Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][CH:2]([F:44])[C:3]1[N:7]([C:8]2[N:13]=[C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[N:11]=[C:10]([N:20]([CH2:34][CH2:35][CH2:36]O)[CH:21]3[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH2:22]3)[N:9]=2)[C:6]2[CH:38]=[CH:39][CH:40]=[C:41]([O:42][CH3:43])[C:5]=2[N:4]=1.CS(Cl)(=O)=O.[N:50]1([C:56]([O:58][C:59]([CH3:62])([CH3:61])[CH3:60])=[O:57])[CH2:55][CH2:54][NH:53][CH2:52][CH2:51]1>>[C:30]([O:29][C:27]([N:24]1[CH2:23][CH2:22][CH:21]([N:20]([C:10]2[N:9]=[C:8]([N:7]3[C:6]4[CH:38]=[CH:39][CH:40]=[C:41]([O:42][CH3:43])[C:5]=4[N:4]=[C:3]3[CH:2]([F:44])[F:1])[N:13]=[C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[N:11]=2)[CH2:34][CH2:35][CH2:36][N:53]2[CH2:52][CH2:51][N:50]([C:56]([O:58][C:59]([CH3:62])([CH3:61])[CH3:60])=[O:57])[CH2:55][CH2:54]2)[CH2:26][CH2:25]1)=[O:28])([CH3:32])([CH3:31])[CH3:33]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: COc1cccc2c1nc(C(F)F)n2-c1nc(N2CCOCC2)nc(N(CCCO)C2CCN(C(=O)OC(C)(C)C)CC2)n1
Agent: CS(=O)(=O)Cl
Product: COc1cccc2c1nc(C(F)F)n2-c1nc(N2CCOCC2)nc(N(CCCN2CCN(C(=O)OC(C)(C)C)CC2)C2CCN(C(=O)OC(C)(C)C)CC2)n1

Procedure:
Sequential reaction of tert-butyl 4-[[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl](3-hydroxypropyl)amino]-1-piperidinecarboxylate with methanesulfonyl chloride and tert-butyl 1-piperazinecarboxylate gave tert-butyl 4-(3-{[1-(tert-butoxycarbonyl)-4-piperidinyl][4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]amino}propyl)-1-piperazinecarboxylate, as an oil; 1H NMR (DMSO-d6) (rotamers) δ 7.94 and 7.90 (2d, J=8.4, 8.3 Hz, 1H), 7.72 and 7.70 (2t, JHF=53.1 53.0 Hz, 1H), 7.42 and 7.38 (2t, J=8.2 Hz, 1H) 6.95 (d, J=8.1 Hz, 1H), 4.75-4.64 and 4.58-4.50 (2m, 1H), 4.14-4.05 (m, 2H), 3.98 and 3.96 (2s, 3H), 3.80-3.77 (m, 4H), 3.69 (br m, 4H), 3.55-3.45 (m, 2H), 2.55-2.50 (m, 4), 2.37-2.28 (m, 9H), 1.67 (br, 5H), 1.42 (s, 9H), 1.39 (s, 9H).
Reaction SMILES: [CH2:1]([N:3]([C:29](=O)[C:30]1[CH:35]=[CH:34][C:33]([OH:36])=[C:32]([F:37])[CH:31]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[CH:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([O:22]C(=O)C(C)(C)C)[CH:16]=[CH:15][C:14]=2[CH2:13]1)[CH3:2].Cl[CH2:40][C:41]([N:43]([CH2:45][CH3:46])[CH3:44])=O>>[CH2:1]([N:3]([CH2:29][C:30]1[CH:35]=[CH:34][C:33]([O:36][CH2:40][CH2:41][N:43]([CH2:45][CH3:46])[CH3:44])=[C:32]([F:37])[CH:31]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[CH:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([OH:22])[CH:16]=[CH:15][C:14]=2[CH2:13]1)[CH3:2]
Reactant: CCN(C)C(=O)CCl
Reactant: CCN(C(=O)c1ccc(O)c(F)c1)c1cc(OC)ccc1C1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Product: CCN(C)CCOc1ccc(CN(CC)c2cc(OC)ccc2C2CCc3cc(O)ccc3C2)cc1F
Yield: 66.7 %

