Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][CH2:2][C:3](Br)=[O:4].[NH:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9][CH2:8][CH2:7]1>C1C=CC=CC=1>[Br:1][CH2:2][C:3]([N:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9][CH2:8][CH2:7]1)=[O:4]
Reactant: c1ccc2c(c1)CCCN2
Reactant: O=C(Br)CBr
Solvent: c1ccccc1
Product: O=C(CBr)N1CCCc2ccccc21
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred solution of 20.2 g. of bromoacetyl bromide in 150 ml. of benzene is added dropwise over 30 minutes, 26.6 g. of 1,2,3,4-tetrahydroquinoline dissolved in 35 ml. of benzene. The reaction mixture is then stirred at room temperature for 18 hours, after which time the precipitate is filtered off. The resultant filtrate is washed successively with 1N HCL solution and with a saturated sodium chloride solution, dried, and the solvent removed under reduced pressure to yield 1-(bromoacetyl)-1,2,3,4-tetrahydroquinoline, b.p. 70°-80° C. (at 0.1 mm. Hg).
Reaction SMILES: CON(C)[C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]3[C:18]([Cl:23])=[N:19][CH:20]=[CH:21][CH:22]=3)[CH:12]=2)[CH:10]=1)=[O:5].[CH3:25][N:26]1[CH:30]=[CH:29][N:28]=[CH:27]1>>[Cl:23][C:18]1[C:17]([C:13]2[CH:12]=[C:11]([N:9]3[CH:10]=[C:6]([C:4]([C:27]4[N:26]([CH3:25])[CH:30]=[CH:29][N:28]=4)=[O:5])[N:7]=[CH:8]3)[CH:16]=[CH:15][CH:14]=2)=[CH:22][CH:21]=[CH:20][N:19]=1
Reactant: CON(C)C(=O)c1cn(-c2cccc(-c3cccnc3Cl)c2)cn1
Reactant: Cn1ccnc1
Product: Cn1ccnc1C(=O)c1cn(-c2cccc(-c3cccnc3Cl)c2)cn1

Procedure:
This compound is prepared by method C using compound 12l and 1-methylimidazole
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[N:6][C:5](Br)=[CH:4][N:3]=1.[S:9]1[CH:13]=[CH:12][CH:11]=[C:10]1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].[Cl-].[Na+]>COCCOC.C(O)C.C(OCC)(=O)C.O.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>[S:9]1[CH:13]=[CH:12][CH:11]=[C:10]1[C:5]1[N:6]=[CH:7][C:2]([NH2:1])=[N:3][CH:4]=1
Reactant: OB(O)c1cccs1
Reactant: Nc1cnc(Br)cn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: CCO
Solvent: COCCOC
Solvent: O
Product: Nc1cnc(-c2cccs2)cn1
Yield: 52.4 %

Procedure:
A mixture of 2-amino-5-bromopyrazine (500 mg, 2.874 mmol), dichlorobis(triphenylphosphine)palladium(II) (290 mg, 0.413 mmol), 2-thiopheneboronic acid (500 mg, 3.907 mmol), and a saturated aqueous sodium carbonate solution (4 mL) in ethylene glycol dimethyl ether (8 mL) and ethanol (8 mL) was heated under reflux overnight. The reaction mixture was cooled, diluted with ethyl acetate, water, and a saturated aqueous sodium chloride solution. After mixing, the layers were separated. The aqueous layer was extracted with ethyl acetate. The combined organic layers was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40M, Silica 1/1 hexanes/ethyl acetate) afforded 5-thiophen-2-yl-pyrazin-2-ylamine (267 mg, 52.4%) as a yellow solid: EI-HRMS m/e calcd for C8H7N3S (M+) 177.0361, found 177.0355.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:19]=[CH:18][CH:17]=[CH:16][C:4]=1[CH2:5][NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N+:13]([O-])=O.C(O)C.[H][H]>C(OCC)(=O)C.[Pd]>[CH3:1][O:2][C:3]1[CH:19]=[CH:18][CH:17]=[CH:16][C:4]=1[CH2:5][NH:6][C:7]1[C:8]([NH2:13])=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: COc1ccccc1CNc1ccccc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: COc1ccccc1CNc1ccccc1N
Yield: 92.3 %

