Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[C:9]([O:13][C:14]([N:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1)=[O:15])([CH3:12])([CH3:11])[CH3:10]>N1C=CC=CC=1>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([N:19]2[CH2:18][CH2:17][N:16]([C:14]([O:13][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:15])[CH2:21][CH2:20]2)=[N:3][CH:4]=1
Reactant: Brc1ccc(Br)nc1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(Br)cn2)CC1
Yield: 39.5 %

Procedure:
A mixed solution of 2,5-dibromopyridine (6.36 g, 26.8 mmol), 1-(tert-butoxycarbonyl)piperazine (5.00 g, 26.8 mmol) and pyridine (100 ml) was stirred at 125° C. for 12 hours, and the solvent was distilled away under reduce pressure. The residue was poured into water, and extracted with ethyl acetate. The extract was washed with water, dried over anhydrous magnesium sulfate, and the solvent was distilled away under reduce pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=10:1) to give the titled compound 3.62 g (39.5%) as solid product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([C:9]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][C:10]=2[C:11]([OH:13])=O)[N:4]=1.[CH3:19][C@@H:20]1[CH2:25][CH2:24][CH2:23][NH:22][C@@H:21]1[CH2:26][NH:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][N:29]=1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([C:9]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][C:10]=2[C:11]([N:22]2[CH2:23][CH2:24][CH2:25][C@@H:20]([CH3:19])[C@H:21]2[CH2:26][NH:27][C:28]2[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:35])[F:36])=[CH:30][N:29]=2)=[O:13])[N:4]=1
Reactant: COc1ccnc(-c2ccc(C)cc2C(=O)O)n1
Reactant: C[C@@H]1CCCN[C@@H]1CNc1ccc(C(F)(F)F)cn1
Product: COc1ccnc(-c2ccc(C)cc2C(=O)N2CCC[C@@H](C)[C@H]2CNc2ccc(C(F)(F)F)cn2)n1

Procedure:
The title compound was prepared following the same general protocol as described in Example A1, using 2-(4-methoxypyrimidin-2-yl)-5-methylbenzoic acid and N-(((2S,3R)-3-methylpiperidin-2-yl)methyl)-5-(trifluoromethyl)pyridin-2-amine. ESI-MS (m/z): 500 [M+1]+.
Reaction SMILES: FC(F)(F)C(O)=O.[N:8]1([C:13]2[CH:14]=[CH:15][C:16](/[CH:21]=[CH:22]/[C:23]([O:25]C(C)(C)C)=[O:24])=[N:17][C:18]=2[O:19][CH3:20])[CH:12]=[CH:11][N:10]=[CH:9]1>ClCCl>[N:8]1([C:13]2[CH:14]=[CH:15][C:16](/[CH:21]=[CH:22]/[C:23]([OH:25])=[O:24])=[N:17][C:18]=2[O:19][CH3:20])[CH:12]=[CH:11][N:10]=[CH:9]1
Reactant: COc1nc(/C=C/C(=O)OC(C)(C)C)ccc1-n1ccnc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1nc(/C=C/C(=O)O)ccc1-n1ccnc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.5 %

Procedure:
A solution of trifluoroacetic acid (3 mL) in dichloromethane (1.5 mL) was added to tert-butyl (E)-3-[5-(1H-imidazol-1-yl)-6-methoxypyridin-2-yl]acrylate (490 mg) under ice-cooling, and the reaction solution was stirred at room temperature for one hour. The reaction solution was concentrated under reduced pressure, diluted with chloroform and then concentrated under reduced pressure. Diethyl ether was added to the residue, and the precipitated solid was collected by filtration. The solid was washed with diethyl ether to obtain the title compound as a solid (345 mg). The property values of the compound are as follows.
Reaction SMILES: [C:1]([C:5]1[C:14]2[O:13][CH2:12][CH2:11][N:10]([CH3:15])[C:9]=2[CH:8]=[C:7]([C:16](=[O:18])[CH3:17])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[Br:19]Br>C(O)(=O)C.C1(C)C=CC=CC=1>[Br:19][CH2:17][C:16]([C:7]1[CH:6]=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[C:14]2[O:13][CH2:12][CH2:11][N:10]([CH3:15])[C:9]=2[CH:8]=1)=[O:18]
Reactant: BrBr
Reactant: CC(=O)c1cc2c(c(C(C)(C)C)c1)OCCN2C
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: CN1CCOc2c1cc(C(=O)CBr)cc2C(C)(C)C
Reaction time: 2.5 h
Yield: 19.7 %