Procedure:
Synthesized from pivalic acid 6-{2-[ethyl(3-fluoro-4-hydroxybenzoyl)amino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (20 mg) and 2-chloro-N-ethyl-N-methylacetamide (10 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (13 mg) was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9](OC)[C:10]=1[O:11][CH3:12])[CH:6]=[O:7].B(Br)(Br)Br.[OH2:19]>C(Cl)Cl>[OH:19][C:8]1[CH:9]=[C:10]([O:11][CH3:12])[C:3]([O:2][CH3:1])=[CH:4][C:5]=1[CH:6]=[O:7]
Reactant: O
Reactant: COc1cc(C=O)cc(OC)c1OC
Agent: BrB(Br)Br
Solvent: ClCCl
Product: COc1cc(O)c(C=O)cc1OC
Temperature: 0 °C
Reaction time: 10 h
Yield: 87 %

Procedure:
To solution of 3,4,5-trimethoxybenzaldehyde (5 g, 25.5 mmol) in CH2Cl2 (125 ml) at 0° C. was added BBr3 (6.39 g, 25.5 mmol). The resulting dark mixture was stirred at 0° C. for 10 hrs after completion of the reaction checked by TLC H2O (100 mL) was then added and the mixture was stirred for 10 min and the aqueous phase was extracted by CH2Cl2. The organic phase was dried over Na2SO4, and evaporated under reduced pressure. The resulting residue was purified by silica gel (CH2Cl2) afforded the 2-hydroxy 4,5dimethoxybenzaldehyde A1 (4.3 g) in 87% yield isolated yellow solid: 1H NMR (500 MHz, CDCl3) δ 11.33 (s, 1H), 9.63 (s, 1H), 6.83 (s, 1H), 6.40 (s, 1H), 3.87 (s, 3H), 3.81 (s, 3H) ppm. Mass: ESI [M+Na]+: 225.06; Elemental anal. calcd. for C9H10O4; C, 59.34; H, 5.53; O, 35.13. found C, 59.14; H, 5.13; O, 34.90.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]([C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[NH:17][C:16]([C:21]([N:23]2[CH2:28][CH2:27][N:26]([S:29]([CH3:32])(=[O:31])=[O:30])[CH2:25][CH2:24]2)=[O:22])=[CH:15]3)=[O:11])[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[F:33][C:34]([F:45])([F:44])[C:35]1[CH:36]=[C:37](B(O)O)[CH:38]=[CH:39][CH:40]=1>>[CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]([C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[N:17]([C:39]2[CH:38]=[CH:37][CH:36]=[C:35]([C:34]([F:45])([F:44])[F:33])[CH:40]=2)[C:16]([C:21]([N:23]2[CH2:24][CH2:25][N:26]([S:29]([CH3:32])(=[O:30])=[O:31])[CH2:27][CH2:28]2)=[O:22])=[CH:15]3)=[O:11])[CH2:6][CH2:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)N1CCN(C(=O)c2ccc3[nH]c(C(=O)N4CCN(S(C)(=O)=O)CC4)cc3c2)CC1
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Product: CC(C)N1CCN(C(=O)c2ccc3c(c2)cc(C(=O)N2CCN(S(C)(=O)=O)CC2)n3-c2cccc(C(F)(F)F)c2)CC1
Yield: 68 %

