([C:27]([F:30])([F:29])[F:28])[N:15]2[CH2:16][CH2:17][N:12]([C:10](=[O:11])[CH2:9][C@H:8]([NH2:7])[CH2:31][C:32]3[CH:37]=[C:36]([F:38])[C:35]([F:39])=[CH:34][C:33]=3[F:40])[CH2:13][C:14]=12)=[O:26])#[N:25]
Reactant: ClCCl
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)N1CCn2c(C(F)(F)F)nc(C(=O)NCC#N)c2C1)Cc1cc(F)c(F)cc1F
Solvent: O=C(O)C(F)(F)F
Product: Cl
Product: N#CCNC(=O)c1nc(C(F)(F)F)n2c1CN(C(=O)C[C@H](N)Cc1cc(F)c(F)cc1F)CC2

Procedure:
(R)-[3-[1-(Cyanomethyl-carbamoyl)-3-trifluoromethyl-5,6-dihydro-8H-imidazo[1,5-a]pyrazin-7-yl]-3-oxo-1-(2,4,5-trifluoro-benzyl)-propyl]-carbamic acid tert-butyl ester 4a (0.3 g, 0.25 mmol) was dissolved in 10 mL of dichloromethane, and 5 mL of trifluoroacetic acid was then added to the solution. The reaction mixture was reacted at room temperature for 1 hour until thin lay chromatography showed the starting material disappeared. The reaction mixture was concentrated under reduced pressure to obtain the title compound (R)-7-[3-amino-4-(2,4,5-trifluoro-phenyl)-butyryl]-3-trifluoromethyl-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine-1-carboxylic acid cyanomethyl-amide hydrochloride 4 (130 mg) as a light yellow solid.
Reaction SMILES: [CH3:1][O-:2].[Na+].CO.[C:6]1([CH3:33])[CH:11]=[CH:10][C:9]([N:12]=[C:13]([OH:32])[C:14]2[C:15](=[CH:19][C:20]([N+]([O-])=O)=[CH:21][C:22]=2[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:16]([OH:18])=[S:17])=[CH:8][CH:7]=1.Cl>CS(C)=O>[C:6]1([CH3:33])[CH:11]=[CH:10][C:9]([N:12]=[C:13]([OH:32])[C:14]2[C:15](=[CH:19][C:20]([O:2][CH3:1])=[CH:21][C:22]=2[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:16]([OH:18])=[S:17])=[CH:8][CH:7]=1
Reactant: C[O-]
Reactant: Cc1ccc(N=C(O)c2c(C(O)=S)cc([N+](=O)[O-])cc2-c2ccccc2)cc1
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: CS(C)=O
Product: COc1cc(C(O)=S)c(C(O)=Nc2ccc(C)cc2)c(-c2ccccc2)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
110 ml of 1.0 M sodium methylate solution in 110 mmols of absolute methanol are evaporated to dryness and the residue is suspended in 200 ml of dimethyl sulfoxide. 39.04 g (100 mmols) of 5-nitro-3-phenylthiophthalic acid N-p-toluylimide in 200 ml of dimethyl sulfoxide are added, the mixture is stirred for one day at 25° C. and then discharged into 1.5 liters of dilute hydrochloric acid and the resulting mixture is extracted with chloroform. The organic phase is washed three times with water, dried over sodium sulfate and evaporated. After recrystallisation from toluene/cyclohexane, 31.68 g (84% of theory) of the title imide, with a melting point of 166°-168° C., are obtained.
Reaction SMILES: C1COCC1.[F:6][C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][C:15]=1[F:16])[C:10](Cl)=[O:11].Cl.[CH3:18][CH:19]1[CH2:23][CH2:22][CH2:21][CH:20]1[NH2:24].C(N(CC)CC)C>C(OCC)(=O)C>[CH3:18][CH:19]1[CH2:23][CH2:22][CH2:21][CH:20]1[NH:24][C:10](=[O:11])[C:9]1[CH:13]=[CH:14][C:15]([F:16])=[C:7]([F:6])[CH:8]=1
Reactant: O=C(Cl)c1ccc(F)c(F)c1
Reactant: CC1CCCC1N
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC1CCCC1NC(=O)c1ccc(F)c(F)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 84.3 %

