Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]2[CH2:8][CH2:9][O:10][C:6]=2[C:5]([CH:11]2[C@H:16]([O:17]CC3C=CC=CC=3)[C@@H:15]([O:25]CC3C=CC=CC=3)[C@H:14]([O:33]CC3C=CC=CC=3)[C@@H:13]([CH2:41][O:42]CC3C=CC=CC=3)[O:12]2)=[CH:4][C:3]=1[CH2:50][C:51]1[CH:56]=[CH:55][C:54]([O:57][CH3:58])=[CH:53][CH:52]=1>C1COCC1.CO.[Pd]>[Cl:1][C:2]1[C:7]2[CH2:8][CH2:9][O:10][C:6]=2[C:5]([C@H:11]2[C@H:16]([OH:17])[C@@H:15]([OH:25])[C@H:14]([OH:33])[C@@H:13]([CH2:41][OH:42])[O:12]2)=[CH:4][C:3]=1[CH2:50][C:51]1[CH:52]=[CH:53][C:54]([O:57][CH3:58])=[CH:55][CH:56]=1
Reactant: COc1ccc(Cc2cc(C3O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)c3c(c2Cl)CCO3)cc1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(Cc2cc([C@@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)c3c(c2Cl)CCO3)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A suspension of compound 50 (407 mg, 0.51 mmol) and Pd/C (10% wt., 50 mg) in THF (5.0 mL) and MeOH (2.5 mL) was stirred at room temperature under an atmosphere of H2 for 24 hours. The mixture was filtered through a Celite pad and concentrated in vacuo. The residue was purified by prep HPLC (C18) to afford the product E021 (65 mg, 27%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([Br:8])=[C:4](Cl)[N:3]=1.[NH2:10][C:11]1[CH:20]=[CH:19][CH:18]=[CH:17][C:12]=1[C:13]([NH:15][CH3:16])=[O:14].C(N(CC)C(C)C)(C)C>C(O)(C)C>[Cl:1][C:2]1[N:3]=[C:4]([NH:10][C:11]2[CH:20]=[CH:19][CH:18]=[CH:17][C:12]=2[C:13]([NH:15][CH3:16])=[O:14])[C:5]([Br:8])=[CH:6][N:7]=1
Reactant: Clc1ncc(Br)c(Cl)n1
Reactant: CNC(=O)c1ccccc1N
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: CNC(=O)c1ccccc1Nc1nc(Cl)ncc1Br
Yield: 76 %

Procedure:
In a similar fashion as outlined in Example 191a, 2,6-dichloro-5-bromopyrimidine was reacted with 2-amino-N-methylbenzamide and N,N-diisopropylethylamine in isopropyl alcohol (microwave −120° C., 10 minutes) to afford 2-(2-chloro-5-bromo-pyrimidin-4-ylamino)-N-methyl-benzamide as a yellow solid in 76% yield. MS: 342.96 (M+H); 1H NMR (d6-dmso): δ 11.96 (s, 1H), δ 8.85 (br s, 1H), δ 8.57 (s, 1H), δ 8.47 (d, J=9 Hz, 1H), δ 7.79 (d, J=8 Hz, 1H), δ 7.57 (t, J=8 Hz, 1H), δ 7.22 (t, J=8 Hz, 1H), δ 2.78 (d, J=5 Hz, 3H).
Reaction SMILES: [CH:1](NC(C)C)(C)C.[Li].[Br:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][N:17]([CH2:28][C:29]([F:32])([F:31])[F:30])[S:18]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)(=[O:20])=[O:19])=[C:12]([F:33])[CH:11]=1.IC>O1CCCC1>[Br:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][N:17]([CH2:28][C:29]([F:30])([F:31])[F:32])[S:18]([CH:21]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH3:1])(=[O:20])=[O:19])=[C:12]([F:33])[CH:11]=1
Reactant: CC(C)NC(C)C
Reactant: O=S(=O)(Cc1ccccc1)N(Cc1ccc(Br)cc1F)CC(F)(F)F
Agent: [Li]
Solvent: CI
Solvent: C1CCOC1
Product: CC(c1ccccc1)S(=O)(=O)N(Cc1ccc(Br)cc1F)CC(F)(F)F
Temperature: -78 °C
Reaction time: 1 h
Yield: 58.8 %