Procedure:
The title compound was synthesized in analogy to example 5, from [5-(4-isopropylpiperazine-1-carbonyl)-1H-indol-2-yl]-(4-methanesulfonyl-piperazin-1-yl)-methanone (example 1) and 3-(trifluoromethyl)phenylboronic acid to afford the desired product as a light-brown foam (68%). MS (ISP): 606.0 (M+H)+.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([P:20]([C:27]2[CH:32]=[C:31]([C:33]([CH3:36])([CH3:35])[CH3:34])[C:30]([O:37][Si](C)(C)C)=[C:29]([C:42]([CH3:45])([CH3:44])[CH3:43])[CH:28]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:8]=[C:9]([C:16]([CH3:19])([CH3:18])[CH3:17])[C:10]=1[O:11][Si](C)(C)C)([CH3:4])([CH3:3])[CH3:2].O>CO>[C:16]([C:9]1[CH:8]=[C:7]([P:20]([C:27]2[CH:32]=[C:31]([C:33]([CH3:36])([CH3:35])[CH3:34])[C:30]([OH:37])=[C:29]([C:42]([CH3:45])([CH3:44])[CH3:43])[CH:28]=2)[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:6]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:10]=1[OH:11])([CH3:17])([CH3:18])[CH3:19]
Reactant: CC(C)(C)c1cc(P(c2ccccc2)c2cc(C(C)(C)C)c(O[Si](C)(C)C)c(C(C)(C)C)c2)cc(C(C)(C)C)c1O[Si](C)(C)C
Solvent: CO
Solvent: O
Product: CC(C)(C)c1cc(P(c2ccccc2)c2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)cc(C(C)(C)C)c1O
Yield: 38.6 %

Procedure:
A solution of 1.0 g (1.5 mmol) of bis(3,5-di-tert-butyl-4-trimethylsilyloxyphenyl)phenylphosphine and 2.0 g of water in 25 ml of methanol is heated at reflux temperature for 4 hours. The solvent is removed in vacuo and the residue purified by flash chromatography (silica gel, 9:1 heptane:ethyl/acetate eluent) to give 0.3 g (34%) of a white solid, m.p. 138°-140° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([NH:11][CH:12]3[CH2:16][CH2:15][CH2:14][CH2:13]3)[CH:10]=1)[NH:7][C:6]([C:17]1[S:18][CH2:19][C@@H:20]([CH2:22][CH2:23][C:24](O)=[O:25])[N:21]=1)=[CH:5]2.[CH3:27][N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([NH:11][CH:12]3[CH2:16][CH2:15][CH2:14][CH2:13]3)[CH:10]=1)[NH:7][C:6]([C:17]1[S:18][CH2:19][C@@H:20]([CH2:22][CH2:23][C:24]([N:31]3[CH2:32][CH2:33][N:28]([CH3:27])[CH2:29][CH2:30]3)=[O:25])[N:21]=1)=[CH:5]2
Reactant: O=C(O)CC[C@@H]1CSC(c2cc3cc(Cl)cc(NC4CCCC4)c3[nH]2)=N1
Reactant: CN1CCNCC1
Product: CN1CCN(C(=O)CC[C@@H]2CSC(c3cc4cc(Cl)cc(NC5CCCC5)c4[nH]3)=N2)CC1
Yield: 28 %

Procedure:
The compound (150 mg, 0.38 mmol) prepared in Example 149 and 1-methylpiperazine instead of morpholine were reacted according to the same procedure as Example 73 to give the title compound (50 mg, Yield 28%).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([C:6]([OH:8])=O)=[CH:2]1.[NH2:9][C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[N:13][C:14]([Cl:20])=[CH:15][CH:16]=2)[N:11]=1.C(#N)C>O>[Cl:20][C:14]1[N:13]=[C:12]2[C:17]([CH:18]=[CH:19][C:10]([NH:9][C:6]([C:3]3[CH:4]=[CH:5][S:1][CH:2]=3)=[O:8])=[N:11]2)=[CH:16][CH:15]=1
Reactant: O=C(O)c1ccsc1
Reactant: Nc1ccc2ccc(Cl)nc2n1
Solvent: CC#N
Solvent: O
Product: O=C(Nc1ccc2ccc(Cl)nc2n1)c1ccsc1
Temperature: 4 °C
Yield: 27.7 %