Procedure:
To a mixture of 10 ml of THF and 0.60 g of 3,4-difluorobenzoyl chloride were added 0.37 g of 2-methylcyclopentylamine hydrochloride and 1.0 g of triethylamine, and the mixture obtained was stirred at room temperature for 3 hours. Then, ethyl acetate was added to the reaction mixture and filtered through Celite. The filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 0.55 g of N-(2-methylcyclopentyl)-3,4-difluorobenzamide.
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]([CH2:7]Cl)=[CH:5][CH:6]=1.BrCC1CCCCO1.[Br:17][C:18]1[CH:26]=[CH:25][CH:24]=[C:23]2[C:19]=1[C:20]1([C:31]3=[CH:32][C:33]4[O:37][CH2:36][O:35][C:34]=4[CH:38]=[C:30]3[O:29][CH2:28]1)[C:21](=[O:27])[NH:22]2>>[Br:17][C:18]1[CH:26]=[CH:25][CH:24]=[C:23]2[C:19]=1[C:20]1([C:31]3=[CH:32][C:33]4[O:37][CH2:36][O:35][C:34]=4[CH:38]=[C:30]3[O:29][CH2:28]1)[C:21](=[O:27])[N:22]2[CH2:7][C:4]1[S:3][C:2]([Cl:1])=[CH:6][CH:5]=1
Reactant: ClCc1ccc(Cl)s1
Reactant: O=C1Nc2cccc(Br)c2C12COc1cc3c(cc12)OCO3
Agent: BrCC1CCCCO1
Product: O=C1N(Cc2ccc(Cl)s2)c2cccc(Br)c2C12COc1cc3c(cc12)OCO3

Procedure:
Following the procedure as described in EXAMPLE 4 and making non-critical variations using 2-chloro-5-(chloromethyl)thiophene to replace 2-(bromomethyl)tetrahydro-2H-pyran, and 4′-bromospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one to replace 5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2″(1′H)-one, 4′-bromo-1′-[(5-chloro-2-thienyl)methyl]spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one was obtained (95%) as a colorless solid: mp 85-87° C.; 1H NMR (300 MHz, DMSO-d6) δ 7.19-7.11 (m, 2H), 6.88-6.85 (m, 2H), 6.76 (d, J=3.8 Hz, 1H), 6.47 (s, 1H), 6.06 (s, 1H), 5.87 (d, J=5.8 Hz, 2H), 4.97 (ABq, 2H), 4.91 (d, J=9.2 Hz, 2H); 13C NMR (75 MHz, DMSO-d6) δ176.9, 157.2, 156.9, 149.3, 143.3, 142.1, 136.3, 130.3, 129.8, 127.7, 126.3, 126.0, 120.2, 116.1, 107.9, 102.6, 101.6, 93.3, 77.2, 59.5, 39.4; MS (ES+) m/z 490.3 (M+1), 488.2 (M+1).
Reaction SMILES: [F:1][CH2:2][C@H:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH3:4].C1([C@@H](C)COS(C2C=CC(C)=CC=2)(=O)=O)C=CC=CC=1>>[F:1][CH2:2][C@@H:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH3:4]
Reactant: C[C@H](CF)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)OC[C@H](C)c2ccccc2)cc1
Product: C[C@@H](CF)c1ccccc1