Procedure:
1-(8-tert-Butyl-4-methyl-3,4-dihydro-2H-benzo[1,4]oxazin-6-yl)ethanone (250 mg, purchased from Chembiotek, India) was heated to from 50° C. to 55° C. in a mixture of acetic acid (4 ml) and toluene (8 ml). At this temperature, bromine (200 mg dissolved in acetic acid) was cautiously added dropwise. After 2.5 h, the heating was removed, and the mixture was admixed at RT with ice-water and extracted three times with toluene. The combined organic phases were dried over sodium sulfate, filtered and concentrated. The crude product was purified using silica gel, so as to obtain 65 mg of the desired compound, as well as a further 43 mg of product which was slightly contaminated and 37 mg of reactant.
Reaction SMILES: CS(O[CH:6]([CH2:21][CH3:22])[CH2:7][CH2:8][CH:9](OS(C)(=O)=O)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(=O)=O.[NH2:23][C:24]1[CH:31]=[CH:30][C:27]([C:28]#[N:29])=[C:26]([Cl:32])[CH:25]=1>C1(C)C=CC=CC=1>[Cl:32][C:26]1[CH:25]=[C:24]([N:23]2[CH:9]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH2:8][CH2:7][CH:6]2[CH2:21][CH3:22])[CH:31]=[CH:30][C:27]=1[C:28]#[N:29]
Reactant: CCC(CCC(OS(C)(=O)=O)c1ccccc1)OS(C)(=O)=O
Reactant: N#Cc1ccc(N)cc1Cl
Solvent: Cc1ccccc1
Product: CCC1CCC(c2ccccc2)N1c1ccc(C#N)c(Cl)c1

Procedure:
Dissolve methanesulfonic acid 4-methanesulfonyloxy-1-phenyl-hexyl ester (1.01 g, 2.88 mmol) in toluene (20 mL) in a reaction tube. Add 4-amino-2-chlorobenzonitrile (1.10 g, 7.2 mmol), purge with nitrogen and cap. Heat the reaction in a 120° C. oil bath for 17 h. Cool, concentrate, and purify by silica gel chromatography using 5-30% EtOAc/hexanes to obtain 0.22 g (25%0 of the title compound as a clear oil. MS (ESI+): 311 (M+1)+, 309 (M−1)−.
Reaction SMILES: C([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][CH:5]=1)(C)=C.[OH:12]O>>[OH:12][C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][CH:5]=1
Reactant: OO
Reactant: C=C(C)c1ccc(OC)cc1
Product: COc1ccc(O)cc1

Procedure:
reacting para-isopropenylanisole with hydrogen peroxide in the presence of a mineral acid and a solvent to yield para- hydroxyanisole.
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]([CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([O:16][CH3:17])[CH:9]=1)[CH3:5].[CH3:18][N:19]([C:21]1[CH:26]=[C:25]([N+:27]([O-:29])=[O:28])[CH:24]=[CH:23][C:22]=1[OH:30])[CH3:20].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(=O)(O)[O-].[Na+]>[CH3:20][N:19]([C:21]1[CH:26]=[C:25]([N+:27]([O-:29])=[O:28])[CH:24]=[CH:23][C:22]=1[O:30][CH2:2][CH2:3][N:4]([CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([O:16][CH3:17])[CH:9]=1)[CH3:5])[CH3:18]
Reactant: COc1ccc(CCN(C)CCCl)cc1OC
Reactant: CN(C)c1cc([N+](=O)[O-])ccc1O
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(CCN(C)CCOc2ccc([N+](=O)[O-])cc2N(C)C)cc1OC
Yield: 55.6 %

