Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]12[O:10][CH:6]([CH:7]([CH3:9])[O:8]1)[CH2:5][CH2:4][CH:3]2[OH:11].[CH2:12](Cl)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.O1CCCC(O)C1>>[CH3:1][C:2]12[O:10][CH:6]([CH:7]([CH3:9])[O:8]1)[CH2:5][CH2:4][CH:3]2[O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: ClCc1ccccc1
Reactant: CC1OC2(C)OC1CCC2O
Agent: OC1CCCOC1
Product: CC1OC2(C)OC1CCC2OCc1ccccc1

Procedure:
18A was treated with benzyl chloride, by the procedure described for treatment of 1A, to give 18, as a liquid, b.p.: 145° C., 0.06 Torr.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[CH:6][C:5]=1[OH:14].F[C:16]1[CH:17]=[CH:18][C:19]([N+:29]([O-:31])=[O:30])=[C:20]([CH:28]=1)[C:21]([N:23]=[S:24]([CH3:27])([CH3:26])=[O:25])=[O:22]>CN(C)C=O>[Cl:3][C:4]1[CH:9]=[C:8]([C:10]([F:12])([F:13])[F:11])[CH:7]=[CH:6][C:5]=1[O:14][C:16]1[CH:17]=[CH:18][C:19]([N+:29]([O-:31])=[O:30])=[C:20]([CH:28]=1)[C:21]([N:23]=[S:24]([CH3:27])([CH3:26])=[O:25])=[O:22]
Reactant: CS(C)(=O)=NC(=O)c1cc(F)ccc1[N+](=O)[O-]
Reactant: Oc1ccc(C(F)(F)F)cc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CS(C)(=O)=NC(=O)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Temperature: 100 °C
Reaction time: 1 h
Yield: 23 %

Procedure:
0.48 g of sodium hydride is placed in 10 ml of absolute dimethylformamide. 1.96 g of o-chloro-p-trifluoromethyl-phenol are added dropwise and the mixture is stirred for 1 hour. 2.6 g of N-(5-fluoro-2-nitrobenzoyl)-S,S-dimethyl-sulphoximine are added and the mixture is heated to 100° C. for 90 minutes. The mixture is then cooled, poured on to 100 ml of ice-water and extracted with 50 ml of ethyl acetate. The ethyl acetate phase is washed with water, dried and evaporated, and the residue is purified by chromatography and crystallized from diethyl ether. There is obtained 1 g of N-[5-(o-chloro-p-trifluoromethyl-phenoxy)-2-nitrobenzoyl]-S,S-dimethyl-sulphoximine, m.p. 122° C.
Reaction SMILES: Cl[C:2]1[C:3]2[C:10]([Cl:11])=[CH:9][N:8]([S:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:4]=2[N:5]=[CH:6][N:7]=1.[NH:21]1[CH2:26][CH2:25][CH:24]([NH:27][C:28](=[O:35])[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:23][CH2:22]1.C(N(CC)C(C)C)(C)C.O>CN1C(=O)CCC1>[Cl:11][C:10]1[C:3]2[C:2]([N:21]3[CH2:26][CH2:25][CH:24]([NH:27][C:28](=[O:35])[C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[CH2:23][CH2:22]3)=[N:7][CH:6]=[N:5][C:4]=2[N:8]([S:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)(=[O:14])=[O:13])[CH:9]=1
Reactant: O=S(=O)(c1ccccc1)n1cc(Cl)c2c(Cl)ncnc21
Reactant: O=C(NC1CCNCC1)c1ccccc1
Solvent: O
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NC1CCN(c2ncnc3c2c(Cl)cn3S(=O)(=O)c2ccccc2)CC1)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