Procedure:
The procedure is similar to that described in Example 1, but starting with 3-thiophenecarboxylic acid (16 g), N,N'-carbonyldiimidazole (20.1 g) and 2-amino-7-chloro-1,8-naphthyridine (16.8 g). The product produced by precipitation in water (10.6 g; m.p. 250° C.) is dissolved in boiling acetonitrile (980 cc). After 2 hours' cooling at 4° C., the crystallised solid is separated by filtration, washed with acetonitrile (2×25 cc) and dried at 40° C. under reduced pressure (0.067 kPa). N-(7-Chloro-1,8-naphthyridin-2-yl)-3-thiophenecarboxamide (7.5 g) is produced, m.p. 254° C.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([O:9][CH3:10])=[O:8].N1C=CC=CC=1.[Br:17][C:18]1[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][CH:19]=1.[OH-].[Na+]>ClCCl>[Br:17][C:18]1[CH:23]=[CH:22][C:21]([S:24]([NH:1][C:2]2[CH:6]=[CH:5][S:4][C:3]=2[C:7]([O:9][CH3:10])=[O:8])(=[O:26])=[O:25])=[CH:20][CH:19]=1
Reactant: COC(=O)c1sccc1N
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)c1sccc1NS(=O)(=O)c1ccc(Br)cc1
Temperature: 45 °C
Yield: 70.8 %

Procedure:
To a solution of methyl 3-aminothiophene-2-carboxylate (2.98 g; 11.7 mmol) in anhydrous dichloromethane (32 mL) were added pyridine (1.54 mL; 19.0 mmol) and 4-bromobenzenesulfonyl chloride (1.49 g; 9.5 mmol) in one portion. The reaction mixture was heated at 45° C. for 71 hours, allowed to cool to room temperature, and then diluted with dichloromethane (100 mL). The resulting mixture was successively washed with aqueous hydrochloric acid (50 mL; 2N) and aqueous saturated sodium chloride (50 mL), dried over magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure to yield an off-white solid. The crude product was dissolved in dichloromethane (100 mL) and treated with aqueous sodium hydroxide (60 mL; 2N) resulting in a white precipitation. The white solid was isolated by filtration and washed with dichloromethane (50 mL). The white solid was then acidified with aqueous hydrochloric acid (60 mL; 6N) and extracted with dichloromethane (2×100 mL). The organic extracts were combined, washed with aqueous saturated sodium chloride, dried over magnesium sulfate, filtered, and concentrated under reduced pressure to yield the title compound as a pale yellow solid (2.53 g).
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH2:9][N:8]([C@@H:11]2[CH2:15][NH:14][C@H:13]([C:16]([NH:18][C:19]3[CH:31]=[CH:30][C:22]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[CH:21][CH:20]=3)=[O:17])[CH2:12]2)[CH2:7][CH2:6]1)(=[O:4])=[O:3].[CH3:32][C:33]([O:36][C:37]([NH:39][C@H:40]([C@H:42]1[CH2:47][CH2:46][C@H:45]([C:48](O)=[O:49])[CH2:44][CH2:43]1)[CH3:41])=[O:38])([CH3:35])[CH3:34]>>[CH3:32][C:33]([O:36][C:37]([NH:39][C@H:40]([C@H:42]1[CH2:43][CH2:44][C@H:45]([C:48]([N:14]2[CH2:15][C@@H:11]([N:8]3[CH2:9][CH2:10][N:5]([S:2]([CH3:1])(=[O:4])=[O:3])[CH2:6][CH2:7]3)[CH2:12][C@H:13]2[C:16]([NH:18][C:19]2[CH:31]=[CH:30][C:22]([C:23]([O:25][C:26]([CH3:28])([CH3:27])[CH3:29])=[O:24])=[CH:21][CH:20]=2)=[O:17])=[O:49])[CH2:46][CH2:47]1)[CH3:41])=[O:38])([CH3:34])[CH3:35]
Reactant: CC(C)(C)OC(=O)c1ccc(NC(=O)[C@@H]2C[C@H](N3CCN(S(C)(=O)=O)CC3)CN2)cc1
Reactant: C[C@H](NC(=O)OC(C)(C)C)[C@H]1CC[C@H](C(=O)O)CC1
Product: C[C@H](NC(=O)OC(C)(C)C)[C@H]1CC[C@H](C(=O)N2C[C@@H](N3CCN(S(C)(=O)=O)CC3)C[C@H]2C(=O)Nc2ccc(C(=O)OC(C)(C)C)cc2)CC1