Procedure:
A portion (1 g, 3.88 mmol) of the 1-chloro-2-[N-(3,4-dimethoxyphenethyl)-N-methylamino]ethane produced in (1) above, 2-(N,N-dimethylamino)-4-nitrophenol (0.598 g, 3.88 mmol) and potassium carbonate (0.536 g, 3.88 mmol) were heated in dimethylformamide (10 ml) at 80° C. for 2 h. Thereafter, the reaction mixture was diluted with a saturated solution of sodium bicarbonate, subjected to extraction with ethyl acetate and dried with anhydrous magnesium sulfate, followed by evaporation of the solvent. The residue was purified by being subjected to column chromatography on silica gel using, as an eluent, chloroform containing methanol (5%) to yield the titled compound 1-[2-(N,N-dimethylamino)-4-nitrophenoxy]-2-[N-(3,4-dimethoxyphenethyl)-N-methylamino]ethane (0.87 g) as a foam.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([OH:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[CH2:13]1[C@@H:17]([CH2:18][CH2:19][CH2:20][CH2:21][C:22](O)=[O:23])[S:16][S:15][CH2:14]1.C(Cl)CCl>CN(C=O)C.CCOC(C)=O>[S:15]1[CH2:14][CH2:13][C@H:17]([CH2:18][CH2:19][CH2:20][CH2:21][C:22]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([OH:12])=[C:6]([CH:11]=2)[C:7]([O:9][CH3:10])=[O:8])=[O:23])[S:16]1
Reactant: COC(=O)c1cc(N)ccc1O
Reactant: O=C(O)CCCC[C@@H]1CCSS1
Solvent: ClCCCl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1cc(NC(=O)CCCC[C@H]2CCSS2)ccc1O
Temperature: 25 °C
Reaction time: 18 h
Yield: 61.2 %

Procedure:
Methyl 5-amino-2-hydroxybenzoate (500 mg, 2.99 mmol) was taken up in DMF (15 mL) along with (R)-α-lipoic acid (TCI, 618 mg, 2.99 mmol) and EDC (630 mg, 3.3 mmol). The resulting reaction mixture was stirred at room temperature for 18 h and then diluted with EtOAc (60 mL). The organic layer was washed with water (3×10 mL), brine, dried (Na2SO4) and concentrated under reduced pressure. Purification by chromatography (95% CH2Cl2, 5% MeOH) afforded 650 mg of (S)-methyl 5-(5-(1,2-dithiolan-3-yl)pentanamido)-2-hydroxybenzoate (61%). Mass calculated for C16H21NO4S2=355.09. found: [M+H]+=356.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[C:8]([C:18]([O:20][CH3:21])=[O:19])=[C:9]([OH:17])[C:10]2[C:15]([CH:16]=1)=[CH:14][CH:13]=[CH:12][CH:11]=2.[CH:22]([O:35][C:36](=[O:72])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1[N:43]([C:60](=[O:71])[C:61]([O:63][CH2:64][C:65]1[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=1)=[O:62])[C:44]1[CH:49]=[CH:48][C:47]([CH2:50][CH:51]([C:57](O)=[O:58])[NH:52][C:53]([O:55][CH3:56])=[O:54])=[CH:46][CH:45]=1)([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.Cl.CN(C)CCCN=C=NCC.ON1C(=O)C2C=CC=CC=2N=N1>CN(C=O)C.C(N(CC)CC)C>[CH:22]([O:35][C:36]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1[N:43]([C:60](=[O:71])[C:61]([O:63][CH2:64][C:65]1[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=1)=[O:62])[C:44]1[CH:45]=[CH:46][C:47]([CH2:50][C@@H:51]([C:57]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]2[C:8]([C:18]([O:20][CH3:21])=[O:19])=[C:9]([OH:17])[C:10]3[C:15]([CH:16]=2)=[CH:14][CH:13]=[CH:12][CH:11]=3)=[O:58])[NH:52][C:53]([O:55][CH3:56])=[O:54])=[CH:48][CH:49]=1)=[O:72])([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: COC(=O)c1c(OCCCCN)cc2ccccc2c1O
Reactant: COC(=O)NC(Cc1ccc(N(C(=O)C(=O)OCc2ccccc2)c2ccccc2C(=O)OC(c2ccccc2)c2ccccc2)cc1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=c1c2ccccc2nnn1O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)N[C@@H](Cc1ccc(N(C(=O)C(=O)OCc2ccccc2)c2ccccc2C(=O)OC(c2ccccc2)c2ccccc2)cc1)C(=O)NCCCCOc1cc2ccccc2c(O)c1C(=O)OC
Temperature: 25 °C
Reaction time: 5 h
Yield: 60.7 %