4,5-dichloro-7-(phenylsulfonyl)-7H-pyrrolo[2,3-d]pyrimidine D40 (400 mg) and N-4-piperidinylbenzamide (300 mg, 1.46 mmol) were dissolved in NMP (4 ml), then N,N-diisopropylethylamine (315 mg, 2.44 mmol) was added dropwise. The reaction was stirred at room temperature for 16 hours then poured into water extracted with EtOAc (2×100 ml). Organic layer was washed with water (4×30 ml), brine (50 ml), dried with MgSO4, filtered and solvent removed. Yellow solid obtained was purified by flash chromatography on silica gel eluting with pet eth/ethyl acetate 3/1 to give the desired product D41 in 260 mg as a yellow solid. LCMS [MH+] 496.0@1.54 min (5 min run)
Reaction SMILES: [N:1]1[C:8]([Cl:9])=[N:7][C:5](Cl)=[N:4][C:2]=1[Cl:3].[F:10][C:11]([F:15])([F:14])[CH2:12][NH2:13].C(N(CC)CC)C.O>CC(C)=O>[Cl:9][C:8]1[N:1]=[C:2]([Cl:3])[N:4]=[C:5]([NH:13][CH2:12][C:11]([F:15])([F:14])[F:10])[N:7]=1
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: NCC(F)(F)F
Solvent: O
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: FC(F)(F)CNc1nc(Cl)nc(Cl)n1
Yield: 45 %

Procedure:
166 g (0.9 mol) of cyanuric chloride were dissolved in 1 liter of warm acetone, the solution was filtered off from the small quantity of insoluble substance, and a solution of 90 g (0.9 mol) of 2,2,2-trifluoroethylamine in 101 g (1.0 mol) of triethylamine was added dropwise at 0° to 5° C., while stirring and cooling with ice. The mixture was stirred for some time, approx. 1 liter of water was added, and the crystals which had formed were filtered off under suction. After the product had been dried, 100 g (=45% of theory) of 2,4-dichloro-6-(2,2,2-trifluoroethylamino)-s-triazine of melting point 115° to 118° C. were obtained.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][C@H:6]([NH:14][C:15](=[O:34])[NH:16][C@@H:17]([CH2:25][CH2:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8].[C:35]([O:39][C:40](=[O:80])[CH2:41][N:42]([CH2:72][C:73](=[O:79])[O:74][C:75]([CH3:78])([CH3:77])[CH3:76])[C:43](=[O:71])[CH2:44][N:45]1[CH:49]=[CH:48][N:47]=[C:46]1[CH2:50][N:51]([CH2:60][C:61]1[CH:66]=[CH:65][C:64]([O:67][CH2:68][C:69]#[CH:70])=[CH:63][CH:62]=1)[CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][C:57](O)=[O:58])([CH3:38])([CH3:37])[CH3:36].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>ClCCCl>[C:75]([O:74][C:73](=[O:79])[CH2:72][N:42]([CH2:41][C:40](=[O:80])[O:39][C:35]([CH3:38])([CH3:37])[CH3:36])[C:43](=[O:71])[CH2:44][N:45]1[CH:49]=[CH:48][N:47]=[C:46]1[CH2:50][N:51]([CH2:60][C:61]1[CH:66]=[CH:65][C:64]([O:67][CH2:68][C:69]#[CH:70])=[CH:63][CH:62]=1)[CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][C:57](=[O:58])[NH:1][CH2:2][CH2:3][CH2:4][CH2:5][C@@H:6]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[NH:14][C:15](=[O:34])[NH:16][C@H:17]([C:18]([O:20][C:21]([CH3:22])([CH3:23])[CH3:24])=[O:19])[CH2:25][CH2:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])([CH3:78])([CH3:76])[CH3:77]
