Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:3]([C:14]2[S:15][CH:16]=[C:17]([C:19]3[CH:20]=[N:21][N:22]([CH3:24])[CH:23]=3)[N:18]=2)=[CH:4][C:5]([NH:8][C:9]([NH:11][CH2:12][CH3:13])=[O:10])=[N:6][CH:7]=1.CC1(C)C(C)(C)[O:29][B:28](B2OC(C)(C)C(C)(C)O2)[O:27]1.C(N(CC)CC)C.C([O-])(=O)C.[K+]>O1CCOCC1.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>[CH2:12]([NH:11][C:9](=[O:10])[NH:8][C:5]1[N:6]=[CH:7][C:2]([B:28]([OH:29])[OH:27])=[C:3]([C:14]2[S:15][CH:16]=[C:17]([C:19]3[CH:20]=[N:21][N:22]([CH3:24])[CH:23]=3)[N:18]=2)[CH:4]=1)[CH3:13]
Reactant: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Reactant: CCNC(=O)Nc1cc(-c2nc(-c3cnn(C)c3)cs2)c(Br)cn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CCNC(=O)Nc1cc(-c2nc(-c3cnn(C)c3)cs2)c(B(O)O)cn1
Temperature: 40 °C
Reaction time: 0.17 h
Yield: 34.2 %

Procedure:
In a 100 mL flask 1-(5-bromo-4-(4-(1-methyl-1H-pyrazol-4-yl)thiazol-2-yl)pyridin-2-yl)-3-ethylurea (Intermediate 97, 1.28 g, 3.14 mmol) was dissolved in 1,4-dioxane (15 mL) at 40° C. and degassed with argon. Bis(triphenylphosphine)palladium chloride (0.221 g, 0.31 mmol) was added and allow it to react for 10 minutes while heating at 40° C. 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (2.394 g, 9.43 mmol) was added and stirred for 10 minutes while heating at 100° C. Triethylamine (1.314 mL, 9.43 mmol) and potassium acetate (0.925 g, 9.43 mmol) were added and the solution was heated at 100° C. for 15 h. The reaction mixture was cooled to room temperature, filtered through a pad of Celite and partitioned between water and ethyl acetate. The layers were separated and the aqueous layer was back extracted three times with ethyl acetate. The organic layers were combined and washed with water and brine, then dried over sodium sulfate and concentrated under reduced pressure, and purified by column chromatography (Silica gel, 0-10% MeOH in CH2Cl2). Isolation gave 400 mg of the title compound as an off-white solid.
Reaction SMILES: C[O:2][C:3](=[O:19])[CH2:4][C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[CH:13][CH:12]=2)[CH:8]=[N:7][CH:6]=1.[OH-].[Li+].Cl>C1COCC1>[C:17]([C:14]1[CH:15]=[CH:16][C:11]([CH2:10][N:9]2[C:5]([CH2:4][C:3]([OH:19])=[O:2])=[CH:6][N:7]=[CH:8]2)=[CH:12][CH:13]=1)#[N:18]
Reactant: COC(=O)Cc1cncn1Cc1ccc(C#N)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: N#Cc1ccc(Cn2cncc2CC(=O)O)cc1

Procedure:
A solution of [1-(4-cyanobenzyl)-1H-imidazol-5-yl]acetic acid methyl ester (4.44 g, 17.4 mmol) in THF (100 ml) and 1M lithium hydroxide (17.4 ml, 17.4 mmol) was stirred at RT for 18 hr. 1M HCl (17.4 ml) was added and the THF was removed by evaporation in vacuo. The aqueous solution was lyophilised to afford the title compound containing lithium chloride as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([O:12][CH3:13])=[C:7]([O:14][CH3:15])[CH:6]=2.[CH3:16][OH:17]>>[CH3:13][O:12][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][C:7]=1[O:14][CH3:15])[N:4]=[CH:3][C:2]([NH:1][CH2:9][C:10]([CH3:11])([CH3:5])[CH2:16][OH:17])=[CH:11]2
Reactant: CO
Reactant: COc1cc2cc(N)cnc2cc1OC
Product: COc1cc2cc(NCC(C)(C)CO)cnc2cc1OC