Procedure:
To a solution of lithium diisopropylamine (2.0 M in THF/heptane/ethylbenzene) (1.2 mL, 2.5 mmol) at −78° C. was slowly added a solution of N-[(4-bromo-2-fluoro-phenyl)methyl]-1-phenyl-N-(2,2,2-trifluoroethyl)methanesulfonamide (1 g, 2.3 mmol) in tetrahydrofuran (11 mL) and the reaction was stirred at −78° C. for 1 hour. Iodomethane (0.16 mL, 2.5 mmol) was then added and the reaction was warmed to ambient temperature and stirred for 2 hours. The reaction was quenched with saturated aqueous NH4Cl and diluted with EtOAc, washed with 1 N aqueous HCl, and brine, dried with MgSO4, concentrated and purified by silica gel column chromatography (0-30% EtOAc in heptane) to give N-[(4-bromo-2-fluoro-phenyl)methyl]-1-phenyl-N-(2,2,2-trifluoroethyl)ethanesulfonamide (614 mg, 60% yield). LCMS (m/z) ES+ 471 [M+18]+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=1)[CH:7]=[C:6]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:5]2=[O:24].[C:25]([C:27]1[CH:28]=[N:29][C:30]([CH3:33])=[N:31][CH:32]=1)#[CH:26].C(N(CC)CC)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>[F:18][C:15]1[CH:16]=[CH:17][C:12]([N:8]2[C:9]3[C:4](=[CH:3][C:2]([C:26]#[C:25][C:27]4[CH:28]=[N:29][C:30]([CH3:33])=[N:31][CH:32]=4)=[CH:11][CH:10]=3)[C:5](=[O:24])[C:6]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:7]2)=[CH:13][CH:14]=1
Reactant: C#Cc1cnc(C)nc1
Reactant: CCOC(=O)c1cn(-c2ccc(F)cc2)c2ccc(Br)cc2c1=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(-c2ccc(F)cc2)c2ccc(C#Cc3cnc(C)nc3)cc2c1=O
Temperature: 150 °C
Yield: 54 %

Procedure:
Compound D (50 mg, 0.13 mmol, 1.0 eq), 5-ethynyl-2-methyl-pyrimidine (30 mg, 0.26 mmol, 2.0 eq), copper(I) iodide (2.5 mg, 0.013 mmol, 0.010 eq), bis(triphenylphosphine)palladium(II) dichloride (4.5 mg, 0.0064 mmol, 0.050 eq) and triethylamine (53.6 μL, 0.38 mmol, 3.0 eq) were dissolved in DMF (1.3 mL) in a microwave vial and heated in a microwave reactor at 150° C. for 15 minutes. The reaction was purified directly using reverse phase chromatography to afford 30 mg (55%) of the title compound as white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.93 (s, 2H), 8.47 (s, 1H), 8.40 (d, J=2.0 Hz, 1H), 7.81-7.76 (m, 3H), 7.53 (t, J=8.7 Hz, 2H), 7.02 (d, J=8.80 Hz, 1H), 4.21 (q, J=7.1 Hz, 2H), 2.66 (s, 3H), 1.25 (t, J=7.1 Hz, 3H); ES-MS [M+1]+: 428.2.
Reaction SMILES: [NH:1]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C@H:2]([C:11]([OH:13])=O)[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][CH:5]=1.CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F.Cl.[CH3:49][NH:50][O:51][CH3:52].O>C(Cl)Cl>[C:17]([O:16][C:14](=[O:15])[NH:1][CH:2]([C:11](=[O:13])[N:50]([O:51][CH3:52])[CH3:49])[CH2:3][C:4]1[CH:5]=[CH:6][C:7]([F:10])=[CH:8][CH:9]=1)([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(F)cc1)C(=O)O
Reactant: CNOC
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: O
Product: CON(C)C(=O)C(Cc1ccc(F)cc1)NC(=O)OC(C)(C)C
Reaction time: 0.5 h
Yield: 99.7 %