Reactant: C#CCOc1ccc(CN(CCCCCC(=O)O)Cc2nccn2CC(=O)N(CC(=O)OC(C)(C)C)CC(=O)OC(C)(C)C)cc1
Reactant: CC(C)(C)OC(=O)CC[C@H](NC(=O)N[C@@H](CCCCN)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: C#CCOc1ccc(CN(CCCCCC(=O)NCCCC[C@H](NC(=O)N[C@@H](CCC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)Cc2nccn2CC(=O)N(CC(=O)OC(C)(C)C)CC(=O)OC(C)(C)C)cc1
Yield: 76.7 %

Procedure:
A solution of (S)-di-tert-butyl 2-(3-((S)-6-amino-1-(tert-butoxy)-1-oxohexan-2-yl)ureido)pentanedioate (0.742 g, 1.52 mmol), 6-(((1-(2-(bis(2-(tert-butoxy)-2-oxoethyl)amino)-2-oxoethyl)-1H-imidazol-2-yl)methyl)(4-(prop-2-yn-1-yloxy)benzyl)amino)hexanoic acid (0.244 g, 0.38 mmol), EDCI (0.290 g, 1.52 mmol), HOBt (0.051 g, 0.38 mmol) and DIPEA (0.40 mL) in DCE (5.0 mL) was stirred at room temperature for 4 h. The solvent was evaporated to give a residue, which was purified by Biotage SP4 eluting with DCM/MeOH to give (14S,18S)-tri-tert-butyl 1-(1-(2-(bis(2-(tert-butoxy)-2-oxoethyl)amino)-2-oxoethyl)-1H-imidazol-2-yl)-8,16-dioxo-2-(4-(prop-2-yn-1-yloxy)benzyl)-2,9,15,17-tetraazaicosane-14,18,20-tricarboxylate (0.3237 g, 77%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 7.64 (t, J=5.4 Hz, 1H), 7.17 (d, J=8.4 Hz, 2H), 6.93 (s, 1H), 6.87 (d, J=8.8 Hz, 2H), 6.74 (s, 1H), 6.26 (d, J=8.4 Hz, 1H), 6.22 (d, J=8.0 Hz, 1H), 5.02 (s, 2H), 4.72 (d, J=2.0 Hz, 2H), 4.24 (s, 2H), 4.03-3.89 (m, 4H), 3.51 (t, J=2.0 Hz, 1H), 3.48 (s, 2H), 3.39 (s, 2H), 2.95 (q, J=6.3 Hz, 2H), 2.22-2.15 (m, 4H), 1.94 (t, J=7.4 Hz, 2H), 1.85-1.04 (m, 34H); MS (ESI), 1111.6 (M+H)+.
Reaction SMILES: C(O)(=O)C.O.[NH2:6]N.C[N:9]([CH:11]=[C:12]1[C:17](=O)[C:16]([CH3:20])([CH3:19])[CH2:15][CH2:14][C:13]1=[O:21])C>C(O)CCC>[CH3:19][C:16]1([CH3:20])[C:17]2[NH:6][N:9]=[CH:11][C:12]=2[C:13](=[O:21])[CH2:14][CH2:15]1
Reactant: CN(C)C=C1C(=O)CCC(C)(C)C1=O
Reactant: NN
Solvent: CC(=O)O
Solvent: O
Solvent: CCCCO
Product: CC1(C)CCC(=O)c2cn[nH]c21
Yield: 51.1 %

Procedure:
According to Scheme 2 Step 2: At 0° C., acetic acid (8.55 mL) followed by hydrazine monohydrate (150 mmol, 7.25 mL), were added slowly to a solution of 2-((dimethylamino)methylene)-4,4-dimethylcyclohexane-1,3-dione (150 mmol, 29.2 g) in butanol (400 mL). The reaction mixture was stirred under reflux for 16 hours. After evaporation of the filtrate, the crude residue was purified by flash chromatography over silica gel cyclohexane/AcOEt (100:0 to 50:50) and then over C18 gel using water/MeOH (100:0 to 50:50) as eluent to yield 7,7-dimethyl-6,7-dihydro-1H-indazol-4(5H)-one (76.7 mmol, 12.6 g, 51%) as a pale yellow solid.