Procedure:
The title compound was prepared as described above for the synthesis of ((S)-2-fluoro-1-methyl-ethyl)-benzene, but using toluene-4-sulfonic acid (R)-2-phenylpropyl ester instead of toluene-4-sulfonic acid (S)-2-phenyl-propyl ester.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:17]2[CH2:22][CH2:21][CH2:20][C@@H:19]([N:23](C)[C:24](=O)OC(C)(C)C)[CH2:18]2)=[C:4]2[C:10]([NH:11][C:12]([CH:14]3[CH2:16][CH2:15]3)=[O:13])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[ClH:1].[Cl:1][C:2]1[C:3]([N:17]2[CH2:22][CH2:21][CH2:20][C@@H:19]([NH:23][CH3:24])[CH2:18]2)=[C:4]2[C:10]([NH:11][C:12]([CH:14]3[CH2:15][CH2:16]3)=[O:13])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: CN(C(=O)OC(C)(C)C)[C@@H]1CCCN(c2c(Cl)cnc3[nH]cc(NC(=O)C4CC4)c23)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN[C@@H]1CCCN(c2c(Cl)cnc3[nH]cc(NC(=O)C4CC4)c23)C1
Product: Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 186.4 %

Procedure:
(R)-tert-Butyl 1-(5-chloro-3-(cyclopropanecarboxamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-yl(methyl)carbamate (0.150 g, 0.335 mmol) was placed in DCM (3 mL) at room temperature. TFA (1 mL) was then added, and the reaction was stirred at room temperature for 1 hour and concentrated to dryness. The resulting residue was then purified by reverse phase chromatography (Biotage SP4, C-18 12M+, 0-50% CH3CN/water). The resulting product was next dissolved in minimal DCM (with MeOH to aid solubility) and added to a stirred solution of 1M HCl in ether. The resulting solid was filtered, washed with ether and dried to give (R)—N-(5-chloro-4-(3-(methylamino)piperidin-1-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide hydrochloride (0.120 g, 85% yield) as a solid. 1H NMR (400 MHz, D2O) δ 8.12 (s, 1H), 7.27 (s, 1H), 3.87-3.84 (m, 1H), 3.42-3.37 (m, 2H), 3.22-3.17 (m, 2H), 2.60 (s, 3H), 2.18-2.15 (m, 1H), 1.82-1.67 (m, 3H), 1.56-1.53 (m, 1H), 0.91-0.80 (m, 4H). LCMS (APCI+) m/z 348 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[CH:5]([O:18][CH2:19][CH3:20])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:16][CH3:17])=[C:11]([CH:15]=1)[C:12]([OH:14])=O)[CH3:2].[F:22][C:23]([F:33])([F:32])[C:24]1[CH:31]=[CH:30][C:27]([CH2:28][NH2:29])=[CH:26][CH:25]=1.C(P(=O)(OCC)OCC)#N.C(N(CC)CC)C>CN(C)C=O.O>[CH2:19]([O:18][CH:5]([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:16][CH3:17])=[C:11]([C:12]([NH:29][CH2:28][C:27]2[CH:26]=[CH:25][C:24]([C:23]([F:22])([F:32])[F:33])=[CH:31][CH:30]=2)=[O:14])[CH:15]=1)[C:4]([O:3][CH2:1][CH3:2])=[O:21])[CH3:20]
Reactant: NCc1ccc(C(F)(F)F)cc1
Reactant: CCOC(=O)C(Cc1ccc(OC)c(C(=O)O)c1)OCC
Agent: CCOP(=O)(C#N)OCC
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C(Cc1ccc(OC)c(C(=O)NCc2ccc(C(F)(F)F)cc2)c1)OCC
Temperature: 25 °C
Reaction time: 16 h
Yield: 72.7 %