Procedure:
To a mixture of methyl 3-(4-aminobutoxy)-1-hydroxy-2-naphthoate (18 mg, 0.055 mmol), 2-{benzyloxyoxalyl-[4-(2-carboxy-2-methoxycarbonylamino-ethyl)-phenyl]-amino}-benzoic acid benzhydryl ester (40 mg, 0.058 mmol), 1-(3-(dimethylamino)propyl)-3-ethylcarbodiimide hydrochloride (13 mg, 0.068 mmol) and 3-hydroxy-1,2,3-benzotriazin-4(3H)-one (13 mg, 0.080 mmol) in DMF (0.2 mL) was added triethylamine (1 drop). The reaction was stirred at ambient temperature for 5 hours, concentrated under reduced pressure and purified on silica gel eluting with 75% ethyl acetate/hexanes to provide the titled compound (32 mg, 61%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][NH:12][S:13]([C:16]1[CH:25]=[CH:24][CH:23]=[C:22]2[C:17]=1[CH:18]=[CH:19][N:20]=[CH:21]2)(=[O:15])=[O:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].N(C(N(C)C)=O)=NC(N(C)C)=O.[C:38]1([CH2:44][CH2:45][CH2:46][OH:47])[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1.C(P(CCCC)CCCC)CCC>O1CCCC1>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][N:12]([S:13]([C:16]1[CH:25]=[CH:24][CH:23]=[C:22]2[C:17]=1[CH:18]=[CH:19][N:20]=[CH:21]2)(=[O:14])=[O:15])[CH2:46][CH2:45][CH2:44][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3].[C:38]1([CH2:44][CH2:45][CH2:46][OH:47])[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: CC(C)(C)OC(=O)NCCCNS(=O)(=O)c1cccc2cnccc12
Agent: CCCCP(CCCC)CCCC
Agent: CN(C)C(=O)N=NC(=O)N(C)C
Agent: OCCCc1ccccc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCCCN(CCCc1ccccc1)S(=O)(=O)c1cccc2cnccc12

Procedure:
A solution of Intermediate 1 (640 mg), 1,1′-azobis(N,N-dimethylformamide) (1200 mg, Aldrich or prepared according to Chemistry Letters, 539 (1994)) and 3-phenyl-1-propanol (710 μl, Tokyo Kasei Kogyo) in tetrahydrofuran (30 ml) was added with tri(n-butyl)phosphine (1.75 ml, Tokyo Kasei Kogyo) with stirring and ice cooling and stirred at room temperature under argon atmosphere for 13.5 hours. The precipitates in the reaction mixture were removed by filtration, and then the solvent was evaporated from the filtrate under reduced pressure. The residue was purified by flash column chromatography (hexane/ethyl acetate mixed solvent) to obtain the title compound (913 mg, mixture with a small amount of 3-phenyl-1-propanol).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[CH:10]([CH3:12])[CH3:11].C1C(=O)N([Br:20])C(=O)C1.[O-]S([O-])=O.[Na+].[Na+]>C(#N)C>[Br:20][C:5]1[CH:4]=[C:3]([CH:10]([CH3:12])[CH3:11])[C:2]([F:1])=[CH:7][C:6]=1[O:8][CH3:9]
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1ccc(C(C)C)c(F)c1
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: COc1cc(F)c(C(C)C)cc1Br
Temperature: 35 °C
Reaction time: 3.5 h