Reaction SMILES: [Si]([O:8][C:9]1[CH:10]=[C:11]([CH:15]2[CH:19]=[C:18]([C:20]3[CH:25]=[C:24](Cl)[CH:23]=[CH:22][C:21]=3[F:27])[CH2:17][N:16]2[C:28]([O:30]C(C)(C)C)=O)[CH:12]=[CH:13][CH:14]=1)(C(C)(C)C)(C)C.C(O)(C(F)(F)[F:38])=O.C[CH2:43][N:44]([CH2:47]C)CC.CN(C)C(Cl)=O>C(Cl)Cl>[F:27][C:21]1[CH:22]=[CH:23][C:24]([F:38])=[CH:25][C:20]=1[C:18]1[CH2:17][N:16]([C:28]([N:44]([CH3:47])[CH3:43])=[O:30])[CH:15]([C:11]2[CH:12]=[CH:13][CH:14]=[C:9]([OH:8])[CH:10]=2)[CH:19]=1
Reactant: CCN(CC)CC
Reactant: CC(C)(C)OC(=O)N1CC(c2cc(Cl)ccc2F)=CC1c1cccc(O[Si](C)(C)C(C)(C)C)c1
Reactant: O=C(O)C(F)(F)F
Agent: CN(C)C(=O)Cl
Solvent: ClCCl
Product: CN(C)C(=O)N1CC(c2cc(F)ccc2F)=CC1c1cccc(O)c1
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
tert-Butyl 2-(3-{[tert-butyl(dimethyl)silyl]oxy}phenyl)-4-phenyl-2,5-dihydro-1H-pyrrole-1-carboxylate (3-2, 1.48 g, 3.82 mmol) was dissolved in anhydrous CH2Cl2 (25 mL) and treated with TFA (5 mL) for 1 hour. The reaction mixture was partitioned between sat. aq. NaHCO3 (100 mL) and ethyl acetate (3×20 mL). The combined organic layers were then washed with sat. aqueous NaCl, dried over sodium sulfate, filtered, and concentrated. The crude amine was then dissolved in CH2Cl2, and treated successively with Et3N (1.6 mL, 11.5 mmol) and dimethylcarbamoyl chloride (0.37 mL, 4.01 mmol), and the resulting solution was stirred 3.5 h at 25° C. Upon completion as judged by mass spectrometry, the reaction was concentrated, redissolved in CH2Cl2 (30 mL) and triethylamine trihydrofluroide complex (0.6 mL, 3.82 mmol) was added and the reaction stirred an additional 12 h at 25° C. Upon completion, the reaction was partitioned between NH4Cl (10 mL) and CH2Cl2 (3×10 mL), and the combined organic layers were concentrated. The desired compound crystallized from CH2Cl2 and as filtered to provide 4-(2,5-difluorophenyl)-2-(3-hydroxyphenyl)-N,N-dimethyl-2,5-dihydro-1H-pyrrole-1-carboxamide 4-1 as a white solid. 1H NMR (300 MHz, CDCl3) δ 7.18 (t, J=7.8 Hz, 2H), 7.00 (m, 3H), 6.90 (s, 1H), 6.84 (d, J=7.7 Hz, 1H), 6.74 (dd, J=7.9, 2.4 Hz, 1H), 4.90 (dd, J=13.4, 3.7 Hz, 1H), 4.50 (d, J=13.4 Hz, 1H), 2.91 (s, 6H). LRMS: m/z (M−CH3) 345.3 found, 345.4 required.
Reaction SMILES: Br[C:2]1[S:6][CH:5]=[C:4]([C:7](=[O:12])[C:8]([F:11])([F:10])[F:9])[CH:3]=1.[C:13]([C:16]1[CH:17]=[C:18](B(O)O)[CH:19]=[CH:20][CH:21]=1)([OH:15])=[O:14]>>[F:9][C:8]([F:11])([F:10])[C:7]([C:4]1[CH:3]=[C:2]([C:20]2[CH:21]=[C:16]([CH:17]=[CH:18][CH:19]=2)[C:13]([OH:15])=[O:14])[S:6][CH:5]=1)=[O:12]
Reactant: O=C(O)c1cccc(B(O)O)c1
Reactant: O=C(c1csc(Br)c1)C(F)(F)F
Product: O=C(O)c1cccc(-c2cc(C(=O)C(F)(F)F)cs2)c1
Yield: 16 %

Procedure:
This compound was synthesized from 1-(5-bromothiophen-3-yl)-2,2,2-trifluoroethanone and 3-carboxyphenylboronic acid as described in example 88 step 3 (150 mg, yield 16%) as a yellow solid. 1H NMR (300 MHz, DMSO-d6) δ 13.26 (br s, 1H), 8.85 (s, 1H), 8.19 (s, 1H), 8.07-8.05 (m, 2H), 7.96-7.93 (d, J=7.9 Hz, 1H), 7.62-7.57 (t, J=7.7 Hz, 1H).