Procedure:
Following the procedure described in Example 8, the compound prepared in Example 6 was treated with trans-4-[(1S)-1-({[(2-methyl-2-propanyl)oxy]carbonyl}amino)ethyl]cyclohexanecarboxylic acid to give the title compound as a light brown solid.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].C(S)CS.[Cl:9][C:10]1[CH:11]=[N:12][CH:13]=[C:14]([Cl:40])[C:15]=1[NH:16][C:17](=[O:39])[C:18]([C:20]1[C:28]2[C:23](=[CH:24][CH:25]=[C:26]([O:29]C)[CH:27]=2)[N:22]([CH2:31][C:32]2[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=2)[CH:21]=1)=[O:19].Cl>ClCCl>[Cl:9][C:10]1[CH:11]=[N:12][CH:13]=[C:14]([Cl:40])[C:15]=1[NH:16][C:17](=[O:39])[C:18]([C:20]1[C:28]2[C:23](=[CH:24][CH:25]=[C:26]([OH:29])[CH:27]=2)[N:22]([CH2:31][C:32]2[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=2)[CH:21]=1)=[O:19]
Reactant: COc1ccc2c(c1)c(C(=O)C(=O)Nc1c(Cl)cncc1Cl)cn2Cc1ccc(F)cc1
Agent: Cl
Agent: SCCS
Agent: [Al+3]
Solvent: ClCCl
Product: O=C(Nc1c(Cl)cncc1Cl)C(=O)c1cn(Cc2ccc(F)cc2)c2ccc(O)cc12
Temperature: 0 °C
Reaction time: 4 h

Procedure:
5 g (38 mmol) anhydrous aluminium chloride is introduced into 50 ml ethane-1,2,-dithiol. A solution of 4.7 g of N-(3,5-dichloropyridin-4-yl)-2-[1-(4-fluorobenzyl)-5-methoxyindol-3-yl]-2-oxoacetamide (10 mmol) in 50 ml of dichloromethane is added at 0° C. The mixture is stirred at 0° C. for 4 hours. 50 ml of 10% hydrochloric acid is added dropwise at from 0 to 10° C. with stirring. The crystallizing product is isolated, washed with water and dried at 20° C. A pure product is obtained by recrystallization from ethanol (180 ml).
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[CH:5]NN=1.CO[C:9](=[O:20])[C:10]1[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=1.[H-].[Na+].C(#N)CC>>[CH3:5][CH:6]([C:9](=[O:20])[C:10]1[CH:11]=[CH:12][C:13]([C:16]([F:17])([F:18])[F:19])=[CH:14][CH:15]=1)[C:2]#[N:1]
Reactant: COC(=O)c1ccc(C(F)(F)F)cc1
Reactant: Nc1cc[nH]n1
Agent: [H-]
Agent: [Na+]
Solvent: CCC#N
Product: CC(C#N)C(=O)c1ccc(C(F)(F)F)cc1
Yield: 96 %

Procedure:
The product was prepared according to the general procedure for aminopyrazole synthesis (route A1) from 4-trifluoromethyl-benzoic acid methyl ester (3.0 g, 14.7 mmol, 1.0 eq), NaH (1.2 g, 29.4 mmol, 2.0 eq) and propionitrile (4.9 mL, 69.4 mmol, 4.7 eq). The crude product was extracted with DCM and used in the following step without further purification (3.2 g, yield: 96%).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.[CH:9]1(B(O)O)[CH2:11][CH2:10]1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].C1(P(C2CCCCC2)C2CCCCC2)CCCCC1>CC([O-])=O.CC([O-])=O.[Pd+2].C1(C)C=CC=CC=1.O>[Cl:8][C:5]1[N:4]=[CH:3][C:2]([CH:9]2[CH2:11][CH2:10]2)=[CH:7][N:6]=1
Reactant: Clc1ncc(Br)cn1
Reactant: OB(O)C1CC1
Agent: [Pd+2]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Solvent: O
Product: Clc1ncc(C2CC2)cn1
Temperature: 100 °C