Procedure:
The reaction is run similar to the preparation in Example 7. To a MeOH solution of 4 Å powdered molecular sieves (0.35 g) under argon is added 3-amino-6,7-dimethoxyquinoline (0.32 g, 1.6 mmol) and 2.2-dimethyl-3-hydroxypropionaldelhyde (0.19 g, 1.9 mmol). The product mixture is chromatographed (3% MeOH/CHCl3) to afford 0.10 g of material which is partitioned between CH2Cl2/10% NaOH. The organic layer is washed with 10% NaOH, H2O, and brine, then dried (MgSO4), and recrystallized from EtOAc/hexanes to provide a light-orange solid (m.p. 170-173.5° C.). Anal. Calcd. for C16H22N2O3: C, 66.18; H, 7.64; N, 9.65; Found: C. 66.11; H, 7.49; N, 9.33.
Reaction SMILES: [CH2:1]([C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([Br:17])[CH:15]=2)[NH:10][C:9]=1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:24](Br)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>CN(C=O)C>[CH2:24]([N:10]1[C:11]2[C:16](=[CH:15][C:14]([Br:17])=[CH:13][CH:12]=2)[C:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[C:9]1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: Brc1ccc2[nH]c(-c3ccccc3)c(Cc3ccccc3)c2c1
Reactant: BrCc1ccccc1
Solvent: CN(C)C=O
Product: Brc1ccc2c(c1)c(Cc1ccccc1)c(-c1ccccc1)n2Cc1ccccc1

Procedure:
The desired product was prepared using a procedure similar to step 2 of example 3. Thus, 3-benzyl-5-bromo-2-phenyl-1H-indole (1.811 g, 5 mmol) was reacted with k-t-butoxide (0.589 g, 5.25 mmol) and benzyl bromide (0.901 g, 5.25 mmol) in DMF (20 ml) to give the product (1.932 g, 4.271 mmol, 85%) as a white solid, mp 155-157° C. 1H NMR (DMSO-d6) δ 3.99 (s, 2H), 5.32 (s, 2H), 6.82 (d, J=7.2 Hz, 2H), 7.07 (d, J=7.3 Hz, 2H), 7.09-7.23 (m, 7H), 7.34-7.39 (m, 3H), 7.43-7.49 (m, 3H), 7.53 (d, J=1.8 Hz, 1H); [ESI(+)], m/z 453/455 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:3]2[CH:10]=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[C:11]([CH2:13][C:14]1([N:25]2[CH:29]=[C:28](B3OC(C)(C)C(C)(C)O3)[CH:27]=[N:26]2)[CH2:17][N:16]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:15]1)#[N:12].[F-].[Cs+].C(O)(C)(C)C>C1CCC(P([C]2[CH][CH][CH][CH]2)C2CCCCC2)CC1.C1CCC(P([C]2[CH][CH][CH][CH]2)C2CCCCC2)CC1.Cl[Pd]Cl.[Fe].O>[N:5]1[C:4]2[NH:8][CH:9]=[CH:10][C:3]=2[C:2]([C:28]2[CH:27]=[N:26][N:25]([C:14]3([CH2:13][C:11]#[N:12])[CH2:15][N:16]([C:18]([O:20][C:21]([CH3:22])([CH3:23])[CH3:24])=[O:19])[CH2:17]3)[CH:29]=2)=[N:7][CH:6]=1
Reactant: CC(C)(C)OC(=O)N1CC(CC#N)(n2cc(B3OC(C)(C)C(C)(C)O3)cn2)C1
Reactant: Clc1ncnc2[nH]ccc12
Agent: Cl[Pd]Cl
Agent: [Fe]
Agent: [CH]1[CH][CH][C](P(C2CCCCC2)C2CCCCC2)[CH]1
Solvent: O
Solvent: CC(C)(C)O
Product: CC(C)(C)OC(=O)N1CC(CC#N)(n2cc(-c3ncnc4[nH]ccc34)cn2)C1
Temperature: 50 °C
Reaction time: 2 h
Yield: 99 %