Procedure:
A solution of 32 g (0.13 mole) of (2-methoxy-benzyl)-(2-nitro-phenyl)-amine (1) and 3.2 g Pd/C in 200 mL of 1:1 ethyl acetate:ethanol is treated at 40 psi of hydrogen for 1 hour. The reaction mixture is then filtered through celite and washed with 200 mL of ethanol. The solvent is then removed in vacuo to afford 28.2 g (0.12 mole, 92%) of N-(2-Methoxy-benzyl)-benzene-1,2-diamine (2).
Reaction SMILES: C[O:2][C:3](=[O:34])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13]([CH:16]2[CH2:21][CH2:20][N:19]([C:22](=[O:32])[NH:23][C:24]3[C:29]([F:30])=[CH:28][CH:27]=[CH:26][C:25]=3[F:31])[CH2:18][CH2:17]2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:33])[CH:11]=2)[CH:6]=1.O.[OH-].[Li+]>C1COCC1.O>[F:31][C:25]1[CH:26]=[CH:27][CH:28]=[C:29]([F:30])[C:24]=1[NH:23][C:22]([N:19]1[CH2:20][CH2:21][CH:16]([C:13]2[C:12]3[C:7](=[CH:8][CH:9]=[C:10]([F:33])[CH:11]=3)[CH:6]=[C:5]([CH2:4][C:3]([OH:34])=[O:2])[C:14]=2[CH3:15])[CH2:17][CH2:18]1)=[O:32]
Reactant: COC(=O)Cc1cc2ccc(F)cc2c(C2CCN(C(=O)Nc3c(F)cccc3F)CC2)c1C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1c(CC(=O)O)cc2ccc(F)cc2c1C1CCN(C(=O)Nc2c(F)cccc2F)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 63.9 %

Procedure:
To a solution of {4-[1-(2,6-difluoro-phenylcarbamoyl)-piperidin-4-yl]-6-fluoro-3-methyl-naphthalen-2-yl}-acetic acid methyl ester (95.4 mg, 0.203 mmol) in THF (8.0 mL) was added a solution of lithium hydroxide monohydrate (97.2 mg, 2.3 mmol) in water (2.0 mL) at room temperature. The resulting solution was stirred overnight at room temperature under a nitrogen atmosphere. Then, the solvent was removed and the residue was combined with water (25 mL). The mixture was neutralized with 1.0 N HCl. The resulting white precipitate was collected by filtration and dried under high vacuum to provide {4-[1-(2,6-difluoro-phenyl-carbamoyl)-piperidin-4-yl]-6-fluoro-3-methyl-naphthalen-2-yl}-acetic acid (59.2 mg, 64%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.46 (br. s, 1H), 8.38 (br. s, 1H), 7.90 (dd, J=9.00, 6.40 Hz, 1H), 7.75-7.85 (m, 1H), 7.65-7.74 (m, 1H), 7.24-7.42 (m, 2H), 7.14 (m, 2H), 4.17-4.38 (m, 2H), 3.79 (m, 3H), 2.99-3.24 (m, 2H), 2.44 (s, 3H), 2.13-2.36 (m, 1H), 1.57-1.73 (m, 2H). MS cald. for C25H24F3N2O3 [(M+H)+]: 457, obsd. 457.2.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:25])=[C:6]([CH:24]=1)[CH2:7][N:8]([C:11]1[N:16]=[N:15][C:14]([C:17]([O:19][CH2:20][CH2:21][CH2:22][CH3:23])=[O:18])=[CH:13][CH:12]=1)[CH2:9][CH3:10].Br[CH2:27][CH:28]1[CH2:30][CH2:29]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:25][CH2:27][CH:28]2[CH2:30][CH2:29]2)=[C:6]([CH:24]=1)[CH2:7][N:8]([C:11]1[N:16]=[N:15][C:14]([C:17]([O:19][CH2:20][CH2:21][CH2:22][CH3:23])=[O:18])=[CH:13][CH:12]=1)[CH2:9][CH3:10]
Reactant: CCCCOC(=O)c1ccc(N(CC)Cc2cc(Br)ccc2O)nn1
Reactant: BrCC1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCOC(=O)c1ccc(N(CC)Cc2cc(Br)ccc2OCC2CC2)nn1
Temperature: 25 °C
Reaction time: 60 h
Yield: 94 %