Procedure:
2-fluoro-1-isopropyl-4-methoxybenzene (compound of formula 3, Scheme 3) (34.3 g, 0.204 mol) was dissolved in acetonitrile (400 mL). The solution was warmed to 35° C., and NBS (40 g, 0.225 mol) was added in a single solid addition. The reaction was maintained at 35° C. and was completed in 3-4 hours. The reaction was quenched with 2M Na2SO3 (40 mL, 0.08 mol). The resulting mixture was concentrated to ¼ of the total volume and diluted with water (400 mL) and petroleum ether (300 mL). The organic layer was cut and washed with water (300 mL), dried over Na2SO4 and filtered. The solvent was removed under reduced pressure to yield 1-bromo-4-fluoro-5-isopropyl-2-methoxybenzene (compound of formula 4, Scheme 3) as a slightly yellow oil (49.26 g, 98%). 1H NMR (CDCl3) δ 1.22 (d, J=6.9 Hz, 6H), 3.14 (sept., J=6.9 Hz, 1H), 3.85 (s, 3H), 6.60 (d, J=11.8 Hz, 1H), 7.37 (d, J=8.0 Hz, 1H).
Reaction SMILES: Br[C:2]1[C:3]2[N:4]([N:8]=[C:9]([Cl:11])[N:10]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:12][N:13]([CH2:18][C:19]1[CH:20]=[C:21](B(O)O)[CH:22]=[CH:23][CH:24]=1)[S:14]([CH3:17])(=[O:16])=[O:15]>>[Cl:11][C:9]1[N:10]=[C:3]2[C:2]([C:23]3[CH:24]=[C:19]([CH:20]=[CH:21][CH:22]=3)[CH2:18][N:13]([CH3:12])[S:14]([CH3:17])(=[O:16])=[O:15])=[CH:7][CH:6]=[CH:5][N:4]2[N:8]=1
Reactant: Clc1nc2c(Br)cccn2n1
Reactant: CN(Cc1cccc(B(O)O)c1)S(C)(=O)=O
Product: CN(Cc1cccc(-c2cccn3nc(Cl)nc23)c1)S(C)(=O)=O