Procedure:
To a 1-L flask equipped with a nitrogen inlet, a thermocouple, and a mechanical stirrer were added 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (4, 39.6 g, 257.6 mmol), tert-butyl 3-(cyanomethyl)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)azetidine-1-carboxylate (3, 100 g, 257.6 mmol, 1.0 equiv), cesium fluoride (136.9 g, 901.4 mmol, 3.5 equiv), tert-butanol (250 mL), water (250 mL), and [1,1′-bis(di-cyclohexylphosphino)ferrocene]dichloropalladium(II) (Pd-127, 351.4 mg, 0.46 mmol, 0.0018 equiv) at ambient temperature. The resulting reaction mixture was de-gassed and refilled with nitrogen for 3 times before being heated to reflux and maintained at reflux under nitrogen for 20-24 hours. When HPLC showed the reaction was complete, the reaction mixture was cooled to 45-55° C. in 30 minutes, the two phases were separated, and the aqueous phase was discarded. To the organic phase was added n-heptane (125 mL) in 30 minutes at 45-55° C. The resulting mixture was slowly cooled to ambient temperature in one hour and stirred at ambient temperature for an additional 2 hours. The solids were collected by filtration, washed with n-heptane (100 mL), and dried under vacuum at 50° C. with nitrogen sweeping to constant weight to afford tert-butyl 3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-(cyanomethyl)-azetidine-1-carboxylate (5, 96.8 g, 97.7 g theoretical, 99%) as a pale yellow solid. For 5: 1H NMR (400 MHz, DMSO-d6) δ 8.89 (s, 1H), 8.68 (s, 1H), 8.44 (s, 1H), 7.60 (d, J=3.5 Hz, 1H), 7.06 (d, J=3.6 Hz, 1H), 4.62-4.41 (m, 2H), 4.31-4.12 (m, 2H), 3.67 (s, 2H), 1.39 (s, 9H) ppm; 13C NMR (101 MHz, DMSO-d6) δ 155.40, 152.60, 150.63, 149.15, 139.76, 129.53, 127.65, 122.25, 116.92, 113.21, 99.71, 79.45, 58.34 (br), 56.80, 27.99, 26.83 ppm; C19H21N7O2 (MW 379.4), LCMS (EI) m/e 380 (M++H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:9]([NH:11][NH2:12])=[O:10])=[N:4][C:5]([Br:8])=[CH:6][N:7]=1.[Br:13][CH2:14][C:15]1[CH:23]=[CH:22][C:18]([C:19](O)=O)=[CH:17][CH:16]=1.BrP(Br)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CCN(C(C)C)C(C)C>CC#N>[Br:8][C:5]1[N:4]=[C:3]([C:9]2[O:10][C:19]([C:18]3[CH:22]=[CH:23][C:15]([CH2:14][Br:13])=[CH:16][CH:17]=3)=[N:12][N:11]=2)[C:2]([NH2:1])=[N:7][CH:6]=1
Reactant: NNC(=O)c1nc(Br)cnc1N
Reactant: O=C(O)c1ccc(CBr)cc1
Agent: BrP(Br)(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: Nc1ncc(Br)nc1-c1nnc(-c2ccc(CBr)cc2)o1
Reaction time: 1 h
Yield: 67.9 %