Procedure:
A solution of n-butyl 6-[N-(5-bromo-2-hydroxybenzyl)-N-ethylamino]pyridazine-3-carboxylate (reference example 3) (0.286 g, 0.69 mmol) in DMF (3.5 ml) was treated with bromomethylcyclopropane (0.1 g, 0.78 mmol) and potassium carbonate (0.473 g, 3.4 mmol). The reaction was allowed to stir at ambient temperature for 60 hours. The solvent was evaporated at reduced pressure (vacuum pump) and the residue partitioned between ethyl acetate and water. The aqueous layer was extracted with ethyl acetate (2×10 ml). The organic layers were combined dried (MgSO4) and evaporated. The residue was purified by chromatography (eluant: ethyl acetate/hexane) to give the title compound as a pale yellow oil (0.3 g, 94%).
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[C:16]3[N:17]([C:21]([C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([NH:30][CH2:31][C:32]5[CH:37]=[CH:36][CH:35]=[C:34]([Cl:38])[CH:33]=5)[N:25]=4)=[CH:22][N:23]=3)[CH:18]=[CH:19][N:20]=2)[CH2:10][CH2:9]1)(C)(C)C>C(O)C.Cl>[Cl:38][C:34]1[CH:33]=[C:32]([CH:37]=[CH:36][CH:35]=1)[CH2:31][NH:30][C:26]1[N:25]=[C:24]([C:21]2[N:17]3[CH:18]=[CH:19][N:20]=[C:15]([NH:14][CH:11]4[CH2:10][CH2:9][CH:8]([NH2:7])[CH2:13][CH2:12]4)[C:16]3=[N:23][CH:22]=2)[CH:29]=[CH:28][CH:27]=1
Reactant: CC(C)(C)OC(=O)NC1CCC(Nc2nccn3c(-c4cccc(NCc5cccc(Cl)c5)n4)cnc23)CC1
Agent: Cl
Solvent: CCO
Product: NC1CCC(Nc2nccn3c(-c4cccc(NCc5cccc(Cl)c5)n4)cnc23)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The mixture of (4-{3-[6-(3-chloro-benzylamino)-pyridin-2-yl]-imidazo[1,2-a]pyrazin-8-ylamino}-cyclohexyl)-carbamic acid tert-butyl ester (430 mg, 0.78 mmol) in ethanol (4 mL) and concentrated HCl (4 mL) was stirred at room temperature overnight. The reaction mixture was then concentrated under reduced pressure. The obtained crude product was purified by preparative-HPLC to give N-{3-[6-(3-chloro-benzylamino)-pyridin-2-yl]-imidazo[1,2-a]pyrazin-8-yl}-cyclohexane-1,4-diamine; hydrochloride. (Yield 100 mg). 1H NMR (300 MHz, CD3OD): δ 8.16-8.13 (m, 2H), 7.91 (t, 1H, J=8.1 Hz), 7.46 (s, 1H), 7.38-7.31 (m, 3H), 7.22-7.17 (m, 2H), 7.04 (d, 1H, J=8.7 Hz), 4.69 (s, 2H), 4.06 (s, 1H), 3.23 (brs, 1H), 2.21 (brs, 4H), 1.76-1.70 (m, 4H). LC-MS: [M+H]+ 448.
Reaction SMILES: S(=O)(=O)(O)O.[CH2:6]([N:13]1[CH2:19][CH2:18][CH2:17][CH:16](C(OCC)=O)[C:15](=[O:25])[CH2:14]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(N1CCCCC(=O)C1C(OCC)=O)C1C=CC=CC=1.[OH-].[Na+]>C(O)C>[CH2:6]([N:13]1[CH2:19][CH2:18][CH2:17][CH2:16][C:15](=[O:25])[CH2:14]1)[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: CCOC(=O)C1CCCN(Cc2ccccc2)CC1=O
Agent: CCOC(=O)C1C(=O)CCCCN1Cc1ccccc1
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCO
Product: O=C1CCCCN(Cc2ccccc2)C1
Temperature: 120 °C
Reaction time: 3 h
Yield: 106.6 %

