Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4](Br)[C:3]=1[Br:9].[CH3:10][C:11]([CH3:17])=[C:12]1[CH:16]=[CH:15][CH:14]=[CH:13]1.C([Li])CCC.[Cl-].[NH4+]>C1(C)C=CC=CC=1>[Br:9][C:3]1[CH:2]=[CH:7][CH:6]=[C:5]2[C:4]=1[CH:13]1[C:12](=[C:11]([CH3:17])[CH3:10])[CH:16]2[CH:15]=[CH:14]1
Reactant: Brc1cccc(Br)c1Br
Reactant: CC(C)=C1C=CC=C1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: Cc1ccccc1
Product: CC(C)=C1C2C=CC1c1c(Br)cccc12
Reaction time: 0.17 h
Yield: 66 %

Procedure:
To a stirred solution of 1,2,3-tribromo-benzene (4.34 g, 13.8 mmol) and 6,6-dimethylfulvene (2.38 g, assay 92.6%, 20.7 mmol) in dry toluene (60 ml) under a nitrogen atmosphere, 5.5 ml of a 2.5M toluene solution of n-butyllithium (14.5 mmol) were added dropwise at −5 to 0° C. within 10 minutes. After a further 10 minutes at 0° C. and 2 hours at ambient temperature, the reaction mixture was poured onto a saturated aqueous solution of ammonium chloride, extracted with ethyl acetate, washed with brine and water, dried over sodium sulphate and evaporated. Purification of the crude material on silca gel in hexane afforded 2.38 g of the desired product as a yellow oil (assay 84% by g.l.c., 55% yield). This reaction is also disclosed in WO 2007/068417.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][CH:4]=1.[ClH:11].[CH3:12][OH:13]>>[ClH:11].[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([C:7](=[NH:8])[O:13][CH3:12])=[CH:5][CH:4]=1
Reactant: CO
Reactant: COc1ccc(C#N)cc1
Agent: Cl
Product: COC(=N)c1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
4-methoxybenzonitrile (12.5 g, 91.1 mmol) was dissolved in methanol (140 mL), through this cooled (−5° C.) solution gaseous HCl was bubbled for about 3 hours. The reaction mixture was then stirred, in a closed flask, at r.t. for 24 hours. Then the excess HCl was stripped by bubbling nitrogen and the resulting solution was concentrated, the residue was taken up with TBME (100 mL) and stirred for 30 min., then filtrated and dried to provide the title product as a colourless powder 19.0 g (quantitative). C9H11NO2.HCl, MW: 201.69 1H-NMR (300 MHz, D2O) ppm: 4.20 (s, 3H), 6.9 (m, 1H); 7.65 (m, 1H); 8.40 (m, 1H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH2:9])[C:5]([Cl:8])=[N:6][CH:7]=1.CC1(C)C(C)(C)OB([C:18]2[CH:30]=[CH:29][C:21]3[N:22]=[C:23]([NH:25][C:26](=[O:28])[CH3:27])[S:24][C:20]=3[CH:19]=2)O1.C(=O)([O-])[O-].[K+].[K+].O>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:9][C:4]1[CH:3]=[C:2]([C:18]2[CH:30]=[CH:29][C:21]3[N:22]=[C:23]([NH:25][C:26](=[O:28])[CH3:27])[S:24][C:20]=3[CH:19]=2)[CH:7]=[N:6][C:5]=1[Cl:8]
Reactant: Nc1cc(Br)cnc1Cl
Reactant: CC(=O)Nc1nc2ccc(B3OC(C)(C)C(C)(C)O3)cc2s1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CC(=O)Nc1nc2ccc(-c3cnc(Cl)c(N)c3)cc2s1
Temperature: 25 °C
Reaction time: 3 h
Yield: 32.5 %