Procedure:
To a suspension of 3-amino-6-bromo-pyrazine-2-carbohydrazide (200 mg, 0.86 mmol) and 4-(bromomethyl)benzoic acid (185 mg, 0.86 mmol) in MeCN (4 mL) at room temperature was added dibromo(triphenyl)phosphorane (1.7 g, 4.14 mmol) and the resulting reaction mixture was stirred for 1 h. The reaction mixture was diluted with acetonitrile (2 mL) and DIPEA (668 mg, 900 μL, 5.2 mmol) was added dropwise and the suspension was allowed to stir overnight. The suspension was filtered, washed with CH3CN and hexane, and air dried to provide 5-bromo-3-(5-(4-(bromomethyl)phenyl)-1,3,4-oxadiazol-2-yl)pyrazin-2-amine (240 mg, 68%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 8.45 (s, 1H), 8.11 (d, J=8.1 Hz, 2H), 7.72 (d, J=8.2 Hz, 2H), 4.82 (s, 2H). LC/MS m/z 412.1 [M+H]+.
Reaction SMILES: NN.CC([N:7]([CH2:11][CH2:12][CH:13]([N:21]1C(=O)C2C(=CC=CC=2)C1=O)[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:8](=[O:10])[O-:9])(C)C>C1COCC1.CO>[NH2:21][CH:13]([CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[CH2:12][CH2:11][NH:7][C:8](=[O:10])[O:9][C:15]([CH3:20])([CH3:16])[CH3:14]
Reactant: CC(C)(C)N(CCC(Cc1ccccc1)N1C(=O)c2ccccc2C1=O)C(=O)[O-]
Agent: NN
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)NCCC(N)Cc1ccccc1
Temperature: 50 °C
Reaction time: 12 h
Yield: 198.6 %

Procedure:
NH2NH2 (577 uL, 18.4 mmol) was added to a THF/MeOH (1:1, 10 mL) solution of 1,1-dimethylethyl[3-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-4-phenylbutyl]carbamate (725 mg, 1.84 mmol) and stirred at 50° C. in a sealed system. After 12 hours, the solids were filtered, washing with methanol. The filtrate was concentrated and purified by column chromatography using 5% MeOH in CHCl3 containing 1% NH4OH to give the title compound (483 mg, quant.) as a white solid: LC-MS (ES) m/z=264 (M+H)+.
Reaction SMILES: [Cl-].[Na+].[Cl:3][C:4]1[N:9]=[C:8]([NH:10][CH2:11][CH:12]2[O:16][CH2:15][CH2:14][O:13]2)[C:7]([N+:17]([O-])=O)=[CH:6][CH:5]=1>C(O)C.O.[Fe]>[NH2:17][C:7]1[C:8]([NH:10][CH2:11][CH:12]2[O:16][CH2:15][CH2:14][O:13]2)=[N:9][C:4]([Cl:3])=[CH:5][CH:6]=1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1NCC1OCCO1
Agent: [Fe]
Agent: [Cl-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Nc1ccc(Cl)nc1NCC1OCCO1
Reaction time: 0.33 h
Yield: 73.5 %