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[C:3]1[CH2:11][O:12][C:13]1[CH:14]=[C:15](N)[CH:16]=[CH:17][CH:18]=1.[CH2:20]([N:22](CC)CC)[CH3:21].C([S:29](Cl)(=[O:31])=[O:30])C>O1CCCC1>[CH2:20]([NH:22][S:29]([C:15]1[CH:16]=[CH:17][CH:18]=[C:13]([O:12][CH2:11][C:3]2[N:2]([CH3:1])[C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=3[N:4]=2)[CH:14]=1)(=[O:31])=[O:30])[CH3:21]
Reactant: CCN(CC)CC
Reactant: Cn1c(COc2cccc(N)c2)nc2ccccc21
Reactant: CCS(=O)(=O)Cl
Solvent: C1CCOC1
Product: CCNS(=O)(=O)c1cccc(OCc2nc3ccccc3n2C)c1
Reaction time: 1 h
Yield: 37.2 %

Procedure:
To a solution of 3-[(1-methyl-2-benzimidazolyl)methoxy]benzenamine (2 g) and triethylamine (0.79 g) in tetrahydrofuran (100 ml) at room temperature is slowly added a solution of ethanesulfonyl chloride (1.0 g) in tetrahydrofuran. The reaction is stirred for 1 hour. The mixture is filtered through a pad of Celite and silica gel and the solvent is removed in vacuo giving an oil. The oil is purified by HPLC and crystallized from hexane to give 1.0 g (37% yield) of product, m.p. 169°-173° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:42])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][C@H:9]2[C:28]([NH:30][C:31]2[CH:39]=[CH:38][C:34]([C:35](O)=[O:36])=[CH:33][C:32]=2[O:40][CH3:41])=[O:29])[CH:5]=[CH:6][CH:7]=1.[CH3:43][N:44]1[CH2:49][CH2:48][N:47]([CH2:50][CH2:51][NH2:52])[CH2:46][CH2:45]1>>[ClH:1].[CH3:41][O:40][C:32]1[CH:33]=[C:34]([C:35](=[O:36])[NH:52][CH2:51][CH2:50][N:47]2[CH2:48][CH2:49][N:44]([CH3:43])[CH2:45][CH2:46]2)[CH:38]=[CH:39][C:31]=1[NH:30][C:28]([C@H:9]1[C@H:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=2[F:42])[C@:12]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10]1)=[O:29]
Reactant: COc1cc(C(=O)O)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2F)[C@H]1c1cccc(Cl)c1F
Reactant: CN1CCN(CCN)CC1
Product: COc1cc(C(=O)NCCN2CCN(C)CC2)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2F)[C@H]1c1cccc(Cl)c1F
Product: Cl

Procedure:
In a manner similar to the method described in Example 14, 4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoic acid (prepared as described in US20100152190A1) was reacted with 2-(4-methylpiperazin-1-yl)ethanamine to give (2R,3S,4R,5S)-4-(4-chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid {2-methoxy-4-[2-(4-methyl-piperazin-1-yl)-ethylcarbamoyl]-phenyl}-amide, hydrochloride. MS (ES+) m/z calcd. for C38H45Cl2F2N6O3: [(M+H)+]: 741. found: 741.