Procedure:
5-bromo-2-chloropyridin-3-amine (1.00 g, 4.82 mmol), N-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]thiazol-2-yl)acetamide (1.73 g, 5.45 mmol), tetrakis(triphenylphosphine)palladium(0) (0.836 g, 0.723 mmol) and potassium carbonate (2.20 g, 15.9 mmol) was suspended in 1,4-dioxane (25 ml) with water (2.5 ml). Argon was bubbled through the suspension for about 30 seconds. The flask was fitted with a reflux condenser and placed into a heat bath (100° C.). The mixture was allowed to stir under inert atmosphere for 3 hours. The progress of the reaction was monitored by LC/MS, which showed desired product. The mixture was allowed to cool to ambient temperature. The mixture was diluted with DCM and saturated sodium bicarbonate solution. The organic layer was extracted with DCM (3×25 ml). Combined organics, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was diluted with ethyl acetate and the precipitate was collected by filtration. The precipitate was washed with hexanes to give N-(6-(5-amino-6-chloropyridin-3-yl)benzo[d]thiazol-2-yl)acetamide (0.500 g, 32.5% yield) as a brown crystalline solid. MS (ESI pos. ion) m/z: 319 (MH+). Calc'd exact mass for C14H11ClN4OS: 318. 1H NMR (400 MHz, DMSO-d6): 2.22 (s, 3H), 5.66 (s, 2H), 7.42 (s, 1H), 7.65 (d, J=8.53 Hz, 1H), 7.81 (d, J=8.53 Hz, 1H), 7.94 (s, 1H), 8.24 (s, 1H), 12.41 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH:7]([NH:12][S:13]([C:16]3[CH:21]=[C:20]([F:22])[CH:19]=[C:18]([F:23])[CH:17]=3)(=[O:15])=[O:14])[CH2:8][NH:9]2)=[CH:4][CH:3]=1.Cl[C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=1)[CH:28]=O>>[CH2:28]([N:9]1[C:10]2[C:5](=[CH:4][CH:3]=[C:2]([Cl:1])[CH:11]=2)[CH2:6][CH:7]([NH:12][S:13]([C:16]2[CH:21]=[C:20]([F:22])[CH:19]=[C:18]([F:23])[CH:17]=2)(=[O:15])=[O:14])[CH2:8]1)[C:27]1[CH:30]=[CH:31][CH:32]=[CH:25][CH:26]=1
Reactant: O=S(=O)(NC1CNc2cc(Cl)ccc2C1)c1cc(F)cc(F)c1
Reactant: O=Cc1cccc(Cl)c1
Product: O=S(=O)(NC1Cc2ccc(Cl)cc2N(Cc2ccccc2)C1)c1cc(F)cc(F)c1

Procedure:
The title compound was prepared from 152C and 3-chlorobenzaldehyde by procedures analogous to those described in Example 22A. HPLC: 99% at 4.20 min (retention time) (Conditions: Phenom Prime S5, C18 (4.6×50 mm); Eluted with 0% to 100% B, 4 min gradient (A=90% H2O−10% MeOH−0.1% TFA and B=10% H2O−90% MeOH−0.1% TFA); Flow rate at 4.0 mL/min, UV detection at 220 nm). MS (ES): m/z 484 [M+H]+.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([C:13]2[C:14]([NH:21][CH2:22][C:23]3[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=3)=[N:15][C:16](SC)=[N:17][CH:18]=2)=[O:12])=[CH:6][CH:5]=1)([CH3:3])[CH3:2]>CCO.[Ni]>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]([NH:10][C:11]([C:13]2[C:14]([NH:21][CH2:22][C:23]3[CH:24]=[CH:25][N:26]=[CH:27][CH:28]=3)=[N:15][CH:16]=[N:17][CH:18]=2)=[O:12])=[CH:8][CH:9]=1)([CH3:3])[CH3:2]
Reactant: CSc1ncc(C(=O)Nc2ccc(C(C)C)cc2)c(NCc2ccncc2)n1
Agent: [Ni]
Solvent: CCO
Product: CC(C)c1ccc(NC(=O)c2cncnc2NCc2ccncc2)cc1