Procedure:
Under a nitrogen atmosphere, a 75%-aqueous sulfuric acid solution (2 ml) was added to a solution of ethyl 1-benzyl-3-oxoazepane-4-carboxylate (150 mg, 0.545 mmol) in ethanol (1 ml) at room temperature, and the resulting mixture was heated to 120° C. After 3 hours, completion of the reaction was confirmed and the resulting mixture was cooled. On the other hand, under a nitrogen atmosphere, a 75%-aqueous sulfuric acid solution (2 ml) was added to a solution of the mixture containing ethyl 1-benzyl-3-oxoazepane-2-carboxylate (200 mg, content=about 75%) in ethanol (1 ml) at room temperature, and the resulting mixture was heated to 120° C. After 12 hours, completion of the reaction was confirmed and the temperature was lowered. The reaction solution was combined with that obtained above, and the combined reaction solution was poured onto ice and adjusted to pH 8 with a 2M-aqueous sodium hydroxide solution. The combined reaction solution thus treated was extracted with ethyl acetate (50 ml×2) and the organic layer was dried over anhydrous magnesium sulfate. The organic layer dried was concentrated under reduced pressure and the resulting residue was purified by a silica gel column chromatography (eluent: hexane/ethyl acetate) to obtain 1-benzylazepan-3-one (118.1 mg, 53%).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][N:11]([NH2:31])[C:12](=[O:30])[NH:13][C:14]1[CH:23]=[C:22]([O:24][CH3:25])[CH:21]=[C:20]([C:26]([CH3:29])([CH3:28])[CH3:27])[C:15]=1[O:16][CH2:17][O:18][CH3:19])=[O:5])[CH3:2].[Cl:32][C:33]1[CH:38]=[CH:37][C:36]([S:39](Cl)(=[O:41])=[O:40])=[CH:35][CH:34]=1.C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH2:1]([O:3][C:4]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][N:11]([NH:31][S:39]([C:36]1[CH:37]=[CH:38][C:33]([Cl:32])=[CH:34][CH:35]=1)(=[O:41])=[O:40])[C:12](=[O:30])[NH:13][C:14]1[CH:23]=[C:22]([O:24][CH3:25])[CH:21]=[C:20]([C:26]([CH3:27])([CH3:29])[CH3:28])[C:15]=1[O:16][CH2:17][O:18][CH3:19])=[O:5])[CH3:2]
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: CCOC(=O)CCCCCN(N)C(=O)Nc1cc(OC)cc(C(C)(C)C)c1OCOC
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCOC(=O)CCCCCN(NS(=O)(=O)c1ccc(Cl)cc1)C(=O)Nc1cc(OC)cc(C(C)(C)C)c1OCOC
Yield: 57.3 %

Procedure:
A mixture of 5 g of {2-[3-(5-ethoxycarbonylpentyl)-3-aminoureido]-4-methoxy-6-tert-butylphenoxy}methoxymethane, 5 g of 4-chlorobenzenesulfonyl chloride, 7.24 g of triethylamine and 20 ml of chloroform was refluxed for 4 hours. The solvent was removed under reduced pressure. Ethyl acetate was added to the residue and the mixture was washed and dried, and the solvent was removed under reduced pressure to give 4 g of {2-[3-(5-ethoxycarbonylpentyl)-3-(4-chlorobenzenesulfonylamino)ureido]-4-methoxy-6-tert-butylphenoxy}methoxymethane (yield: 57%, state: oily product, IR (film): 3400, 1732, 1710, 1610, 1590 cm-1).
Reaction SMILES: C(O)#C[OH:3].[CH3:5][C@H:6]1[C:13](S[C@@H]2CN[C@H]([C@H](O)[C@H]3CNCC3)C2)=C(C(O)=O)N2[C@H:7]1[C@@H:8]([C@H:30](O)[CH3:31])[C:9]2=O.Cl>>[CH3:5][CH:6]([CH2:7][C:8]([OH:3])([C:30]#[CH:31])[CH3:9])[CH3:13]
Reactant: OC#CO
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)O)=C(S[C@@H]3CN[C@H]([C@H](O)[C@@H]4CCNC4)C3)[C@H](C)[C@H]12
Agent: Cl
Product: C#CC(C)(O)CC(C)C

Procedure:
For example, any commercially available product may be used for the acetylene diol compound. The commercially available product includes, for example, “Olfin (trade name) E1010” and “Olfin (trade name) E1004” as well as “Surfynol (trade name) 440” and “Surfynol (trade name) 465” produced by Nissin Chemical Industry Co., Ltd.; and “Acetylenol (trade name) E40” and “Acetylenol (trade name) E100” produced by Kawaken Fine Chemicals Co., Ltd.
Reaction SMILES: [Br:1]Br.[F:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:5]=1[OH:11].S(S([O-])=O)([O-])(=O)=O.[Na+].[Na+]>C(=S)=S.Br>[Br:1][C:8]1[CH:9]=[C:4]([F:3])[C:5]([OH:11])=[C:6]([F:10])[CH:7]=1
Reactant: Oc1c(F)cccc1F
Reactant: BrBr
Agent: Br
Agent: O=S([O-])S(=O)(=O)[O-]
Agent: [Na+]
Solvent: S=C=S
Product: Oc1c(F)cc(Br)cc1F
Reaction time: 16 h
Yield: 23 %