Reaction SMILES: [CH3:1][N:2]([CH3:17])[CH:3]([CH2:7][CH2:8][S:9][S:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1)[C:4]([OH:6])=[O:5].O[N:19]1[C:23](=[O:24])[CH2:22][CH2:21][C:20]1=[O:25].C(Cl)CCl>CC(N(C)C)=O>[CH3:17][N:2]([CH3:1])[CH:3]([CH2:7][CH2:8][S:9][S:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1)[C:4]([O:6][N:19]1[C:23](=[O:24])[CH2:22][CH2:21][C:20]1=[O:25])=[O:5]
Reactant: CN(C)C(CCSSc1ccccn1)C(=O)O
Reactant: O=C1CCC(=O)N1O
Solvent: ClCCCl
Solvent: CC(=O)N(C)C
Product: CN(C)C(CCSSc1ccccn1)C(=O)ON1C(=O)CCC1=O
Yield: 34.4 %

Procedure:
2-(dimethylamino)-4-(pyridin-2-yldisulfanyl)butanoic acid (218) (92 mg, 0.338 mmol), 1-hydroxypyrrolidine-2,5-dione (65 mg, 0.565 mmol) and EDC (185 mg, 0.965 mmol) was stirred in 3 ml of DMA at 50° C. overnight. The mixture was evaporated and purified on a SiO2 column eluted with from 1:10 to 1:4 of methanol/CH2Cl2 to afford 43 mg (35%) of the title product. 1H NMR (CDl3OD) 8.40 (m, 1H), 7.83 (m, 2H), 7.22 (m, 1H), 3.34 (m, 1H), 2.82 (m, 2H), 2.75 (s, 4H), 2.66 (s, 6H), 1.98 (m, 2H); 13C NMR 177.21, 161.78, 161.12, 150.68, 139.37, 122.70, 121.66, 70.80, 44.16, 43.15, 36.06, 27.38; ESI MS m/z+369.2 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]([O:6][CH2:7][CH:8]2[C:17]3[C:12](=[CH:13][C:14]([OH:20])=[C:15]([O:18]C)[CH:16]=3)[CH2:11][CH2:10][NH:9]2)=[CH:4][CH:3]=1.O.O.O.[I-].[Li+].C(O)(=O)C1C=CC=CC=1>CO>[ClH:1].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH2:7][CH:8]2[C:17]3[C:12](=[CH:13][C:14]([OH:20])=[C:15]([OH:18])[CH:16]=3)[CH2:11][CH2:10][NH:9]2)=[CH:21][CH:22]=1
Reactant: COc1cc2c(cc1O)CCNC2COc1ccc(Cl)cc1
Agent: O=C(O)c1ccccc1
Agent: [I-]
Agent: [Li+]
Solvent: O
Solvent: CO
Product: Cl
Product: Oc1cc2c(cc1O)C(COc1ccc(Cl)cc1)NCC2

Procedure:
A mixture of 1-(4-chlorophenoxy)methyl-6-hydroxy-7-methoxy-1,2,3,4-tetrahydroisoquinoline (100 mg), lithium iodide trihydrate (150 mg) and benzoic acid (38 mg) was heated in an oil bath of 200° to 210° C. for 0.5 hour. After the reaction, the precipitated solid was dissolved in methanol absorbed with hydrogen chloride, and then insoluble material was filtered off. The filtrate was concentrated, and to the residue was added a small amount of ether, and the mixture was allowed to stand. The precipitated crystals were collected by filtration, and dried to give 1-(4-chlorophenoxy)methyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline hydrochloride, mp 226° C. The product was identified with a sample by I.R. spectrum and N.M.R. spectrum.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[N:5][C:6]([NH:9][CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18]C)=[C:14]([C:20]([F:23])([F:22])[F:21])[CH:13]=2)=[N:7][CH:8]=1)[CH3:2].[F:24][C:25]([F:36])([F:35])[O:26][C:27]1[CH:34]=[CH:33][C:30]([CH2:31]Br)=[CH:29][CH:28]=1>>[CH2:1]([C:3]1[CH:4]=[N:5][C:6]([N:9]([CH2:31][C:30]2[CH:33]=[CH:34][C:27]([O:26][C:25]([F:24])([F:35])[F:36])=[CH:28][CH:29]=2)[CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[C:14]([C:20]([F:23])([F:22])[F:21])[CH:13]=2)=[N:7][CH:8]=1)[CH3:2]
Reactant: FC(F)(F)Oc1ccc(CBr)cc1
Reactant: CCc1cnc(NCCc2ccc(OC)c(C(F)(F)F)c2)nc1
Product: CCc1cnc(N(CCc2ccc(O)c(C(F)(F)F)c2)Cc2ccc(OC(F)(F)F)cc2)nc1

Procedure:
Similarly prepared from 5-ethyl-N-{2-[4-methoxy-3-(trifluoromethyl)phenyl]ethyl}pyrimidin-2-amine and 4-trifluoromethoxy benzyl bromide.