Procedure:
A mixture of N-[4-(isopropyl)phenyl]{2-methylthio-4-[(4-pyridylmethyl)amino]pyrimidin-5-yl}carboxamide (50 mg, 0.13 mmol, Step B) and Raney-Ni in EtOH (10 mL) was heated at reflux for 2 h. The resulting mixture was filtered, and the filtrate was concentrated to give the titled compound. MS (ES+): 348 (M+H)+; (ES−): 346 (M−H)−. Calc'd C20H21N5O−347.42.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:14]2[CH:15]=[C:16]3[C:22]([C:23]4[CH:24]=[N:25][N:26]([CH2:28][C:29]5[CH:34]=[CH:33][CH:32]=[C:31]([F:35])[CH:30]=5)[CH:27]=4)=[CH:21][N:20]([S:36]([C:39]4[CH:45]=[CH:44][C:42]([CH3:43])=[CH:41][CH:40]=4)(=[O:38])=[O:37])[C:17]3=[N:18][CH:19]=2)[CH:5]=[N:6][C:7]=1[N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1.[CH3:46][C@H:47]1[CH2:49][O:48]1.CCN(C(C)C)C(C)C>C(O)C>[F:1][C:2]1[C:7]([N:8]2[CH2:13][CH2:12][N:11]([CH2:46][C@@H:47]([OH:48])[CH3:49])[CH2:10][CH2:9]2)=[N:6][CH:5]=[C:4]([C:14]2[CH:15]=[C:16]3[C:22]([C:23]4[CH:24]=[N:25][N:26]([CH2:28][C:29]5[CH:34]=[CH:33][CH:32]=[C:31]([F:35])[CH:30]=5)[CH:27]=4)=[CH:21][N:20]([S:36]([C:39]4[CH:45]=[CH:44][C:42]([CH3:43])=[CH:41][CH:40]=4)(=[O:37])=[O:38])[C:17]3=[N:18][CH:19]=2)[CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4cnc(N5CCNCC5)c(F)c4)cnc32)cc1
Reactant: C[C@H]1CO1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4cnc(N5CCN(C[C@H](C)O)CC5)c(F)c4)cnc32)cc1
Yield: 97.3 %

Procedure:
Using similar reaction conditions as described in step-i of example-82A, 5-(5-fluoro-6-(piperazin-1-yl)pyridin-3-yl)-3-(1-(3-fluorobenzyl)-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine (product of step 1 of example 179) (127 mg, 0.203 mmol) was alkylated using (S)-2-methyloxirane (23 mg, 0.406 mmol), DIPEA (105 mg, 0.812 mmol) and ethanol (5 mL) to get 135 mg (97.8% yield) of the titled compound. MS: m/z=684.7 (M+1).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:12]=[CH:11][C:10]([C:13](Cl)=[O:14])=[CH:9][N:8]=1.[NH2:16][N:17]1[C:25]2[C:20](=[C:21]([F:26])[CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18]1.C([O-])([O-])=O.[K+].[K+].O>CCOC(C)=O>[F:26][C:21]1[CH:22]=[CH:23][CH:24]=[C:25]2[C:20]=1[CH:19]=[CH:18][N:17]2[NH:16][C:13]([C:10]1[CH:9]=[N:8][C:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)=[N:12][CH:11]=1)=[O:14]
Reactant: Nn1ccc2c(F)cccc21
Reactant: O=C(Cl)c1cnc(-c2ccccn2)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(Nn1ccc2c(F)cccc21)c1cnc(-c2ccccn2)nc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 17.3 %

Procedure:
A suspension of 2-(pyridine-2-yl)-pyrimidine-5-carbonyl chloride (0.44 g) in EtOAc (20 mL) is added portion wise to a mixture of 1-amino-4-fluoroindole (0.30 g) and K2CO3 (0.276 g) in EtOAc (10 mL)/water (20 mL) and the resulting mixture is stirred at rt for 24 h. The aqueous phase is separated and extracted twice with EtOAc. The combined organic layer is washed with water and brine, dried (MgSO4), filtered and concentration in vacuo. The residue is purified by silica gel chromatography eluting with EtOAc to afford 2-(pyridin-2-yl)pyrimidine-5-carboxylic acid-(4-fluoroindol-1-yl)amide (0.115 g, 17%) as a solid. MS: 334 (M+H); 1H NMR (300 MHz, DMSO-d6): δ 6.65 (d, 1H), 6.89-6.95 (q, 1H), 7.16-7.23 (m, 1H), 7.32-7.35 (d, 1H), 7.57 (d, 1H), 7.57-7.64 (m, 1H), 8.02-8.08 (t, 1H), 8.50-8.52 (d, 1H), 8.82-8.83 (d, 1H), 9.49 (s, 2H), 12.30 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[OH:12])[C:5]([O:7][CH3:8])=[O:6].Br[CH:14]1[CH2:17][CH2:16][CH2:15]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[O:12][CH:14]1[CH2:17][CH2:16][CH2:15]1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: BrC1CCC1
Reactant: COC(=O)c1ccc(O)c(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc(OC2CCC2)c(Br)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 40.3 %