Procedure:
0.58 g of 5-(3-ethoxy-2-ethoxy-3-oxopropyl)-2-methoxybenzoic acid and 0.34 g of 4-(trifluoromethyl)benzylamine were dissolved in 7 ml N,N-dimethylformamide, and 0.30 ml diethyl cyanophosphonate and 0.27 ml triethylamine were added thereto under ice-cooling. The reaction mixture was stirred at room temperature for 16 hours, then poured into iced water and extracted with ethyl acetate. The organic layer was washed with 1N hydrochloric acid and brine in this order, dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was subjected to silica gel column chromatography, and from fractions eluted with hexane-ethyl acetate (3:1), 0.64 g of ethyl 2-ethoxy-3-(4-methoxy-3-(([4-(trifluoromethyl)benzyl)amino)carbonyl)phenyl)propanoate was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([S:10][CH3:11])=[N:7][C:6]=2[CH:12]=1.[C:13]1([CH3:24])[CH:18]=[CH:17][C:16]([S:19]([O:22]C)(=[O:21])=[O:20])=[CH:15][CH:14]=1>>[S:19]([C:16]1[CH:17]=[CH:18][C:13]([CH3:24])=[CH:14][CH:15]=1)([O-:22])(=[O:21])=[O:20].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([S:10][CH3:11])=[N+:7]([CH3:13])[C:6]=2[CH:12]=1
Reactant: COS(=O)(=O)c1ccc(C)cc1
Reactant: CSc1nc2cc(Cl)ccc2s1
Product: CSc1sc2ccc(Cl)cc2[n+]1C
Product: Cc1ccc(S(=O)(=O)[O-])cc1

Procedure:
5-Chloro-2-(Methylthio)benzothiazole (5.0 g, 0.023 mol) and 4.40 g methyl p-toluenesulfonate were heated to 152° C. for 7 minutes. Upon cooling, the mixture solidified and then was triturated with acetone to give 7.82 g (84%), mp 170°-185° C.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4](=[CH2:8])[CH2:5][CH2:6][OH:7].Cl[C:10]1[N:15]=[C:14](Cl)[N:13]=[C:12](Cl)[N:11]=1.[OH2:18]>O1CCCC1>[CH3:8][C:4](=[CH2:3])[CH2:5][CH2:6][O:7][C:10]1[N:15]=[C:14]([O:18][CH2:6][CH2:5][C:4]([CH3:8])=[CH2:3])[N:13]=[C:12]([O:7][CH2:6][CH2:5][C:4]([CH3:3])=[CH2:8])[N:11]=1
Reactant: C=C(C)CCO
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=C(C)CCOc1nc(OCCC(=C)C)nc(OCCC(=C)C)n1
Temperature: 0 °C
Reaction time: 3 h
Yield: 76 %

Procedure:
To 16.6 g of sodium hydride (purity: 60% or more), 600 mL of tetrahydrofuran was added and the resultant reaction mixture was cooled down to 0° C., followed by dropping 34.5 g of 3-methyl-3-buten-1-ol into the reaction mixture at 4° C. or less to be added. After the completion of the dropping, the resultant reaction mixture was stirred at room temperature for 3 hours. Then, the reaction mixture was cooled down again to 0° C. and into the reaction mixture, 18.5 g of 2,4,6-trichloro-1,3,5-triazine dissolved in 110 mL of tetrahydrofuran was slowly dropped at 15° C. or less to be added. At room temperature, the reaction was effected over one night and to the reaction mixture, water was added, followed by extracting the resultant reaction mixture with ethyl acetate. The extract was washed with water and was dried over anhydrous sodium sulfate and from the extract, the solvent was distilled off to obtain 31.1 g of a crude product. The crude product was recrystallized (ethyl acetate:hexane=1:10) and the filtrate was purified with a column (ethyl acetate:hexane=1:4) to obtain 26.1 g of 2,4,6-tri(3-methyl-3-butene-1-oxy)-1,3,5-triazine which is the objective substance as a white solid. Yield: 76%, Purity: 97.0% (GC)
Reaction SMILES: C([O-])(=O)C.[Na+].[F:6][C:7]1[CH:12]=[CH:11][C:10]([C:13](=[O:21])[CH2:14][C:15]2[CH:20]=[CH:19][N:18]=[N:17][CH:16]=2)=[CH:9][CH:8]=1.[Br:22]Br.O>C(O)(=O)C>[Br:22][CH:14]([C:15]1[CH:20]=[CH:19][N:18]=[N:17][CH:16]=1)[C:13]([C:10]1[CH:9]=[CH:8][C:7]([F:6])=[CH:12][CH:11]=1)=[O:21]
Reactant: BrBr
Reactant: O=C(Cc1ccnnc1)c1ccc(F)cc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: O=C(c1ccc(F)cc1)C(Br)c1ccnnc1
Reaction time: 0.5 h