Procedure:
A solution of bromine (1.6 g) in dry carbon disulphide (10 cm3) was added over 5 minutes to a solution of 2,6-difluorophenol (1.3 g) in dry carbon disulphide (10 cm3). To the stirred reaction mixture was added 5 drops of 48% hydrogen bromide solution. The mixture was heated for 2 hours at the reflux temperature, then allowed to stand at the ambient temperature (ca 22° C.) for 16 hours. After a further period of heating (4 hours) the mixture was allowed to stand for 24 hours before being poured onto water (20 cm3). To the mixture was added saturated sodium metabisulphite solution (30 cm3). The layers were separated, and the organic phase was washed with saturated sodium hydrogen carbonate solution (20 cm3) and water (20 cm3). The organic layer was dried over anhydrous sodium sulphate then evaporated under reduced pressure to given an oil which solidified. The crude product was distilled in a Kugelrohr apparatus at an oven temperature of 100° C. under reduced pressure (ca. 20 mmHg). The distillate crystallised to give 4-bromo-2,6-difluorophenol as a white solid (0.48 g).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([CH2:15][NH:16][C:17]2[N:26]=[C:25]([N:27]([CH3:29])[CH3:28])[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]=2)[CH2:11][CH2:10]1)(C)(C)C.Cl.C(N(C(C)C)CC)(C)C.[Br:41][C:42]1[CH:47]=[CH:46][C:45]([S:48](Cl)(=[O:50])=[O:49])=[C:44]([O:52][C:53]([F:56])([F:55])[F:54])[CH:43]=1>CCOC(C)=O.C(Cl)Cl>[Br:41][C:42]1[CH:47]=[CH:46][C:45]([S:48]([NH:7][CH2:8][C@H:9]2[CH2:10][CH2:11][C@H:12]([CH2:15][NH:16][C:17]3[N:26]=[C:25]([N:27]([CH3:29])[CH3:28])[C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[N:18]=3)[CH2:13][CH2:14]2)(=[O:50])=[O:49])=[C:44]([O:52][C:53]([F:55])([F:54])[F:56])[CH:43]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1OC(F)(F)F
Reactant: CN(C)c1nc(NC[C@H]2CC[C@H](CNC(=O)OC(C)(C)C)CC2)nc2ccccc12
Agent: Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)c1nc(NC[C@H]2CC[C@H](CNS(=O)(=O)c3ccc(Br)cc3OC(F)(F)F)CC2)nc2ccccc12
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
To a suspension of trans-{4-[(4-dimethylamino-quinazolin-2-ylamino)-methyl]cyclohexylmethyl}-carbamic acid tert-butyl ester (3.84 g, 9.28 mmol) in EtOAc (50 mL) was added 4 M hydrogen chloride in EtOAc (38 mL). The mixture was stirred at ambient temperature for 40 min and concentrated to give a white solid. To a suspension of the solid in CH2Cl2 (50 mL) was added diisopropylethylamine (6.46 mL, 37.1 mmol). The mixture was cooled at 4° C. and a solution of 4-bromo-2-trifluoromethoxy-benzenesulfonyl chloride (3.31 g, 9.75 mmol) in CH2Cl2 (10 mL) was added below 5° C. The reaction mixture was stirred at 4° C. for 1.5 hr. The reaction was quenched with saturated aqueous NaHCO3 The aqueous layer was extracted with CHCl3 (three times). The combined organic layer was dried over MgSO4, filtered, concentrated, and purified by flash chromatography (NH-silica gel, 20% EtOAc in hexane) to give trans-4-bromo-N-{4-[(4-dimethylamino-quinazolin-2-ylamino)-methyl]-cyclohexylmethyl}-2-trifluoromethoxy-benzenesulfonamide (3.45 g, 60%) as a pale yellow solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:8]2[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[N:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.C([N-]C(C)C)(C)C.[Li+].[C:24](=[O:26])=[O:25].[OH-].[Na+]>O1CCCC1.O>[Cl:1][C:2]1[C:3]([N:8]2[C:12]([C:24]([OH:26])=[O:25])=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[N:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C=O
Reactant: O=[N+]([O-])c1ccn(-c2ncccc2Cl)n1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1cc([N+](=O)[O-])nn1-c1ncccc1Cl
Temperature: -78 °C
Reaction time: 1 h
Yield: 48.3 %