Procedure:
A mixture of methyl 3-bromo-4-hydroxybenzoate (Description 64, 2.3 g, 10 mmol), bromocyclobutane (2.0 g, 15 mmol) and potassium carbonate (2.42 g, 17.5 mmol) in DMF (25 ml) was stirred at room temperature for 3 days then at 70° C. for 6 h. The mixture was cooled, diluted with water (150 ml) and extracted with ethyl acetate (4×25 ml). The combined organic fractions were washed with aqueous sodium hydroxide (1M, 25 ml), dried (MgSO4), and the solvent was evaporated under reduced pressure to give the title compound as a gum (1.15 g). 1H NMR (CDCl3) δ 1.66-1.77 (1 H, m), 1.88-1.93 (1 H, m), 2.22-2.31 (2 H, m), 2.46-2.60 (2 H, m), 3.89 (3 H, s), 4.75 (1 H, app. pent, J 7.0 Hz), 6.74 (1 H, d, J 8.6 Hz), 7.91 (1 H, dd, J 8.6, 2.1 Hz), and 8.23 (1 H, d, J 2.1 Hz).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1.[CH2:18]([O:20][CH2:21][C:22](O)=[O:23])[CH3:19]>>[CH2:18]([O:20][CH2:21][C:22]([NH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1)=[O:23])[CH3:19]
Reactant: CCOCC(=O)O
Reactant: CN1CCC(c2c[nH]c3ccc(N)cc23)CC1
Product: CCOCC(=O)Nc1ccc2[nH]cc(C3CCN(C)CC3)c2c1
Yield: 96.4 %

Procedure:
Beginning with 12.0 mg (0.05 mMol) 5-amino-3-(1-methylpiperidin-4-yl)-1H-indole and 11.0 μL (0.10 mMol) ethoxyacetic acid, 15.2 mg (97%) of the title compound were recovered.
Reaction SMILES: C(O)(=O)C.C(O)(=O)C.C(O)(=O)C.[CH3:13][C:14]1[N:19]=[C:18]([NH2:20])[N:17]=[C:16]([NH2:21])[C:15]=1[N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1.F[C:29]1[CH:34]=[CH:33][C:32]([S:35]([N:38]([CH3:40])[CH3:39])(=[O:37])=[O:36])=[CH:31][CH:30]=1.[F-].[K+].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[NH2:20][C:18]1[N:17]=[C:16]([NH2:21])[C:15]([N:22]2[CH2:27][CH2:26][N:25]([C:29]3[CH:30]=[CH:31][C:32]([S:35]([N:38]([CH3:40])[CH3:39])(=[O:36])=[O:37])=[CH:33][CH:34]=3)[CH2:24][CH2:23]2)=[C:14]([CH3:13])[N:19]=1
Reactant: CN(C)S(=O)(=O)c1ccc(F)cc1
Reactant: Cc1nc(N)nc(N)c1N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [F-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CC(=O)O
Product: Cc1nc(N)nc(N)c1N1CCN(c2ccc(S(=O)(=O)N(C)C)cc2)CC1
Temperature: 120 °C
Yield: 33.2 %

Procedure:
A mixture of 10.4 g (0.05 mole) of 6-methyl-5-(1-piperazinyl)-2,4-pyrimidinediamine triacetate, 10.1 g (0.05 mole) of 4-fluoro-N,N-dimethylbenzenesulfonamide, 6.4 g (0.055 mole) of anhydrous potassium fluoride, and 27.6 g (0.2 mole) of powdered potassium carbonate in 100 ml of dimethylsulfoxide was heated at 120° C. for four hours. The reaction mixture was cooled and poured into 300 ml of ice water. The solid was collected and washed with ml of water. Recystallization from N,N-dimethylformamide gave 6.5 g of the product as an off-white solid, mp 301°-304° C.
Reaction SMILES: CC(N=NC(C#N)(C)C)(C#N)C.C1C(=O)N(Br)C(=[O:16])C1.[F:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[O:46][C:31]3=[N:32][CH:33]=[C:34]([C:36]4[CH:37]=[C:38]([CH:43]=[CH:44][CH:45]=4)[C:39]([O:41][CH3:42])=[O:40])[CH:35]=[C:30]3[C:29]=2[CH3:47])=[CH:24][CH:23]=1.C[N+]1([O-])CCOCC1>C(Cl)(Cl)(Cl)Cl.CCOC(C)=O>[F:21][C:22]1[CH:23]=[CH:24][C:25]([C:28]2[O:46][C:31]3=[N:32][CH:33]=[C:34]([C:36]4[CH:37]=[C:38]([CH:43]=[CH:44][CH:45]=4)[C:39]([O:41][CH3:42])=[O:40])[CH:35]=[C:30]3[C:29]=2[CH:47]=[O:16])=[CH:26][CH:27]=1
Reactant: COC(=O)c1cccc(-c2cnc3oc(-c4ccc(F)cc4)c(C)c3c2)c1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: C[N+]1([O-])CCOCC1
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Product: COC(=O)c1cccc(-c2cnc3oc(-c4ccc(F)cc4)c(C=O)c3c2)c1
Temperature: 76 °C
Reaction time: 2 h
Yield: 20.2 %