Procedure:
To a suspension of 13 g of iron powder in 650 mL of ethanol and 350 mL of water, 14 g of sodium chloride was added, and the mixture was heated under reflux while stirring for 20 minutes. Thereto was added 10 g of 6-chloro-N-(1,3-dioxolan-2-ylmethyl)-3-nitropyridin-2-amine at 65° C., and the mixture was heated under reflux while stirring for 30 minutes. The insoluble substance was filtered off, the solvent was distilled off to be 300 mL under reduced pressure, ethyl acetate was added thereto, the organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The organic layer and the extract were combined, the resultant solution was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The resultant residue was purified by basic silica gel column chromatography using an eluent of ethyl acetate to obtain 6.5 g of 3-amino-6-chloro-2-(1,3-dioxolan-2-ylmethyl)aminopyridine as a light purple solid.
Reaction SMILES: [F:1][C:2]1[CH:28]=[CH:27][CH:26]=[CH:25][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[C:7]([C:14]2[N:19]=[C:18]3[NH:20][CH:21]=[N:22][C:23](=[O:24])[C:17]3=[CH:16][N:15]=2)=[N:6]1.Cl[C:30]1C(C(OC)=O)=CN=C(C2C3C(=NC=CC=3)N(CC3C=CC=CC=3F)N=2)N=1.Cl.C(N)(=N)C.C(N(CC)CC)C>>[F:1][C:2]1[CH:28]=[CH:27][CH:26]=[CH:25][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[C:7]([C:14]2[N:19]=[C:18]3[NH:20][C:21]([CH3:30])=[N:22][C:23](=[O:24])[C:17]3=[CH:16][N:15]=2)=[N:6]1
Reactant: O=c1nc[nH]c2nc(-c3nn(Cc4ccccc4F)c4ncccc34)ncc12
Reactant: COC(=O)c1cnc(-c2nn(Cc3ccccc3F)c3ncccc23)nc1Cl
Agent: CC(=N)N
Agent: Cl
Solvent: CCN(CC)CC
Product: Cc1nc(=O)c2cnc(-c3nn(Cc4ccccc4F)c4ncccc34)nc2[nH]1

Procedure:
In analogy to the preparation process for 7-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]pyrimido[4,5-d]pyrimidin-4(1H)-one (example 152), proceeding from 100 mg (0.25 mmol) of methyl 4-chloro-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]pyrimidine-5-carboxylate (example 106A), 47.5 mg (0.50 mmol) of acetamidine hydrochloride and 175 μl (1.26 mmol) of triethylamine, 32 mg (31% of theory) of the target compound were obtained.
Reaction SMILES: [CH:1]([N:14]1[CH2:17][CH:16]([NH:18][NH:19]C(OC(C)(C)C)=O)[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:27]>O1CCOCC1>[ClH:27].[CH:1]([N:14]1[CH2:15][CH:16]([NH:18][NH2:19])[CH2:17]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)NNC1CN(C(c2ccccc2)c2ccccc2)C1
Agent: Cl
Solvent: C1COCCO1
Product: NNC1CN(C(c2ccccc2)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
The title compound was prepared as described in WO2010079443A1. To a mixture of tert-butyl 2-(1-benzhydrylazetidin-3-yl)hydrazinecarboxylate (16 g) and 4 N HCl in dioxane (10 mL/1 g) was stirred at 25° C. for 3 h. The solvent was completely evaporated off to obtain a crude product. The crude product was washed with diethyl ether to obtain a white solid, 1-benzhydryl-3-hydrazinylazetidine hydrochloride (15.5 g). This was used as is for the next step.
Reaction SMILES: C([Li])CCC.[CH2:6]([C:9]1[C:10]([F:16])=[N:11][CH:12]=[CH:13][C:14]=1I)[CH:7]=[CH2:8].[CH3:17][CH2:18][C:19](=[O:22])[CH2:20][CH3:21].O>CCCCCC.C1COCC1>[CH2:6]([C:9]1[C:10]([F:16])=[N:11][CH:12]=[CH:13][C:14]=1[C:19]([OH:22])([CH2:20][CH3:21])[CH2:18][CH3:17])[CH:7]=[CH2:8]
Reactant: C=CCc1c(I)ccnc1F
Reactant: CCC(=O)CC
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: O
Solvent: C1CCOC1
Product: C=CCc1c(C(O)(CC)CC)ccnc1F
Temperature: -75 °C
Reaction time: 6 h