Procedure:
175 a) A suspension of [3-(bromomethyl)phenyl]boronic acid (1.0 g, 4.6 mmol), N-methyl-methanesulfonamide (0.56 g, 5.1 mmol) and potassium carbonate (1.9 g, 14 mmol) in acetone (10 mL) was stirred for 6 hours at room temperature. The mixture was diluted with dichloromethane (50 mL), filtered through a plug of diatomaceous earth and evaporated under reduced pressure. Crude (3-{[methyl(methylsulfonyl)amino]methyl}phenyl)boronic acid was isolated as a yellow viscous oil (1.08 g, 88%). MS=266 (M+Na)+. 175 b) N-[3-(2-Chloro-[1,2,4]triazolo[1,5-a]pyridin-8-yl)-benzyl]-N-methyl-methanesulfonamide was prepared from 8-bromo-2-chloro-[1,2,4]triazolo[1,5-a]pyridine (500.0 mg, 2.151 mmol) and (3-{[methyl(methylsulfonyl)amino]methyl}phenyl)boronic acid (650.0 mg, 2.674 mmol) in a manner analogous to Example 2c. Product isolated as a pale yellow foam (0.331 g, 44%). 1H NMR (400 MHz, CDCl3, δ, ppm): 8.51 (d, J=6.8 Hz, 1H), 7.99-7.95 (m, 2H), 7.74 (d, J=7.4 Hz, 1H), 7.54 (t, J=7.6 Hz, 1H), 7.45 (d, J=7.6 Hz, 1H), 7.18 (t, J=7.1 Hz, 1H), 4.42 (s, 2H), 2.92 (s, 3H), 2.84 (s, 3H). MS=351 (MH)+. 175 c) N-Methyl-N-(3-{2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-[1,2,4]triazolo[1,5-a]pyridin-8-yl}-benzyl)-methanesulfonamide was prepared from N-[3-(2-chloro-[1,2,4]triazolo[1,5-a]pyridin-8-yl)-benzyl]-N-methyl-methanesulfonamide (75.0 mg, 0.214 mmol) and 4-(4-methyl-piperazin-1-yl)-phenylamine (45.0 mg, 0.235 mmol) with 2,2′-bis-dicyclohexylphosphanyl-biphenyl (24.0 mg, 0.0439 mmol) as the ligand in a manner analogous to Example 2d. Product isolated as a yellow foam (0.007 g, 6%). 1H NMR (400 MHz, CDCl3, δ, ppm): 8.41 (d, J=6.7 Hz, 1H), 7.99 (d, J=7.7 Hz, 1H), 7.95 (s, 1H), 7.57 (d, J=7.4 Hz, 1H), 7.55-7.46 (m, 3H), 7.42 (d, J=7.4 Hz, 1H), 7.00-6.91 (m, 3H), 6.65 (s, 3H), 4.42 (s, 2H), 3.19-3.14 (m, 4H), 2.87 (s, 3H), 2.83 (s, 3H), 2.63-2.57 (m, 4H), 2.37 (s, 3H). MS=506 (MH)+.
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[CH:10]=[N:11][CH:12]=[C:13](Br)[CH:14]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].[B:16](OC(C)C)([O:21]C(C)C)[O:17]C(C)C.C([Li])CCC.CCCCCC>O1CCCC1.O>[C:1]([NH:5][S:6]([C:9]1[CH:14]=[C:13]([B:16]([OH:21])[OH:17])[CH:12]=[N:11][CH:10]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)NS(=O)(=O)c1cncc(Br)c1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: [Li]CCCC
Solvent: O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)(C)NS(=O)(=O)c1cncc(B(O)O)c1
Temperature: -78 °C
Reaction time: 3.5 h
Yield: 50.3 %

Procedure:
A solution of 5-bromo-pyridine-3-sulfonic acid tert-butylamide (CAS 911111-80-3; WO2010007) (11.4 g, 39 mmol) in tetrahydrofuran (200 ml) was treated with triisopropyl borate (33 ml, 144 mmol) and cooled to −78° C. A solution of n-butyl lithium in hexane (1.6M, 90 ml, 144 mmol) was added cautiously whereby the reaction temperature was kept below −60° C. The reaction mixture was stirred for 3.5 hours at −78° C. For the workup, the reaction mixture was treated with water (300 ml), stirred at room temperature for 15 minutes, and then extracted with ethyl acetate. The aqueous layer was separated and acidified with hydrochloric acid (3M) to pH 4. Thereafter, solid sodium chloride was added, and the aqueous layer was extracted with ethyl acetate. The organic layers were combined, dried over magnesium sulphate, filtered, and the solvent evaporated to give a light yellow amorphous product. For purification, the residue was dissolved at room temperature in a 3:1-mixture of water and isopropanol (100 ml). More water was added (total volume: 200 ml), then the solution cooled to 0° C., stirred for 30 minutes. The precipitate was filtrated, the solid washed with water and dried at high vacuum to give the 5-(N-tert-butylsulfamoyl)pyridin-3-ylboronic acid (5.06 g, 50% yield) as an off-white solid. MS (ISN): m/z=257.1 [M−H]−.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:12]2[C:7](=[CH:8][C:9]([S:13]([N:16]3[CH2:23][CH2:22][CH2:21][C@@H:17]3[C:18]([OH:20])=[O:19])(=[O:15])=[O:14])=[CH:10][CH:11]=2)[C:6]([NH:24][C:25]([NH2:27])=[NH:26])=[N:5][CH:4]=1.[H-].[Na+].[C:30](OC(=O)[C@H]1CCCN1NS(C1C=C2C(C(Cl)=CN=C2Cl)=CC=1)(=O)=O)([CH3:33])([CH3:32])[CH3:31]>COCCOC.CCOC(C)=O>[C:30]([O:19][C:18](=[O:20])[C@H:17]1[CH2:21][CH2:22][CH2:23][N:16]1[S:13]([C:9]1[CH:8]=[C:7]2[C:12]([C:3]([Cl:2])=[CH:4][N:5]=[C:6]2[NH:24][C:25]([NH2:27])=[NH:26])=[CH:11][CH:10]=1)(=[O:15])=[O:14])([CH3:33])([CH3:32])[CH3:31]
Reactant: CC(C)(C)OC(=O)[C@H]1CCCN1NS(=O)(=O)c1ccc2c(Cl)cnc(Cl)c2c1
Reactant: N=C(N)Nc1ncc(Cl)c2ccc(S(=O)(=O)N3CCC[C@@H]3C(=O)O)cc12
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)[C@H]1CCCN1S(=O)(=O)c1ccc2c(Cl)cnc(NC(=N)N)c2c1
Temperature: 60 °C
Yield: 75.9 %