Procedure:
To a solution of Boc-Phe(4-F)-OH (5.0 g, 17.7 mmol) in methylene chloride (89 ml), BOP reagent (9.39 g, 21.2 mmol), N,O-dimethylhydroxylamine hydrochloride (2.07 g, 21.2 mmol) and TEA (5.92 ml, 42.5 mmol) were added under cooling with ice and stirred for 30 min. The reaction mixture was mixed with water and extracted with methylene chloride. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated to remove the solvent under reduced pressure. The thus obtained residue was subjected to silica gel column chromatography (developing solvent: ethyl acetate:n-hexane=1:1), giving the titled compound (5.76 g, 100%).
Reaction SMILES: C[S:2][C:3](=S)[NH:4][N:5]=[CH:6][C:7]1[N:8]=[C:9]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[NH:10][C:11]=1[CH2:12][CH2:13][CH3:14].CSC(=S)NN=CC1N=C(CC2C=CC=CC=2)NC=1C>>[CH2:15]([C:9]1[N:8]2[C:3](=[S:2])[NH:4][N:5]=[CH:6][C:7]2=[C:11]([CH2:12][CH2:13][CH3:14])[N:10]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CCCc1[nH]c(Cc2ccccc2)nc1C=NNC(=S)SC
Agent: CSC(=S)NN=Cc1nc(Cc2ccccc2)[nH]c1C
Product: CCCc1nc(Cc2ccccc2)n2c(=S)[nH]ncc12

Procedure:
The procedure of Example 65 is repeated substituting an equimolecular amount of 3-[(2-benzyl-5-n-propylimidazolyl)methylene]dithiocarbazic acid methyl ester for the 3-[(2-benzyl-5-methylimidazolyl)methylene]dithiocarbazic acid methyl ester employed in that example. There is thus obtained the title compound in equally good yield.
Reaction SMILES: [C:1]1([CH:7]=[N:8][N:9]2[CH2:13][CH2:12][NH:11][C:10]2=[O:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Br[CH2:18][CH2:19][CH2:20][CH2:21][Cl:22]>CN(C)C=O>[C:1]1([CH:7]=[N:8][N:9]2[CH2:13][CH2:12][N:11]([CH2:18][CH2:19][CH2:20][CH2:21][Cl:22])[C:10]2=[O:14])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: ClCCCCBr
Reactant: O=C1NCCN1N=Cc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1N(CCCCCl)CCN1N=Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 89.2 %

Procedure:
A stirred mixture of 1-phenylmethylenamino-2-imidazolidinone (27.6 g, 0.1458 mole) [prepared as in Example A, Part II] in dimethylformamide (500 ml) is treated portionwise with 60% NaH in mineral oil (5.8 g, 0.1458 mole) over 30 minutes. The resulting mixture is stirred at ambient temperature 30 minutes, then heated at 80°-90° C. for 30 minutes. The resulting thick mixture is cooled to ambient temperature, and 1-bromo-4-chlorobutane (50.0 g, 0.2916 mole, 2 eq) is added in one portion. The mixture is heated at 80°-90° C. After 30 minutes, a near-solution is formed followed, by gradual precipitation of a small amount of solid. The mixture is heated at 80°-90° C. temperature for 3 hours, then stirred at ambient temperature for 18 hours. The mixture is filtered (celite) removing a small amount of insoluble material. The filtrate is concentrated under reduced pressure to an oily residue. This residue is triturated with H2O giving a solid. The solid is collected and air-dried. This solid is triturated by stirring in anhydrous ether (350 ml) for one hour. The solid is collected and air-dried to give 36.4 g (0.130 mole) of 1-phenylmethyleneamino-3-(4-chlorobutyl)-2-imidazolidinone.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[CH:7]=[O:8].[Br:9]Br>C(Cl)Cl>[Br:9][C:5]1[S:4][C:3]([CH:7]=[O:8])=[C:2]([CH3:1])[CH:6]=1
Reactant: BrBr
Reactant: Cc1ccsc1C=O
Solvent: ClCCl
Product: Cc1cc(Br)sc1C=O
Temperature: 70 °C
Reaction time: 4 h
Yield: 67.6 %