Procedure:
8.65 g (38.5 mmol) of 3-chloro-2-(3-nitro-1H-pyrazol-1-yl)pyridine were dissolved in 196 ml of tetrahydrofuran and, under argon, cooled to −78° C. 21.4 mL (42.7 mmol) of a 2 molar solution of lithium diisopropylamide in THF were then added dropwise. The mixture was allowed to stir for 1 hour at −78° C., and a total of 1500 g of powdered dry ice were then added a little at a time. The mixture was stirred at −78° C. until the evolution of carbon dioxide had ceased and then allowed to warm to room temperature. Initially, 679 ml of water were then added, and the pH was subsequently adjusted to 11 using 1N sodium hydroxide solution. The aqueous phase was extracted repeatedly with ethyl acetate. The combined organic phases were dried over magnesium sulphate and the solvent was distilled off under reduced pressure, which gave 5.0 g (47% of theory) of 1-(3-chloropyridin-2-yl)-3-nitro-1H-pyrazole-5-carboxylic acid. log P: 0.90; MH+: 269.0; 1H-NMR (400 MHz, CD3CN, δ, ppm): 7.77 (m, 2H), 8.33 (m, 1H), 8.62 (m, 1H).
Reaction SMILES: OC[C@H](NC(=O)[C@H](C)CCCC1C=CC=CC=1)C1C=CC=CC=1.[CH3:24][C@@H:25]([CH2:29][CH2:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:26]([OH:28])=[O:27]>>[CH3:24][C@H:25]([CH2:29][CH2:30][CH2:31][C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)[C:26]([OH:28])=[O:27]
Reactant: C[C@@H](CCCc1ccccc1)C(=O)O
Agent: C[C@H](CCCc1ccccc1)C(=O)N[C@@H](CO)c1ccccc1
Product: C[C@H](CCCc1ccccc1)C(=O)O

Procedure:
-(−)-2-Methyl-5-phenylpentanoic acid was prepared from 19mc(i) (30 g) in the same manner (S)-(+)-2-methyl-5-phenylpentanoic acid was prepared from 19mb(i) as described above. The residue was purified by silica gel chromatography. Elution with ethyl acetate-heptane-acetic acid (20:80:0.4 v/v/v) afforded the title compound (20.8 g) as a clear oil; TLC Rf 0.51 (solvent system: 30:70:1 v/v/v ethyl aceate-hepatane-acetic acid; HPLC retention time 24.46 min; Chiralpak IA 4.6×25 mm 5μ, at a wavelength of 208 nm 0.75 mL/min, 99:1:0.5 heptane: 2-propanol:acetic acid, chiral purity 99.32% (R), 0.68% (S); MS (ESI−) m/z 191.1 (M−H)−; 1H-NMR (CDCl3) δ 7.31-7.26 (m, 2H), 7.21-7.15 (m, 3H), 2.67-2.57 (m, 2H), 2.54-2.44 (m, 1H), 1.79-1.59 (m, 3H) 1.58-1.41 (m, 1H), 1.18 (d, J=6.96 Hz, 3H).
Reaction SMILES: [CH:1]1([N:6]2[CH2:11][CH2:10][N:9]([C:12]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[NH:19][C:18]([C:23]([N:25]3[CH2:30][CH2:29][C:28]([F:32])([F:31])[CH2:27][CH2:26]3)=[O:24])=[CH:17]4)=[O:13])[CH2:8][CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:33][C:34]1[CH:35]=[C:36](B(O)O)[CH:37]=[CH:38][CH:39]=1.N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[Cl:33][C:34]1[CH:39]=[C:38]([N:19]2[C:20]3[C:16](=[CH:15][C:14]([C:12]([N:9]4[CH2:8][CH2:7][N:6]([CH:1]5[CH2:5][CH2:4][CH2:3][CH2:2]5)[CH2:11][CH2:10]4)=[O:13])=[CH:22][CH:21]=3)[CH:17]=[C:18]2[C:23]([N:25]2[CH2:26][CH2:27][C:28]([F:31])([F:32])[CH2:29][CH2:30]2)=[O:24])[CH:37]=[CH:36][CH:35]=1
Reactant: OB(O)c1cccc(Cl)c1
Reactant: O=C(c1ccc2[nH]c(C(=O)N3CCC(F)(F)CC3)cc2c1)N1CCN(C2CCCC2)CC1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(c1ccc2c(c1)cc(C(=O)N1CCC(F)(F)CC1)n2-c1cccc(Cl)c1)N1CCN(C2CCCC2)CC1
Yield: 76 %