Procedure:
N-[(4-Chloro-1-guanidino-7-isoquinolinyl)sulphonyl]-D-proline hydrochloride ##STR41## Guanidine hydrochloride (220 mg, 2.3 mmol) was added in one portion to a stirred suspension of NaH (55 mg, 80% dispersion by wt in mineral oil, 1.83 mmol) in DME (8 mL) and the mixture was heated at 60° C. under N2 for 30 min. 1-{[(1,4-Dichloro-7-isoquinolinyl)sulphonyl]amino}-D-proline t-butyl ester (250 mg, 0.58 mmol) was added and the mixture heated at reflux for 5 h. The cooled mixture was diluted with EtOAc, washed with water, brine, dried (MgSO4) and the solvents evaporated in vacuo. The residue was purified by column chromatography upon silica gel using CH2Cl2 -MeOH-0.880NH3 (97:3:0.3) as eluant to give N-[(4-chloro-1-guanidino-7-isoquinolinyl)sulphonyl]-D-proline t-butyl ester (200 mg, 0.44 mmol) as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([O:9][CH3:10])[N:3]=1.Cl[CH2:12][CH:13]=O.C(=O)(O)[O-].[Na+].C>O.C1C=CC=CC=1>[Cl:8][C:6]1[N:5]=[C:4]([O:9][CH3:10])[N:3]2[CH:12]=[CH:13][N:1]=[C:2]2[CH:7]=1
Reactant: COc1nc(N)cc(Cl)n1
Reactant: O=CCCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: c1ccccc1
Product: COc1nc(Cl)cc2nccn12
Temperature: 80 °C

Procedure:
A mixture of 1.7 g (0.011 mole) of 4-amino-6-chloro-2-methoxypyrimidine and 3.0 g (0.015 mole) of 50% aqueous chloroacetaldehyde in 20 ml of water was heated at 80° C. for one hour, and was then cooled in an ice bath with concomitant neutralization with sodium bicarbonate. The mixture was extracted with three 50 ml portions of chloroform which were then dried over magnesium sulfate and evaporated. The residue obtained was dissolved in boiling benzene, treated with decolorizing charcoal, and filtered. The residue which was obtained by evaporation of the filtrate was triturated with diethyl ether to provide a yellow solid. The solid was purified on a preparative scale high pressure liquid chromatograph, using a mixture of 75% ethyl acetate/25% hexanes as the eluent. Recrystallization from cyclohexane gave white solid 7-chloro-5-methoxyimidazo[1,2-c]pyrimidine, m.p. 115°-118° C. Analysis: Calculated for C7H6H3OCl: %C,45.8; %H, 3.3; %N, 22.9; Found: %C, 45.4; %H, 3.1; %N, 23.4.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-])=O)=[CH:6][C:3]=1[C:4]#[N:5].[OH-].[Na+]>C(O)(C)C.Cl>[NH2:10][C:7]1[CH:8]=[CH:9][C:2]([Cl:1])=[C:3]([CH:6]=1)[C:4]#[N:5]
Reactant: N#Cc1cc([N+](=O)[O-])ccc1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Product: N#Cc1cc(N)ccc1Cl
Yield: 95.7 %