Procedure:
To 0° C. cooled solution of 3-methylthiophene-2-carbaldehyde (10.0 g, 79.3 mmol, 1.0 eq) in DCM (100 mL) was added drop wise a solution of bromine (12.6 g, 79.3 mmol, 1.0 eq) and the resulting mixture was stirred 70° C. for 4 h. The reaction was cooled to room temperature and diluted with DCM (100 mL). The resulting organic layer was washed with water (100 mL), saturated sodium bicarbonate solution (100 mL), brine (100 mL), dried (Na2SO4) and filtered. The filtrate was rotary evaporated to afford 11 g of the desired product as a brown solid. 1HNMR (400 MHz, CDCl3) δ 9.87 (s, 1H), 6.93 (s, 1H), 2.51 (s, 3H); ESI-MS (m/z) 205, 207 [(MH)+, Br79,81].
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([N+:13]([O-])=O)=[CH:9][CH:8]=2)=[C:4]([CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[CH:3]=1.O.O.Cl[Sn]Cl>CO>[Cl:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][CH:8]=2)=[C:4]([CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[CH:3]=1
Reactant: O=[N+]([O-])c1ccc(Oc2ccc(Cl)cc2C2CCCCC2)cc1
Agent: Cl[Sn]Cl
Solvent: CO
Solvent: O
Product: Nc1ccc(Oc2ccc(Cl)cc2C2CCCCC2)cc1

Procedure:
The nitro intermediate (10 mmol) obtained above was dissolved in MeOH (20 mL), and treated with SnCl2.2H2O (50 mmol), according to General Procedure I. The reaction mixture was heated under reflux until completion, as indicated by TLC or HPLC. The solvent was removed in vacuuo and the residue was treated with 4.0 N aqueous NaOH to pH˜8. The residue was extracted with EtOAc (2×50 mL), washed with 1.0 N aqueous NaOH, brine and dried over sodium sulfate. The solvent was removed in vacuuo to afford the desired 4-(4-chloro-2-cyclohexylphenoxy) aniline, which was used directly for further transformation without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][C:3]=1F.[CH2:13]([OH:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[CH2:13]([O:20][C:3]1[CH:4]=[C:5]([CH2:8][C:9]([OH:11])=[O:10])[CH:6]=[CH:7][C:2]=1[Cl:1])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: OCc1ccccc1
Reactant: O=C(O)Cc1ccc(Cl)c(F)c1
Product: O=C(O)Cc1ccc(Cl)c(OCc2ccccc2)c1

Procedure:
Prepared according to the procedure described in Example 24, Step 1, using the following starting materials: 4-chloro-3-fluorophenylacetic acid and benzyl alcohol.
Reaction SMILES: Cl.[CH3:2][C:3]1[N:4]=[C:5]([NH2:9])[S:6][C:7]=1[CH3:8].C(N(CC)CC)C.[C:17]12([C:27](Cl)=[O:28])[CH2:26][CH:21]3[CH2:22][CH:23]([CH2:25][CH:19]([CH2:20]3)[CH2:18]1)[CH2:24]2>C1COCC1>[CH3:2][C:3]1[N:4]=[C:5]([NH:9][C:27]([C:17]23[CH2:26][CH:21]4[CH2:20][CH:19]([CH2:25][CH:23]([CH2:22]4)[CH2:24]2)[CH2:18]3)=[O:28])[S:6][C:7]=1[CH3:8]
Reactant: O=C(Cl)C12CC3CC(CC(C3)C1)C2
Reactant: Cc1nc(N)sc1C
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1nc(NC(=O)C23CC4CC(CC(C4)C2)C3)sc1C
Yield: 74 %

Procedure:
To a solution of 4,5-dimethyl-thiazol-2-ylamine hydrochloride (1.65 g, 10.0 mmol) in THF (100 mL) was added triethylamine (4.2 mL, 30 mmol) and adamantane-1-carbonyl chloride (2.2 g, 11 mmol). The mixture was heated at reflux overnight and then concentrated under reduced pressure. The residue was diluted with ethyl acetate, washed with 1M NaHCO3, dried (Na2SO4), filtered and concentrated. Purification by column chromatography (SiO2, 10% ethyl acetate: 90% hexanes) afforded 2.15 g (74%) of the title compound. MS (ESI+) m/z 291 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([C:14]#[N:15])[C:11]=1[O:12][CH3:13])[C:5]([O:7]C)=[O:6].O.[OH-].[Li+]>O1CCCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([C:14]#[N:15])[C:11]=1[O:12][CH3:13])[C:5]([OH:7])=[O:6]
Reactant: COC(=O)c1cc(Cl)c(OC)c(C#N)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COc1c(Cl)cc(C(=O)O)cc1C#N
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 98.9 %