Procedure:
AIBN (22.2 mg, 0.135 mmol) was added to a stirring solution of NBS (88 mg, 0.49 mmol) and methyl 3-(2-(4-fluorophenyl)-3-methylfuro[2,3-b]pyridin-5-yl)benzoate (163 mg, 0.451 mmol) in CCl4 (40 mL) and was heated to 76° C. The mixture was allowed to stir for 2 hours. The reaction was concentrated and diluted with DMSO (1 mL) and treated with NMO (63 mg, 0.54 mmol) and subjected to MW irradiation (150° C.) for 10 min. The mixture was diluted with EtOAc and washed with 10% NaHSO4 2× followed by H2O and Brine. The organic phase was dried over Na2SO4, filtered and concentrated and was purified on silica gel (Biotage, EtOAc/hexanes gradient, fraction collection at λ=254 nm) to to give the expected product methyl 3-(2-(4-fluorophenyl)-3-formylfuro[2,3-b]pyridin-5-yl)benzoate (34 mg, 0.091 mmol, 20% yield) consistent by LCMS and NMR. 1H NMR (500 MHz, DMSO-d6) δ ppm 10.31 (1H, s), 8.79 (1H, d, J=2.44 Hz), 8.74 (1H, d, J=2.44 Hz), 8.28 (1H, s), 8.16-8.25 (2H, m), 8.00-8.13 (2H, m), 7.72 (1H, t, J=7.78 Hz), 7.49-7.57 (2H, m), 3.92 (3H, s). LC-MS retention time: 1.72 min; m/z (MH+): 376. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Waters XBridge 5u C18 4.6×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 5% acetonitrile/95% H2O/10 mM ammonium acetate and solvent B was 5% H2O/95% acetonitrile/10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode.
Reaction SMILES: FC(F)(F)C(O)=O.[CH:8]([N:11]1[C:15]([C:16]2[N:25]=[C:24]3[N:18]([CH2:19][CH2:20][O:21][C:22]4[CH:29]=[C:28]([CH:30]5[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]5)[CH:27]=[CH:26][C:23]=43)[CH:17]=2)=[N:14][CH:13]=[N:12]1)([CH3:10])[CH3:9].Br[CH2:37][C:38]([NH2:40])=[O:39]>>[CH:8]([N:11]1[C:15]([C:16]2[N:25]=[C:24]3[C:23]4[CH:26]=[CH:27][C:28]([CH:30]5[CH2:35][CH2:34][N:33]([CH2:37][C:38]([NH2:40])=[O:39])[CH2:32][CH2:31]5)=[CH:29][C:22]=4[O:21][CH2:20][CH2:19][N:18]3[CH:17]=2)=[N:14][CH:13]=[N:12]1)([CH3:10])[CH3:9]
Reactant: NC(=O)CBr
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(C3CCNCC3)cc1OCC2
Solvent: O=C(O)C(F)(F)F
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(C3CCN(CC(N)=O)CC3)cc1OCC2