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[NH:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[C:12]([Br:17])[CH:11]=1)([CH3:4])([CH3:3])[CH3:2].Br[C:20]1[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][N:21]=1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.O.CCOC(C)=O>[C:1]([O:5][C:6](=[O:18])[NH:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:20]2[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][N:21]=2)=[C:12]([Br:17])[CH:11]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCCc1ccc(O)c(Br)c1
Reactant: FC(F)(F)c1ccc(Br)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)NCCc1ccc(Oc2ccc(C(F)(F)F)cn2)c(Br)c1
Temperature: 60 °C
Reaction time: 8 h
Yield: 78.4 %

Procedure:
[2-(3-bromo-4-hydroxy-phenyl)-ethyl]-carbamic acid tert-butyl ester (2.212 mmol, 1 eq), 2-bromo-5-(trifluoromethyl)-pyridine (2.212 mmol, 1 eq) and potassium carbonate (5.531 mmol, 1.5 eq) were suspended in dimethylsulfoxide (25 ml). The reaction mixture was stirred at 60° C. overnight. Reaction mixture was diluted with water (150 ml) and extraction with EtOAc followed (7×15 ml). Organic layers were combined, washed with brine, dried over MgSO4, filtered and evaporated giving {2-[3-bromo-4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl]-ethyl}-carbamic acid tert-butyl ester (1.734 mmol, yield=78%, purity=93%). [M+H]+=461.29 1H NMR (300 MHz, CDCl3) δ/ppm 1.43 (s, 9H), 2.74-2.84 (m, 2H), 3.29-3.45 (m, 2H), 4.51-4.65 (m, 1H), 7.02-7.15 (m, 2H), 7.16-7.23 (m, 1H), 7.45-7.50 (m, 1H), 7.86-7.95 (m, 1H), 8.35-8.41 (m, 1H)
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:17][C:18]([C:20]2[N:24]([CH:25]([CH3:27])[CH3:26])[N:23]=[CH:22][CH:21]=2)=[O:19])[C:5]2[C:9]([CH:10]=1)=[N:8][N:7](C1CCCCO1)[CH:6]=2.[CH3:28][C:29]1[NH:40][C:32]2=[N:33][CH:34]=[CH:35][C:36](B(O)O)=[C:31]2[CH:30]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].O1CCOCC1>CO.O>[CH3:27][CH:25]([N:24]1[C:20]([C:18]([NH:17][C:4]2[CH:3]=[C:2]([C:36]3[CH:35]=[CH:34][N:33]=[C:32]4[NH:40][C:29]([CH3:28])=[CH:30][C:31]=34)[CH:10]=[C:9]3[C:5]=2[CH:6]=[N:7][NH:8]3)=[O:19])=[CH:21][CH:22]=[N:23]1)[CH3:26]
Reactant: CC(C)n1nccc1C(=O)Nc1cc(Br)cc2nn(C3CCCCO3)cc12
Reactant: Cc1cc2c(B(O)O)ccnc2[nH]1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: CO
Solvent: O
Product: Cc1cc2c(-c3cc(NC(=O)c4ccnn4C(C)C)c4cn[nH]c4c3)ccnc2[nH]1
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
A microwave vial was charged with N-[6-bromo-2-(tetrahydro-2H-pyran-2-yl)-2H-indazol-4-yl]-1-(1-methylethyl)-1H-pyrazole-5-carboxamide (70 mg), (2-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)boronic acid (29 mg), tripotassium phosphate (103 mg) and Solvias catalyst (9 mg), 1,4-dioxane (1.2 ml) and water (0.24 ml). The reaction was heated under microwave irradiation at 100° C. for 30 min, twice. Further (2-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)boronic acid (10 mg) and Solvias catalyst (9 mg) were added and the reaction heated under microwave irradiation at 100° C. for 30 min. Again further (2-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)boronic acid (11 mg), tripotassium phosphate (30 mg) and Solvias catalyst (9 mg) were added and the reaction heated under microwave irradiation at 100° C. for 30 min. The reaction was passed through a silica cartridge, preconditioned with methanol, washing with methanol. The solvent was evaporated and the residue was dissolved in DMSO:methanol (1:1, v/v) and purified by MDAP (Method A). Appropriate fractions were evaporated to dryness, dissolved in methanol (2 ml) and 2 M HCl (aq) (0.5 ml) and left at room temperature for 30 min. The solvent was evaporated, the residue was dissolved in DMSO:methanol (1:10, v/v) and passed through an aminopropyl cartridge preconditioned with methanol, washing with methanol. The solvent was evaporated and the residue was purified by MDAP (method A). Purified fractions were evaporated to dryness, dissolved in methanol, passed through an aminopropyl cartridge preconditioned with methanol, washing with methanol, then evaporated to dryness to give title compound, 19 mg.