Procedure:
Methyl 3-chloro-5-cyano-4-methoxybenzoate (1.02 g) was dissolved in tetrahydrofuran (15 mL) and water (6 mL), and lithium hydroxide monohydrate (759 mg) was added to the solution, and then the mixture was stirred at room temperature for 90 minutes. The organic solvent was distilled off and the aqueous layer was washed with n-hexane. The aqueous layer was acidified with 1N hydrochloric acid and then extracted with ethyl acetate. The organic layer was washed with saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound (946 mg) as a colorless crystal.
Reaction SMILES: O=[CH:2][CH:3]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:4][NH:5][C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9].[NH2:19][C:20]1([C:25]([O:27][CH3:28])=[O:26])[CH2:24][CH2:23][CH2:22][CH2:21]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)(Cl)Cl.C(Cl)Cl.C(=O)(O)[O-].[Na+]>[C:8]([O:7][C:6]([NH:5][CH2:4][CH:3]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:2][NH:19][C:20]1([C:25]([O:27][CH3:28])=[O:26])[CH2:24][CH2:23][CH2:22][CH2:21]1)=[O:12])([CH3:11])([CH3:10])[CH3:9]
Reactant: COC(=O)C1(N)CCCC1
Reactant: CC(C)(C)OC(=O)NCC(C=O)c1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: COC(=O)C1(NCC(CNC(=O)OC(C)(C)C)c2ccccc2)CCCC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Into a solution of tert-butyl (3-oxo-2-phenylpropyl)carbamate from Step B (0.5 g, 2 mmol) in dry chloroform (20 mL) was added methyl 1-amino-1-cyclopentanecarboxylate (0.431 g, 3.01 mmol). After 15 minutes, sodium triacetoxyborohydride (0.893 g, 4.21 mmol) was added. After 4 hours of stirring at ambient temperature, the reaction mixture was diluted with DCM and 5% sodium bicarbonate. The layers were separated and the aqueous layer was extracted once with DCM. The combined organics were dried over sodium sulfate, filtered, and concentrated in vacuo to yield a residue, which was subjected to a normal phase chromatography, eluting with a gradient of 1-6% methanol in DCM. Concentration of the fractions containing the product provided the title compound. MS: m/z=377 (M+1).
Reaction SMILES: [CH2:1]([CH:3]([O:6][C:7]1[C:12]([C:13](O)=[O:14])=[C:11]([NH:16][C:17]2[C:22]([CH3:23])=[CH:21][C:20]([CH3:24])=[CH:19][C:18]=2[CH3:25])[N:10]=[C:9]([CH3:26])[N:8]=1)[CH2:4][CH3:5])[CH3:2].CSC>C1COCC1>[CH2:1]([CH:3]([O:6][C:7]1[C:12]([CH2:13][OH:14])=[C:11]([NH:16][C:17]2[C:22]([CH3:23])=[CH:21][C:20]([CH3:24])=[CH:19][C:18]=2[CH3:25])[N:10]=[C:9]([CH3:26])[N:8]=1)[CH2:4][CH3:5])[CH3:2]
Reactant: CCC(CC)Oc1nc(C)nc(Nc2c(C)cc(C)cc2C)c1C(=O)O
Solvent: C1CCOC1
Solvent: CSC
Product: CCC(CC)Oc1nc(C)nc(Nc2c(C)cc(C)cc2C)c1CO
Reaction time: 0.5 h