Procedure:
0.70 g (5.2 mmol) of sodium acetate is added to a solution of 1.02 g (4.70 mmol) of 1-(4-fluorophenyl)-2-pyridazin-4-ylethanone in 20 ml of acetic acid and then 0.26 ml (5.2 mmol) of bromine in solution in a few ml of acetic acid is added dropwise (slight exotherm). After 30 minutes at ambient temperature, the reaction medium is cooled and 60 ml of water are added. The product is extracted with diethyl ether. The cooled organic phase is washed with an aqueous solution of sodium hydrogen carbonate, dried over sodium sulfate and filtered. This solution (approximately 50 ml) is used rapidly, as it is, in the rest of the synthesis.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[O:11][CH3:12].S(Cl)([Cl:15])=O.[Cl-].[Al+3].[Cl-].[Cl-].[C:21]1([S:27]([N:30]2[C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[CH:32]=[CH:31]2)(=[O:29])=[O:28])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.Cl>ClC(Cl)C>[OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([Cl:15])=[O:7])=[CH:4][C:3]=1[O:11][CH3:12].[OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([C:32]2[C:33]3[C:38](=[CH:37][CH:36]=[CH:35][CH:34]=3)[N:30]([S:27]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)(=[O:29])=[O:28])[CH:31]=2)=[O:8])=[CH:4][C:3]=1[O:11][CH3:12]
Reactant: COc1cc(C(=O)O)ccc1O
Reactant: O=S(Cl)Cl
Reactant: O=S(=O)(c1ccccc1)n1ccc2ccccc21
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CC(Cl)Cl
Product: COc1cc(C(=O)Cl)ccc1O
Product: COc1cc(C(=O)c2cn(S(=O)(=O)c3ccccc3)c3ccccc23)ccc1O
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
4-Hydroxy-3-methoxybenzoyl chloride, which was prepared from 4-hydroxy-3-methoxybenzoic acid (1.01 g) and thionyl chloride (0.53 ml), was dissolved in dichloroethane (10 ml). The resultant solution was added on ice to a suspension of aluminum chloride (2.08 g) in dichloroethane (20 ml). Following, 1-(phenylsulfonyl)indole (1.85 g) in dichloroethane (10 ml) was added to the resultant with cooling on ice bath and stirred for 1.5 hours at room temperature. The reaction mixture was poured into 1N HCl (100 ml). The precipitate was collected by filtration and washed with water and methanol, obtaining 1.22 g of 3-(4-hydroxy-3-methoxybenzoyl)-1-(phenylsulfonyl)-indole as colorless crystals.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:9]([OH:11])=[N:8][CH:7]=[N:6][C:5]=2[S:4][CH:3]=1.[Cl:12]Cl>C(O)(=O)C>[Cl:12][C:3]1[S:4][C:5]2[N:6]=[CH:7][N:8]=[C:9]([OH:11])[C:10]=2[C:2]=1[CH3:1]
Reactant: ClCl
Reactant: Cc1csc2ncnc(O)c12
Solvent: CC(=O)O
Product: Cc1c(Cl)sc2ncnc(O)c12
Reaction time: 48 h
Yield: 82 %