Procedure:
3.60 g (18.6 mmol) 5-bromo-2-chloropyrimidine, 4.80 g (55.8 mmol) cyclopropyl boronic acid, 13.8 g (65.1 mmol) K3PO4,568 mg (2.03 mmol) tricyclohexylphosphine and 4 mL water are added to 80 mL toluene. The mixture is degassed thoroughly and charged with 627 mg (2.79 mmol) Pd(OAc)2. After degassing again the mixture is stirred at 100° C. over night, filtered and the solvent is removed in vacuo. The crude product is purified by column chromatography (silica gel, PE/EtOAc 90/10→70/30).
Reaction SMILES: [CH2:1]([OH:23])[C@H:2]1[O:7][C@H:6]([O:8][CH2:9][C@H:10]2[O:14][C:13]([OH:17])([CH2:15][OH:16])[C@@H:12]([OH:18])[C@@H:11]2[OH:19])[C@H:5]([OH:20])[C@@H:4]([OH:21])[C@@H:3]1[OH:22]>[Ni]>[CH2:1]([OH:23])[C@H:2]1[O:7][C@H:6]([O:8][CH2:9][C@@H:10]([OH:14])[C@@H:11]([OH:19])[C@H:12]([OH:18])[C@@H:13]([OH:17])[CH2:15][OH:16])[C@H:5]([OH:20])[C@@H:4]([OH:21])[C@@H:3]1[OH:22]
Reactant: OC[C@H]1O[C@H](OC[C@H]2OC(O)(CO)[C@@H](O)[C@@H]2O)[C@H](O)[C@@H](O)[C@@H]1O
Agent: [Ni]
Product: OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO[C@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Yield: 49.7 %

Procedure:
In accordance with the process described in Example 1, 7.5 kg isomaltulose were dissolved at 80° C. to form a 75% by weight aqueous solution and then transferred to a heated autoclave equipped with an agitator and having a capacity of 20 l. In the autoclave the solution was mixed with an aqueous catalyst suspension containing 500 g Raney nickel. Hydrogenation and crystallization were then carried out as described in Example 1. After a reaction period of 3 hours, the isomaltulose charge had been hydrogenated to form 3.75 kg each of isomaltitol and glucopyranosido-1,6-mannitol. 3.45 kg isomaltitol and 3.45 kg glucopyranosido-1,6-mannitol could then be obtained therefrom in crystal form by means of the fractional crystallization operation described in Example 1.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]([CH3:13])[C:10]([NH2:12])=[O:11])#[CH:2].[Cl:14][C:15]1[N:20]=[C:19](Cl)[C:18]([CH3:22])=[CH:17][N:16]=1.F[B-](F)(F)F.C([PH+](C(C)(C)C)C(C)(C)C)(C)(C)C>CN(C=O)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:14][C:15]1[N:20]=[C:19]([C:2]#[C:1][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[CH:9]([CH3:13])[C:10]([NH2:12])=[O:11])[C:18]([CH3:22])=[CH:17][N:16]=1
Reactant: C#Cc1ccccc1C(C)C(N)=O
Reactant: Cc1cnc(Cl)nc1Cl
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: CC(C)(C)[PH+](C(C)(C)C)C(C)(C)C
Solvent: CN(C)C=O
Product: Cc1cnc(Cl)nc1C#Cc1ccccc1C(C)C(N)=O
Temperature: 60 °C
Reaction time: 2.5 h

Procedure:
A suspension of 2-(2-ethynylphenyl)propanamide K7 (2.00 g, 11.5 mmol), 2,4,-dichloro-5-methylpyrimidine (2.45 g, 15.0 mmol), CuI (0.044 g, 0.33 mmol), PdCl2(PPh3)2 (0.162 g, 0.231 mmol) and tri-t-butylphosphonium tetrafluoroborate (0.067 g, 0.23 mmol) in DMF (15 mL) was bubbled with N2 for 10 minutes. Et3N (10 mL) was added and the reaction mixture was stirred under N2 at 60° C. for 2.5 hours. The mixture was cooled, diluted with Et2O and the precipitate was isolated by filtration and washed with Et2O then water to give the title compound A48 as a white solid (2.08 g, 60%). LCMS-A: rt 5.86 min; m/z 300 [M+H]+.
Reaction SMILES: [CH:1](NC(C)C)(C)C.C([Li])CCC.[CH:13]1([C:18]([O:20][CH3:21])=[O:19])[CH2:17][CH2:16][CH2:15][CH2:14]1.CI.Cl>C1COCC1.CCOCC.O>[CH3:1][C:13]1([C:18]([O:20][CH3:21])=[O:19])[CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: COC(=O)C1CCCC1
Reactant: CC(C)NC(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)C1(C)CCCC1
Temperature: 25 °C