Procedure:
To a solution of 4-(1-ethyl-propoxy)-2-methyl-6-(2,4,6-trimethyl-phenylamino)-pyrimidine-5-carboxylic acid in dry THF was added BH3.DMS. The resulting mixture was heated at reflux. The mixture was quenched with dilute HCl and stirred for 30 minutes, adjusted pH to 7.5–8.5, then extracted with ethyl acetate. The organic layer was separated, dried and concentrated to give a crude material. The crude material was purified through silica gel column chromatography to give the title compound as a solid, mp. 121–123° C., Anal. For C20H29N3O2 calc. C, 69.94; H, 8.51; N, 12.23; found: C, 69.73; H, 8.47; N, 11.99.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:21])[C:7]=1[CH2:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([O:19][CH3:20])=[CH:16][CH:17]=2)[CH2:12][NH:11][N:10]=1.N#N.[C:24](N1C=CN=C1)([N:26]1[CH:30]=CN=[CH:27]1)=[O:25].CNC>C1COCC1.C(O)C>[CH3:27][N:26]([CH3:30])[C:24]([N:11]1[N:10]=[C:9]([CH2:8][C:7]2[C:6]([Cl:21])=[CH:5][N:4]=[CH:3][C:2]=2[Cl:1])[C:18]2[C:13](=[CH:14][C:15]([O:19][CH3:20])=[CH:16][CH:17]=2)[CH2:12]1)=[O:25]
Reactant: COc1ccc2c(c1)CNN=C2Cc1c(Cl)cncc1Cl
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: CNC
Agent: N#N
Solvent: CCO
Solvent: C1CCOC1
Product: COc1ccc2c(c1)CN(C(=O)N(C)C)N=C2Cc1c(Cl)cncc1Cl
Yield: 36.1 %

Procedure:
A solution of 4-(3,5-dichloro-pyridin-4-ylmethyl)-7-methoxy-1,2-dihydro-phthalazine (1 g, 3.1 mmoles), prepared as described in example 22, in dry THF (35 ml), under stirring and dry N2 at room temperature, was added with 1,1′-carbonyldiimidazole (0.6 g, 3.72 mmoles), then the mixture was refluxed for 3 hours, cooled, added with 5.6M dimethylamine in ethanol (5 ml) and refluxed again. After 44 hours the mixture was cooled, poured into water/ice and extracted more times with CH2Cl2. The organic phases were washed with 5% NaOH, then with water, anhydrified and concentrated. The residue was flash chromatographed (eluent: hexane/ethyl acetate 1:1), then crystallised from acetonitrile (30 ml) to give 0.44 g of the title compound (yield: 36.4%). m.p.: 160-162° C.
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[C:4]([OH:13])[CH:3]=1.[I:14]Cl.O.S([O-])([O-])=O.[Na+].[Na+]>CCCCCCC>[F:1][C:2]1[C:12]([I:14])=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[C:4]([OH:13])[CH:3]=1
Reactant: ClI
Reactant: CCOC(=O)c1ccc(F)cc1O
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCCCCCC
Product: CCOC(=O)c1cc(I)c(F)cc1O
Reaction time: 1 h

Procedure:
Ethyl 4-fluoro-2-hydroxybenzoate (10.2 g, 55 mmol)) was dissolved in n-heptane. Iodo monochloride (12 g, 74 mmol) was added dropwise at ambient temperature with sniffing. After 1 h, water was added and then solid sodium sulfite in small portions until the suspension was decolourized. More n-heptane was added to clear solution and the phases separated. The organic phase was dried and concentrated. The product crystallized on cooling. It was collected by filtration and washed with cold n-heptane. The crude yield was 10 g. The product was a mixture of ethyl 4-fluoro-2-hydroxy-5-iodobenzoate (about 80%) and the 5 chloro analogue (about 20%).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[C:11]([CH3:17])[CH:10]=2)=[CH:5][CH:4]=1.B(Br)(Br)Br.O>C(Cl)Cl>[OH:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[C:11]([CH3:17])[CH:10]=2)=[CH:7][CH:8]=1
Reactant: COc1ccc(-c2ccc(C#N)c(C)c2)cc1
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: Cc1cc(-c2ccc(O)cc2)ccc1C#N
Temperature: 25 °C
Reaction time: 14 h
Yield: 94.8 %