Procedure:
The title compound was synthesized in analogy to example 66, from [5-(4-cyclopentyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(4,4-difluoro-piperidin-1-yl)-methanone (example 8), 3-chlorphenylboronic acid, copper(II) acetate and pyridine in dichloromethane, to give the desired product as a white solid (76%).
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][N:23]=1)[C:18]([OH:20])=O.CC1ON=C(C2C=CC=CC=2)C=1COC1C=CC(C(O)=O)=CN=1.[F:47][C:48]([F:52])([F:51])[CH2:49][NH2:50]>>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][N:23]=1)[C:18]([NH:50][CH2:49][C:48]([F:52])([F:51])[F:47])=[O:20]
Reactant: Cc1onc(-c2ccccc2)c1COc1cc(C(=O)O)ccn1
Reactant: NCC(F)(F)F
Agent: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)O)cn1
Product: Cc1onc(-c2ccccc2)c1COc1cc(C(=O)NCC(F)(F)F)ccn1
Yield: 51 %

Procedure:
As described for example 8b, 2-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-isonicotinic acid (78 mg, 0.3 mmol), instead of 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid, was converted, using 2,2,2-trifluoroethylamine instead of methylamine, to the title compound (49 mg, 51%) which was obtained as a white solid. MS: m/e=392.3 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([CH:8]2[CH2:10][CH2:9]2)[N:5]=[C:4]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:3]=1Br.[CH3:17][Si:18]([CH3:35])([CH3:34])/[CH:19]=[CH:20]/[Sn](CCCC)(CCCC)CCCC>O1CCOCC1.C(OCC)(=O)C.O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[NH2:1][C:2]1[N:7]=[C:6]([CH:8]2[CH2:10][CH2:9]2)[N:5]=[C:4]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:3]=1/[CH:20]=[CH:19]/[Si:18]([CH3:35])([CH3:34])[CH3:17]
Reactant: CCOC(=O)c1nc(C2CC2)nc(N)c1Br
Reactant: CCCC[Sn](/C=C/[Si](C)(C)C)(CCCC)CCCC
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CCOC(=O)c1nc(C2CC2)nc(N)c1/C=C/[Si](C)(C)C
Temperature: 120 °C
Yield: 57.2 %

Procedure:
Ethyl 6-amino-5-bromo-2-cyclopropylpyrimidine-4-carboxylate (0.5 g, 1.747 mmol, see WO 2005063721 for preparation) and tetrakis (triphenylphosphine) palladium(0) (0.214 g, 0.185 mmol) were added to a 20 mL Biotage microwave reaction vessel. The vessel was sealed and purged with nitrogen gas. (E)-trimethyl(2(tributylstannyl)vinyl)silane (0.96 g, 2.466 mmol) in dioxane (8.74 ml) was added and the reaction mixture was heated at 120° C. for 6 h. The cooled reaction mixture was diluted with ethyl acetate and water. The organic phase was washed with saturated sodium chloride, dried over magnesium sulfate, filtered, and concentrated onto silica. Purification by flash chromatography (SiO2, 0-40% EtOAc:Hex gradient) provided the title compound as a tan solid (0.305 g, 57% yield): mp 99-101° C.; 1H NMR (400 MHz, DMSO-d6) δ 0.12 (s, 9H), 0.85-0.94 (m, 4H), 1.25 (t, J=7.1 Hz, 3H), 1.91 (tt, J=7.0, 5.6 Hz, 1H), 4.20 (q, J=7.1 Hz, 2H), 6.03 (d, J=19.1 Hz, 1H), 6.70 (d, J=19.2 Hz, 1H), 7.01 (s, 2H); ESIMS m/z 306 ([M+H]+), 304 ([M−H]−).