Procedure:
To a stirred solution of diisopropylamine (3.95 g, 39.0 mmol) in dry THF (50 ml) at -78° C. under an atmosphere of nitrogen was added n- butyllithium (2.5M, 11.7 ml, 29.3 mmol). The mixture was stirred for 10 minutes before methyl cyclopentanecarboxylate (Aldrich) (2.5 g, 19.5 mmol) was added dropwise. Stirring was continued for a further 10 minutes before methyl iodide (8.31 g, 58.5 mmol) was added dropwise. The reaction mixture was stirred at -78° C. for a further 1 hour before being allowed to warm up to room temperature and being stirred for a further 1 hour. The reaction mixture was poured onto an admixture of water and ether (1:1, 100 ml) and acidified with dilute hydrochloric acid (2M). The aqueous solution was separated and extracted further with ether (3×25 ml) and the combined ether layers were washed with water (2×50 ml), saturated sodium chloride solution (50 ml) and dried over MgSO4. Filtration and evaporation of solvent under reduced pressure yielded methyl 1-methylcyclopentanecarboxylate as a colourless oil (2.38 g, b.p. 106° C. at 10 mmHg[Kugelrohr]).
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[O:3][C:4]1[CH:5]=[C:6]([CH:10]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]([F:24])([F:23])[F:22])[CH:15]=2)[C:11]([OH:13])=[O:12])[CH:7]=[CH:8][CH:9]=1.[Li]CCCC.Br[CH2:33][C:34]1[N:39]=[CH:38][CH:37]=[CH:36][N:35]=1>C1COCC1>[N:35]1[CH:36]=[CH:37][CH:38]=[N:39][C:34]=1[CH2:33][C:10]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]([F:24])([F:23])[F:22])[CH:15]=1)([C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([O:3][C:2]([F:25])([F:26])[F:1])[CH:5]=1)[C:11]([OH:13])=[O:12]
Reactant: O=C(O)C(c1cccc(OC(F)(F)F)c1)c1cccc(OC(F)(F)F)c1
Reactant: BrCc1ncccn1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=C(O)C(Cc1ncccn1)(c1cccc(OC(F)(F)F)c1)c1cccc(OC(F)(F)F)c1
Temperature: -15 °C
Reaction time: 0.75 h

Procedure:
At −15° C. to a solution of 2,2-bis(3-(trifluoromethoxy)phenyl)acetic acid prepared as described in Procedure 73 (607 mg, 1.6 mmol) in THF (6 mL) was added nBuLi (1.6 mL, 2M in hexane, 3.2 mmol). The mixture was stirred at −15° C. for 45 min. 2-(Bromomethyl)pyrimidine (412 mg, crude) in THF (1 mL) was added and the reaction mixture was allowed to warm to rt and stirred for 18 h, then quenched with saturated NH4Cl. The aqueous layer was extracted with EtOAc (3×50 mL). The combined organic layer was dried over MgSO4, filtered and concentrated to give 3-(pyrimidin-2-yl)-2,2-bis(3-(trifluoromethoxy)phenyl)propanoic acid as a yellow solid (437 mg, 58% crude). This crude solid was carried onto the next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][NH:11][C:12]([C:14]2[S:15][CH:16]=[CH:17][CH:18]=2)=O)[CH:6]=[CH:7][CH:8]=1.P(Cl)(Cl)(Cl)=O>N>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:6](=[CH:7][CH:8]=1)[C:12]([C:14]1[S:15][CH:16]=[CH:17][CH:18]=1)=[N:11][CH2:10][CH2:9]2
Reactant: COc1cccc(CCNC(=O)c2cccs2)c1
Agent: N
Solvent: O=P(Cl)(Cl)Cl
Product: COc1ccc2c(c1)CCN=C2c1cccs1
Temperature: 0 °C
Yield: 110.1 %