Procedure:
The product from Example 106A (5.60 g, 25.4 mmol) in CH2Cl2 (120 mL) at 78° C. was treated with 1.0 M BBr3 (in CH2Cl2, 76 mL, 76.0 mmol) dropwise over 1 hour. After stirring for 14 hours at room temperature, the mixture was warmed to 0° C. (ice bath) and treated with water (0.5 mL). After 10 minutes, additional water was added (2.0 mL), ice bath was removed, and 5.0 mL of water was added. The mixture was then treated with another 20 mL of water and allowed to stir for 45 minutes. The mixture was filtered and the filtrate extracted with CH2Cl2. The CH2Cl2 layers were combined, dried over sodium sulfate, filtered, and the filtrate concentrated under reduced pressure to provide the title compound as an off-white powder (5.04 g, 94% yield). 1HNMR (300 MHz, CDCl3) δ 2.35 (s, 3H), 5.0 (s, 1H), 6.79-7.50 (m, 7H); MS (DCI) m/z 210 (+H)+.
Reaction SMILES: [C:1]([OH:8])(=[O:7])/[CH:2]=[CH:3]/[C:4]([OH:6])=[O:5].C([O-])(=O)/C=C/C([O-])=[O:13]>>[C:1]([OH:8])(=[O:7])[C@H:2]([CH2:3][C:4]([OH:6])=[O:5])[OH:13]
Reactant: O=C(O)/C=C/C(=O)O
Reactant: O=C([O-])/C=C/C(=O)[O-]
Product: O=C(O)C[C@H](O)C(=O)O

Procedure:
An NH4 fumarate suspension with 400 g/l (calculated as fumaric acid) is introduced in a vessel and set at pH 8.0. The fumarate is first introduced partly in undissolved form. 35 g/l of cell mass (calculated as dry mass)--grown according to example A--is suspended in this liquid. After 36 hours incubation at 32° C., 378 g of L-malic acid per liter of fermentation liquid is produced.
Reaction SMILES: [Li]CCCC.N(C(C)C)C(C)C.[CH:13]1([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:16][CH2:15][CH2:14]1.Br[CH2:23][CH2:24][CH2:25][CH2:26][Cl:27].[NH4+].[Cl-]>C1COCC1>[Cl:27][CH2:26][CH2:25][CH2:24][CH2:23][C:13]1([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:16][CH2:15][CH2:14]1
Reactant: ClCCCCBr
Reactant: CCOC(=O)C1CCC1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CCOC(=O)C1(CCCCCl)CCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 85.3 %

Procedure:
Under an N2 atmosphere at ˜7° C., BuLi (2.5M in hexanes, 52.8 mL, 132 mmol) was added drop wise to a solution of iPr2NH (18.52 mL, 132 mmol, distilled from NaOH) in dry THF (70 mL) in 10 min. The reaction mixture was allowed to warm to rt, stirred for 0.5 h, cooled to −60° C. and then, ethyl 1-cyclobutanecarboxylate (prepared according to Török, B.; Molnár, Á., J. Chem. Soc. Perkin Trans. 1, 1993, 7, 801-804, 14.05 g, 110 mmol) in dry THF (30 mL) was added dropwise in 20 min. The resulting mixture was allowed to warm to 0° C. in 20 min., cooled again to −60° C. and then, a solution of 1-bromo-4-chlorobutane (19.1 mL, 165 mmol) in dry THF (30 mL) was added dropwise in 20 min, after which the temperature was raised to −20° C. in 15 min. After 1.5 h, the temperature was raised to −10° C. and stirring was continued for 1 h. The reaction mixture was allowed to reach rt, poured into a mixture of aqueous saturated NH4Cl (200 mL) and ice (50 mL) and extracted with Et2O (500 mL). The organic layer was washed with brine (250 mL), dried (Na2SO4) and evaporated in vacuo. The remaining oil was purified by fractional distillation under reduced pressure to give ethyl 1-(4-chlorobutyl)-1-cyclobutanecarboxylate (20.53 g, 86%) as a thin, colorless oil. 1H NMR (CDCl3): δ=4.13 (q, J=7.1 Hz, 2H), 3.51 (t, J=6.8 Hz, 2H), 2.50-2.32 (m, 2H), 1.96-1.70 (m, 8H), 1.40-1.20 (m, 2H), 1.26 (t, J=7.2 Hz, 3H). 13C NMR (CDCl3): δ=176.6, 60.3, 47.6, 44.8, 37.3, 32.8, 30.1 (2×), 22.4, 15.8, 14.4. HRMS calcd for C11H20(37Cl)O2 (MH+): 221.1122. found: 221.1116.