Procedure:
Following the procedure for 143, 2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-8-piperidin-4-yl-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene trifluoroacetic acid salt was reacted with 2-bromo acetamide to give 226 as a white solid. 1H NMR δ (ppm) (DMSO-d): 8.27 (1 H, d, J=8.27 Hz), 7.84 (2 H, d, J=2.70 Hz), 7.15 (1 H, s), 7.06 (1 H, s), 7.01 (1 H, d, J=8.43 Hz), 6.87 (1 H, s), 5.87-5.78 (1 H, m), 4.44 (4 H, d, J=6.92 Hz), 2.90-2.78 (4 H, m), 2.15-2.06 (2 H, m), 1.68 (5 H, s), 1.42 (6 H, d, J=6.59 Hz). LCMS: RT=2.57 min, M+H+=436
Reaction SMILES: [NH:1](C(OCC1C=CC=CC=1)=O)[C@H:2]([C:26]([O:28]CC1C=CC=CC=1)=[O:27])[CH2:3][CH2:4][C:5]([NH:7][C@H:8]([C:12]([NH:14][CH2:15][C:16]([O:18]CC1C=CC=CC=1)=[O:17])=[O:13])[CH:9]([CH3:11])[CH3:10])=[O:6].O>C(O)C.[Pd]>[NH2:1][C@H:2]([C:26]([OH:28])=[O:27])[CH2:3][CH2:4][C:5]([NH:7][C@H:8]([C:12]([NH:14][CH2:15][C:16]([OH:18])=[O:17])=[O:13])[CH:9]([CH3:11])[CH3:10])=[O:6]
Reactant: CC(C)[C@H](NC(=O)CC[C@H](NC(=O)OCc1ccccc1)C(=O)OCc1ccccc1)C(=O)NCC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Solvent: O
Product: CC(C)[C@H](NC(=O)CC[C@H](N)C(=O)O)C(=O)NCC(=O)O
Reaction time: 5 h

Procedure:
Z-Glu(Val-Gly-OBzl)-OBzl described above (6.20 g, 10.03 mmol) was suspended in ethanol (200 ml), 10% palladium/carbon (1.50 g) was added to the suspension, and a reduction reaction was performed under a hydrogen atmosphere at 55° C. for 5 hours. During the reaction, 100 ml in a total volume of water was gradually added. The catalyst was removed by filtration using a Kiriyama funnel, and the filtrate was concentrated under reduced pressure to a half volume. The reaction solution was further filtered through a membrane filter, and the filtrate was concentrated under reduced pressure. After the residue was dissolved in a small volume of water, ethanol was added to precipitate a crystal, and the crystal was collected by filtration and dried under reduced pressure to obtain γ-Glu-Val-Gly as a white powder (2.85 g, 9.40 mmol).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]([CH3:13])=[N:10][C:9]=2[C:14]([N:16]2[CH2:21][CH2:20][CH2:19][C@@H:18]([CH3:22])[C@@H:17]2[CH2:23][NH:24]C(=O)OC(C)(C)C)=[O:15])=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:24][CH2:23][C@H:17]1[C@H:18]([CH3:22])[CH2:19][CH2:20][CH2:21][N:16]1[C:14]([C:9]1[N:10]=[C:11]([CH3:13])[S:12][C:8]=1[C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1)=[O:15]
Reactant: Cc1nc(C(=O)N2CCC[C@@H](C)[C@@H]2CNC(=O)OC(C)(C)C)c(-c2ccc(F)cc2)s1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1nc(C(=O)N2CCC[C@@H](C)[C@@H]2CN)c(-c2ccc(F)cc2)s1
Yield: 60 %

Procedure:
To a solution of rac-trans-tert-butyl ((3-methylpiperidin-2-yl)methyl)carbamate (37 mg, 162 μmol) from the previous step in DMF was added DIPEA (85 μl, 486 μmol) followed by 5-(4-fluorophenyl)-2-methylthiazole-4-carboxylic acid (57 mg, 243 μmol) and HATU (123 mg, 324 μmol). The reaction was allowed to stir at rt for 15 h, and was then concentrated in vacuo to remove the DMF. The crude residue was taken up in EtOAc and washed with sat aq. NaHCO3, brine, dried (MgSO4), and concentrated. The crude residue was purified by chromatography on silica gel (EtOAc/hexanes) to give rac-trans-tert-butyl ((1-(5-(4-fluorophenyl)-2-methylthiazole-4-carbonyl)-3-methylpiperidin-2-yl)methyl)carbamate as a light yellow oil. To a solution of this carbamate in DCM was added TFA (1:1 v/v). The reaction was aged at rt. When analytical reverse-phase HPLC indicated disappearance of starting material, the reaction was concentrated in vacuo. The crude residue was taken up in EtOAc, and washed with satd. aq. NaHCO3, brine, dried (MgSO4), and concentrated to afford the title compound as a pale yellow oil (34 mg, 60%). MS (ESI) 348.2 (M+H).
Reaction SMILES: S(Cl)([Cl:3])=O.[CH2:5]([O:15][CH2:16][CH:17](O)[CH2:18][N:19]1[CH:23]=[CH:22][N:21]=[CH:20]1)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]>>[Cl:3][CH:17]([CH2:16][O:15][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[CH2:18][N:19]1[CH:23]=[CH:22][N:21]=[CH:20]1
Reactant: CCCCCCCCCCOCC(O)Cn1ccnc1
Reactant: O=S(Cl)Cl
Product: CCCCCCCCCCOCC(Cl)Cn1ccnc1