Procedure:
A mixture of 2-chloro-5-nitrobenzonitrile (10 g, 54.8 mmol) and stannous chloride dihydrate (56 g, 248.6 mmol) in isopropyl alcohol (125 mL) and concentrated hydrochloric acid solution (62.5 mL) was heated to reflux for 1 hour. The mixture was then cooled and neutralized with sodium hydroxide solution (2N). The aqueous layer was extracted with methylene chloride. The combined organic layers were dried over magnesium sulfate and concentrated to afford the title compound (8 g, 96%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:30](=[O:32])[CH3:31])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:29])[C:15]2[CH:20]=[C:19]([S:21]([CH3:24])(=[O:23])=[O:22])[CH:18]=[CH:17][C:16]=2[O:25][CH:26]([CH3:28])[CH3:27])[CH2:10][CH2:9]1.[CH3:33][Li]>O1CCCC1.CCOCC>[F:1][C:2]1[CH:3]=[C:4]([C:30]([OH:32])([CH3:33])[CH3:31])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:9][CH2:10][N:11]([C:14]([C:15]2[CH:20]=[C:19]([S:21]([CH3:24])(=[O:23])=[O:22])[CH:18]=[CH:17][C:16]=2[O:25][CH:26]([CH3:28])[CH3:27])=[O:29])[CH2:12][CH2:13]1
Reactant: CC(=O)c1ccc(N2CCN(C(=O)c3cc(S(C)(=O)=O)ccc3OC(C)C)CC2)c(F)c1
Reactant: [Li]C
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)N1CCN(c2ccc(C(C)(C)O)cc2F)CC1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of 0.173 mmol 1-{3-Fluoro-4-[4-(2-isopropoxy-5-methanesulfonyl-benzoyl)-piperazin-1-yl]-phenyl}-ethanone in tetrahydrofuran (2 ml) was added dropwise 0.190 mmol 1.6M Methyllithium solution in ether at −75° C. The mixture was stirred for 2 hours and then allowed to warm to 0° C. The mixture was quenched with a 20% NH4Cl solution and extracted 3 times with ethyl acetate. The combined extracts were dried over Na2SO4, filtered and the solvent was removed in vacuo. The residue was purified on silica, eluting with dichloromethane/MeOH to yield after evaporation the title compound.
Reaction SMILES: [CH2:1]([OH:6])[C:2]#[C:3][CH2:4][OH:5].[O:7]1[CH:12]=[CH:11][CH2:10][CH2:9][CH2:8]1>C1(C)C=CC(S(O)(=O)=O)=CC=1.CCOCC>[O:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH:8]1[O:5][CH2:4][C:3]#[C:2][CH2:1][OH:6]
Reactant: OCC#CCO
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOCC
Product: OCC#CCOC1CCCCO1
Yield: 68.8 %

Procedure:
To a mixture of 5.0 g of 2-butyne-1,4-diol and 10 milligrams of p-toluenesulfonic acid and 150 ml of dry ether there was added dropwise with stirring at room temperature 4.9 g of 3,4-dihydro-2H-pyran. After stirring overnight at ambient temperature the ether was evaporated and the residue was poured into 200 ml of water. The aqueous solution was extracted with hexane (2×100 ml) and then re-extracted with ether (3×100 ml). The combined ether extracts were washed with 100 ml of brine, dried over magnesium sulfate and evaporated to yield 6.8 g of 4-tetrahydropyranoxy-2-butyn-1-ol.