Procedure:
To a solution of 5-methylthieno[2,3-d]pyrimidin-4-ol (2 g, 12 mmol) in acetic acid (30 mL) at room temperature, chlorine gas was bubbled for 3 h. The reaction mixture was stirred at same temperature for 2 days. The solvent was evaporated under reduced pressure at 40° C. and the residue was dissolved in ethyl acetate (30 mL) and washed with sat. NaHCO3 solution (3×20 mL). The organic layer was dried over sodium sulfate and evaporated to get the title compound as a pale yellow solid (2 g, 82%). 1H NMR (400 MHz, CDCl3 and CD3OD): δ 7.90 (s, 1H), 2.55 (s, 3H). MS (ESI) m/z: Calculated: 200.65; Observed: 201.3 (M++1).
Reaction SMILES: Cl.[CH2:2]([NH:18][C:19]1[CH:27]=[CH:26][C:22]([C:23](Cl)=[O:24])=[CH:21][CH:20]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17].[CH3:28][S:29]([NH2:32])(=[O:31])=[O:30]>N1C=CC=CC=1>[CH2:2]([NH:18][C:19]1[CH:27]=[CH:26][C:22]([C:23]([NH:32][S:29]([CH3:28])(=[O:31])=[O:30])=[O:24])=[CH:21][CH:20]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: CS(N)(=O)=O
Reactant: CCCCCCCCCCCCCCCCNc1ccc(C(=O)Cl)cc1
Agent: Cl
Solvent: c1ccncc1
Product: CCCCCCCCCCCCCCCCNc1ccc(C(=O)NS(C)(=O)=O)cc1

Procedure:
A solution of 25.2 g. of 4-(hexadecylamino)benzoyl chloride hydrochloride and 5.8 g. of methanesulfonamide in 250 ml. of pyridine was stirred under reflux for 2 hours and then concentrated in vacuo. The residue was partitioned between water and diethyl ether; the aqueous layer acidified with 1 N HCl, and the organic layer separated, dried (MgSO4), and evaporated. Crystallization of the residual white solid from 60% aqueous acetic acid followed by CH2Cl2 -hexane afforded the product as a white solid.
Reaction SMILES: [CH3:1][C:2]1([C:7]2[S:11][C:10]([CH2:12][N:13]3[N:17]=[C:16]([NH2:18])[CH:15]=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[F:19][C:20]1[CH:21]=[C:22]([C:26]2[O:30][CH:29]=[N:28][C:27]=2[C:31](O)=[O:32])[CH:23]=[CH:24][CH:25]=1>>[C:2]([C:7]1[S:11][C:10]([CH2:12][N:13]2[N:17]=[C:16]([NH:18][C:31]([C:27]3[N:28]=[CH:29][O:30][C:26]=3[C:22]3[CH:23]=[CH:24][CH:25]=[C:20]([F:19])[CH:21]=3)=[O:32])[CH:15]=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: O=C(O)c1ncoc1-c1cccc(F)c1
Reactant: CC1(c2ccc(Cn3ncc(N)n3)s2)OCCO1
Product: CC(=O)c1ccc(Cn2ncc(NC(=O)c3ncoc3-c3cccc(F)c3)n2)s1

Procedure:
Following general procedure A followed by B, starting from 2-[5-(2-methyl-[1,3]dioxolan-2-yl)-thiophen-2-ylmethyl]-2H-[1,2,3]triazol-4-ylamine and 5-(3-fluoro-phenyl)-oxazole-4-carboxylic acid.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[C:7]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[N:8][O:9][C:10]=2[CH3:11])[N:3]=[CH:2]1.[Cl:18][C:19]1[CH:20]=[C:21](B(O)O)[CH:22]=[CH:23][C:24]=1[F:25]>>[Cl:18][C:19]1[CH:20]=[C:21]([N:1]2[CH:5]=[C:4]([C:6]3[C:7]([C:12]4[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=4)=[N:8][O:9][C:10]=3[CH3:11])[N:3]=[CH:2]2)[CH:22]=[CH:23][C:24]=1[F:25]
Reactant: Cc1onc(-c2ccccc2)c1-c1c[nH]cn1
Reactant: OB(O)c1ccc(F)c(Cl)c1
Product: Cc1onc(-c2ccccc2)c1-c1cn(-c2ccc(F)c(Cl)c2)cn1
Yield: 5 %

Procedure:
As described for Example 3, 4-(1H-imidazol-4-yl)-5-methyl-3-phenyl-isoxazole (112.6 mg, 0.5 mmol) was converted, using 3-chloro-4-fluorophenylboronic acid instead of 4-fluorophenylboronic acid, to the title compound (8 mg, 5%) which was obtained as a white solid. MS (ESI): m/e=353.9 [M+H]+.