Procedure:
27 ml (43.3 mmol) of 1.6M butyllithium in hexane are added, at −75° C., to a solution of 11.4 g (43.3 mmol) of 3-allyl-2-fluoro-4-iodopyridine (prepared according to the process described in J.O.C., 1993, 58, pp.7832) in 250 ml of THF. After 30 minutes' stirring at −75° C. a solution of 4.6 ml of 3-pentanone in 100 ml of THF is added dropwise. The reaction mixture is stirred for 6 hours at −75° C. After returning to room temperature, the mixture is hydrolysed with 100 ml of water and extracted with ethyl acetate. The organic phase is dried, concentrated and purified by chromatography over silica (eluant:cyclohexane/ethyl acetate 8/2) to yield the expected product.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[NH:19][N:18]=[N:17][N:16]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:20]CN(C(C)C)C(C)C.CI>CN1C(=O)CCC1.O>[CH3:20][N:18]1[N:17]=[N:16][C:15]([C:12]2[CH:13]=[CH:14][C:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[CH:10][CH:11]=2)=[N:19]1
Reactant: CCN(C(C)C)C(C)C
Reactant: c1ccc(COc2ccc(-c3nnn[nH]3)cc2)cc1
Solvent: CI
Solvent: CN1CCCC1=O
Solvent: O
Product: Cn1nnc(-c2ccc(OCc3ccccc3)cc2)n1
Temperature: 18 °C

Procedure:
To a stirred solution containing 337 g of the tetrazole and 362 mL of DIPEA in 1 L of NMP cooled to 18° C. under N2 was added dropwise over 1.5 hrs 200 g of methyl iodide in 170 mL NMP. After stirring an additional hour at room temperature, the reaction mixture was diluted with 340 mL of water and the reaction mixture was diluted with 340 mL of water and cooled to 18° C. The resulting solid was collected, washed with water, recrystallized from ethanol and dried in vacuo at 50° C. to give 232.3 g of 2-methyl-5-(4-benzyloxyphenyl)-2H-tetrazole.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[C:9]([C:11]([OH:13])=[O:12])[CH:8]=[CH:7][N:6]=1)(=[O:3])[CH3:2].Cl.[CH3:15]O>>[C:1]([NH:4][C:5]1[CH:10]=[C:9]([C:11]([O:13][CH3:15])=[O:12])[CH:8]=[CH:7][N:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1cc(C(=O)O)ccn1
Reactant: CO
Agent: Cl
Product: COC(=O)c1ccnc(NC(C)=O)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 84 %

Procedure:
To 2-(acetamido)pyridine-4-carboxylic acid (25 g, 139 mmol) was added a saturated solution of anhydrous hydrogen chloride in methanol (600 mL). The cloudy suspension was stirred for 16 h at RT and refluxed for 24 h. The resulting solution was concentrated, dissolved in chloroform, washed with saturated sodium bicarbonate, brine, dried (magnesium sulfate) and concentrated to give the title compound as a white solid (17.86 g, 84%). TLC Rf 0.55 (5% methanol/chloroform); 1H NMR (CDCl3) δ3.96 (3H, s), 4.80 (2H, s),7.12 (1H, J=5 Hz, d), 7.19 (1H, s), 8.10 (1H, d, J=5 Hz).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([C:14]([OH:16])=[O:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH2:23](Br)[CH:24]=[CH2:25].O>CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([C:14]([O:16][CH2:25][CH:24]=[CH2:23])=[O:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C=CCBr
Reactant: CC(C)(C)OC(=O)N1CCCC(C(=O)O)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C=CCOC(=O)C1CCCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 1-(tert-butoxycarbonyl)-3-piperidinecarboxylic acid (50.0 g) in N,N-dimethylformamide (500 ml) were added potassium carbonate (60.3 g) and allyl bromide (28.3 ml), and the mixture was stirred at room temperature for 3 hours. To the reaction mixture was added water (600 ml), and the mixture was extracted with ethyl acetate (600 ml). The organic layer was sequentially washed with water (600 ml) and saturated aqueous sodium chloride solution (400 ml). The separated aqueous layer was extracted with ethyl acetate (300 ml) again. The combined organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. To a solution of the resulting residue in n-hexane/ethyl acetate (4/1, 400 ml) was added silica gel (70 g), and the mixture was stirred at room temperature. The mixture was filtered, and the filtrate was concentrated under reduced pressure to give the titled compound (62.5 g).
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH:9]=[C:8]([C:11]2[CH:12]=[C:13]3[CH2:19][C@@:18]([CH3:26])([CH:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)[O:17][C:14]3=[CH:15][N:16]=2)[CH2:7][CH2:6]1)(=[O:4])=[O:3].Cl[C:28]1[N:33]=[CH:32][C:31]([Cl:34])=[CH:30][N:29]=1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[Cl:34][C:31]1[CH:30]=[N:29][C:28]([N:23]2[CH2:24][CH2:25][CH:20]([C@@:18]3([CH3:26])[O:17][C:14]4=[CH:15][N:16]=[C:11]([C:8]5[CH2:9][CH2:10][N:5]([S:2]([CH3:1])(=[O:3])=[O:4])[CH2:6][CH:7]=5)[CH:12]=[C:13]4[CH2:19]3)[CH2:21][CH2:22]2)=[N:33][CH:32]=1
Reactant: Clc1cnc(Cl)nc1
Reactant: C[C@@]1(C2CCNCC2)Cc2cc(C3=CCN(S(C)(=O)=O)CC3)ncc2O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: C[C@@]1(C2CCN(c3ncc(Cl)cn3)CC2)Cc2cc(C3=CCN(S(C)(=O)=O)CC3)ncc2O1