Reaction SMILES: CO[C:3]1[CH:11]=[C:10](N)[C:9](Cl)=[CH:8][C:4]=1[C:5]([OH:7])=O.C(N1C=CN=C1)([N:16]1C=CN=C1)=O.[CH3:26][N:27]([CH:31]1[CH2:33][CH2:32]1)[CH2:28][CH2:29]N.O>O1CCCC1>[CH3:26][N:27]([CH:31]1[CH2:33][CH2:32]1)[CH2:28][CH2:29][C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[C:5]([NH2:16])=[O:7]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CN(CCN)C1CC1
Reactant: COc1cc(N)c(Cl)cc1C(=O)O
Solvent: C1CCOC1
Solvent: O
Product: CN(CCc1ccccc1C(N)=O)C1CC1
Reaction time: 1 h

Procedure:
15.6 g of N-acetyl-N'-methylcyclopropylethylenediamine are refluxed during two hours with 80 ml of 15% hydrochloric acid. The solution is then saturated with sodium hydroxide, extracted with ethyl ether, the organic extract is dried and evaporated at 20° C./15 mm/Hg. Gas-chromatographically pure N-acetyl-N'-methyl-N'-cyclopropylethylene is thus obtained. 8.06 g (0.04 mole) of 2-methoxy-4-amino-5-chlorobenzoic acid and 7.12 g (0.044 mole) of carbonyldiimidazole are suspended in 80 ml of tetrahydrofuran and kept at 30° C. until the gas evolution stopped. A solution containing 5.7 g (0.05 mole) of N-methyl-N-cyclopropylethylenediamine in 15 ml of tetrahydrofuran is then slowly added at room temperature, and thereafter the temperature is kept at 50° C. for one hour. After cooling down, the mixture is poured into water, the solid is removed by filtration and crystallized from alcohol, thus obtaining 9.6 (80.6%) of 2-methoxy-4-amino-5-chloro-N-(2-(methylcyclopropylamino)ethyl-benzamide having a melting point of 164°-5° C. Hydrochloride, m.p. 130°-2° C.
Reaction SMILES: [H-].[Na+].[C:3]1([N:9]2[C:13]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[C:12]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[NH:11][C:10]2=[O:26])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:27][O:28][C:29](=[O:38])[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36]Br>CN(C=O)C>[CH3:27][O:28][C:29](=[O:38])[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][N:11]1[C:12]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[C:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:9]([C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[C:10]1=[O:26]
Reactant: O=c1[nH]c(-c2ccccc2)c(-c2ccccc2)n1-c1ccccc1
Reactant: COC(=O)CCCCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)CCCCCCCn1c(-c2ccccc2)c(-c2ccccc2)n(-c2ccccc2)c1=O

Procedure:
The product is produced as described in example 1 from 1.2 g of NaH (80% suspension in mineral oil), 12 g of 1.4.5-triphenyl-4-imidazolin-2-one, 80 cc. of DMF, 9.5 g of 8-bromocaprylic acid methyl ester and 1.2 g of NaJ.