Procedure:
A solution of thiophene-2-carboxylic acid [2-(3-methoxyphenyl)ethyl]amide (1.480 g, 5.66 mmol) in phosphorous oxychloride (10 ml, 107.3 mmol) was refluxed under N2 for 24 hr. The cooled reaction mixture was then slowly added to ice-water (50 ml) with stirring and basified to pH 10 with concentrated ammonia (60 ml). This was extracted with CHCl3 (4×25 ml) and the combined extracts were dried over MgSO4 then concentrated in vacuo to give 1.517 g (96% yield) of yellow oil.
Reaction SMILES: [Si](O[CH:9]1[CH2:13][CH2:12][C@@H:11]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[O:10]1)(C(C)(C)C)(C)C.C[Si]([Br:25])(C)C>C(Cl)Cl>[Br:25][CH:9]1[CH2:13][CH2:12][C@@H:11]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[O:10]1
Reactant: CC(C)(C)[Si](C)(C)OC1CC[C@@H](c2ccc(F)cc2)O1
Reactant: C[Si](C)(C)Br
Solvent: ClCCl
Product: Fc1ccc([C@@H]2CCC(Br)O2)cc1
Temperature: -70 °C
Reaction time: 1.5 h

Procedure:
(5S)-2-(t-Butyldimethylsilyloxy)-5-(4-fluorophenyl) tetrahydrofuran (212, 1 g, 3.4 mmol) was dissolved in 10 mL of dry methylene chloride (degassed by bubbling argon prior to use). This solution was cooled to -70° C. and, while stirring at the same temperature under dry argon, trimethylsilyl bromide (550 μL, 4.1 mmol) was added dropwise. The stirring was continued for an additional 1.5 hours to yield (5S)-2-bromo-5-(4-fluorophenyl) tetrahydrofuran which was used without isolation (see below). In a separate flask, 3-t-butyldimethylsilyloxy-but-1-yne (840 mg, 4.5 mmol) was dissolved in dry THF (10 mL). The solution was cooled to -60° C. and, while stirring at the same temperature under dry argon, n-butyllithium (1.8 mL of 2.5M solution in hexane, 4.5 mmol) was added dropwise. The stirring was continued for an additional 0.5 hours. The resulting solution was added dropwise, through a cannula to the stirred solution of the 2-bromotetrahydrofuran (made above) at -70° C. The stirring was continued at -78° C. for additional 1.5 hours. The reaction flask was then left in the freezer (-78° C.) over night (though the TLC did not show any change). The reaction mixture was poured into 2M solution of ammonium chloride (100 mL) and extracted with methylene chloride (3×75 mL). The solution was dried over sodium sulfate and the solvent removed in vacuo; The residue was purified via flash column chromatography (eluent, 10% ethyl acetate in hexane) to obtain two components. From the proton NMR analysis, the less polar one was identified as (2S,5S)-trans-2-(3-t-butyldimethylsilyloxy-but-1-ynyl)-5-(4-fluorophenyl) tetrahydrofuran (213, 765 mg, 65%). 1H-NMR (CDCl3) δ 7.29 (2H, m), 7.01 (2H, t, J=8.7 Hz), 5.09 (1H, t, J=7.1 Hz), 4.91-4.97 (2H, m), 4.55-4.62 (1H, m), 2.26-2.50 (2H, m), 2.05-2.17 (1H, m), 1.75-1.88 (1H, m), 1.38 (3H, d, J=6.6 Hz), 0.90 (9H,s), 0.12 (6H, s). The more polar component was assigned to be (2R,5S)-cis-2-(3-t-butyldimethylsilyloxy-but-1-ynyl)-5-(4-fluorophenyl) tetrahydrofuran (214, 190 mg, 16%).