Procedure:
The title compound is prepared from (S)-5-(1-methanesulfonyl-1,2,3,6-tetrahydro-pyridin-4-yl)-2-methyl-2-piperidin-4-yl-2,3-dihydro-furo[2,3-c]pyridine (Intermediate 41; the configuration of the stereocenter is arbitrarily assigned) and 2,5-dichloro-pyrimidine in dimethylsulfoxide at 105° C. in the presence of potassium carbonate. LC (method 6): tR=1.78 min; Mass spectrum (ESI+): m/z=490 [M+H]+.
Reaction SMILES: N[C@H](C(O)=[O:11])CC1C=CC=CC=1.C1C(N)=NC(=O)N([C@@H]2O[C@H](COP(OCCCCCCCCCCCCCCCC(O)=O)(O)=O)[C@@H](O)[C@@H]2O)C=1.CC1(C)S[C@@H]2[C@H](NC([C@H](N)C3C=CC=CC=3)=O)C(=O)N2[C@H]1C(O)=O.C1[C@H](N)[C@@H](O[C@H]2O[C@H](CN)[C@@H](O)[C@H](O)[C@H]2O)[C@H](O)[C@@H]([O:96][C@H:97]2[O:102][C@H:101]([CH2:103][OH:104])[C@@H:100]([OH:105])[C@H:99](N)[C@H:98]2[OH:107])[C@@H]1N>>[O:104]=[CH:103][C@@H:101]([C@H:100]([C@@H:99]([C@@H:98]([CH2:97][OH:96])[OH:107])[OH:11])[OH:105])[OH:102]
Reactant: NC[C@H]1O[C@H](O[C@H]2[C@H](O)[C@@H](O[C@H]3O[C@H](CO)[C@@H](O)[C@H](N)[C@H]3O)[C@H](N)C[C@@H]2N)[C@H](O)[C@@H](O)[C@@H]1O
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Agent: CC1(C)S[C@@H]2[C@H](NC(=O)[C@H](N)c3ccccc3)C(=O)N2[C@H]1C(=O)O
Agent: Nc1ccn([C@@H]2O[C@H](COP(=O)(O)OCCCCCCCCCCCCCCCC(=O)O)[C@@H](O)[C@@H]2O)c(=O)n1
Product: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO

Procedure:
Two strains (designated as WWQ51.1 and WSQ1) were constructed from the E. coli phenylalanine overproducing strain E. coli NST74 by transformation with pCA16 and pKSM-pdc1 and selection for ampicillin and kanamycin resistance, as described in Example 4. Since preliminary experiments showed similar patterns for both constructs, we chose strain WWQ51.1 for further studies.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4](=[O:14])[CH:5]([Cl:13])[C:6]1[CH:11]=[CH:10][C:9](F)=[CH:8][CH:7]=1.[F:16][C:17]([F:27])([F:26])C1C=C(C=CC=1)C=O.FC1C=CC(C=O)=CC=1>>[CH3:1][O:2][C:3](=[O:15])[C:4](=[O:14])[CH:5]([Cl:13])[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:17]([F:27])([F:26])[F:16])[CH:7]=1
Reactant: COC(=O)C(=O)C(Cl)c1ccc(F)cc1
Reactant: O=Cc1cccc(C(F)(F)F)c1
Agent: O=Cc1ccc(F)cc1
Product: COC(=O)C(=O)C(Cl)c1cccc(C(F)(F)F)c1

Procedure:
This compound was synthesised as 3-chloro-3-(4-fluoro-phenyl)-2-oxo-propionic acid methyl ester but using 3-trifluoromethylbenzaldehyde instead 4-fluorobenzaldehyde.
Reaction SMILES: [C:1]([NH:18][C@H:19]([C:28](O)=[O:29])[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=1)([O:3][CH2:4][CH:5]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]2[C:6]1=[CH:7][CH:8]=[CH:9][CH:10]=2)=[O:2].[NH2:31][CH2:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34].ON1C2N=CC=CC=2N=N1.CN1CCOCC1.C(Cl)CCl>C(Cl)Cl>[CH:16]1[C:17]2[CH:5]([CH2:4][O:3][C:1]([NH:18][C@@H:19]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=3)[C:28]([NH:31][CH2:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])=[O:29])=[O:2])[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[C:12]=2[CH:13]=[CH:14][CH:15]=1
Reactant: CC(C)(C)OC(=O)CN
Reactant: O=C(N[C@@H](Cc1ccc(O)cc1)C(=O)O)OCC1c2ccccc2-c2ccccc21
Agent: On1nnc2cccnc21
Solvent: CN1CCOCC1
Solvent: ClCCl
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)CNC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OCC1c2ccccc2-c2ccccc21

Procedure:
Following the procedure as described in Example 24, except using Fmoc-Tyrosine (4.97 g, 12.32 mmol), tert-butyl 2-aminoacetate, 1.00HCl (2.168 g, 12.94 mmol), 1-hydroxy-7-azabenzotriazole (0.503 g, 3.70 mmol), CH2Cl2 (125 mL), N-methylmorpholine (1.490 mL, 13.55 mmol), EDC (2.61 g, 13.61 mmol) and stirring at room temp for 18 h, 6.76 g (quantitative yield) of the title compound is isolated as a white, sticky solid. Purification is done by BIOTAGE® Silica gel chromatography on a 90 g Thompson Single Step silica cartridge using a linear gradient from 100% CH2Cl2 to 50% EtOAc/CH2Cl2 over 10 column volumes. LC/MS (Condition A): ret. T=3.98 min, (M+H)+ 517.27. 1H NMR (500 MHz, methanol-d4) δ ppm 7.80 (2 H, d, J=7.63 Hz), 7.58 (2 H, d, J=7.32 Hz), 7.25-7.45 (4 H, m), 7.09 (2 H, d, J=7.93 Hz), 6.71 (2 H, d, J=8.24 Hz), 4.36 (2 H, dd, J=9.92, 6.26 Hz), 4.15-4.25 (2 H, m), 3.84 (2 H, d, J=1.53 Hz), 3.11 (2 H, dd, J=13.89, 4.73 Hz), 2.79 (2 H, dd, J=13.89, 9.92 Hz), 1.48 (9 H, s).