Procedure:
Thionyl chloride (5 ml.) and 1.6 g. of 1-[3'-(n-decyloxy)-2'-hydroxypropyl]imidazole are warmed gently for a period of 2 hours and the solution is then evaporated to dryness. The residue is dissolved in dichloromethane and rendered basic with aqueous potassium carbonate solution. The organic layer is separated, dried over magnesium sulfate and evaporated to yield 1-[2'-chloro-3'-(n-decyloxy)propyl]imidazole.
Reaction SMILES: [C:1]1([SH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:8]([O:13]C)(=[O:12])/[CH:9]=[CH:10]/[CH3:11].[OH-].[Na+]>CO.O.[Na]>[C:1]1([S:7][CH:10]([CH3:11])[CH2:9][C:8]([OH:13])=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Sc1ccccc1
Reactant: C/C=C/C(=O)OC
Agent: [Na+]
Agent: [Na]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(CC(=O)O)Sc1ccccc1
Temperature: 120 °C
Yield: 32.6 %

Procedure:
0.25 g of sodium in small pieces, in 50 ml (0.5 mol) of thiophenol, is heated to 90°-95° C whilst stirring, and 52.5 ml (0.55 mol) of methyl crotonate are added dropwise. The mixture is heated further for 1 hour at 120° C and 85 g (boiling point/5 mm Hg = 137°-138° C) of the resulting ester are distilled in vacuo. 53 g (0.25 mol) of this ester in solution in 200 ml of methanol are hydrolysed with 16 g (0.4 mol) of NaOH in 200 ml of water. The mixture is heated for 2 hours under reflux, the alcohol is evaporated in vacuo, the residue is taken up in water and the product is precipitated with concentrated HCl and extracted with ether. The extract is washed with water and dried, and 32 g (65%) of a white oil are obtained.
Reaction SMILES: [O-]CC.[Na+].[C:5]([O:13][CH2:14][CH3:15])(=[O:12])[CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8].[CH2:16]([O:23][C:24]([NH:26][CH2:27][CH2:28][CH2:29][CH2:30]Br)=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(O)C>[CH2:16]([O:23][C:24]([NH:26][CH2:27][CH2:28][CH2:29][CH2:30][CH:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[C:5]([O:13][CH2:14][CH3:15])=[O:12])=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CCOC(=O)CC(=O)OCC
Reactant: O=C(NCCCCBr)OCc1ccccc1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C(CCCCNC(=O)OCc1ccccc1)C(=O)OCC
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 83 %

Procedure:
An ethanol (130.2 ml) solution of sodium ethoxide (5.83 g) was added with diethyl malonate (13 ml) and stirred at room temperature for 5 minutes. This solution was added with an ethanol (55.8 ml) solution of the 1-benzyloxycarbonylamino-4-bromobutane (4.9 g) obtained in the above step (b), and stirred at 40° C. for 20 hours. The reaction system was concentrated under reduced pressure without any treatment, and the residue was added with saturated aqueous ammonium chloride, and then the organic substances were extracted with ethyl acetate. The organic layer was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (1.2 kg, hexane:ethyl acetate=2:1) to obtain diethyl 2-(4-benzyloxycarbonylaminobutyl)malonate (5.2 g, 83%).
Reaction SMILES: C[O-].[Na+].C[O:5][C:6](=O)[CH:7]([O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[O:19][CH3:20])[C:8](OC)=[O:9].Cl.[CH:23]([NH2:25])=[NH:24]>CO>[CH3:20][O:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[O:12][C:7]1[C:8]([OH:9])=[N:24][CH:23]=[N:25][C:6]=1[OH:5]
Reactant: N=CN
Reactant: COC(=O)C(Oc1ccccc1OC)C(=O)OC
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COc1ccccc1Oc1c(O)ncnc1O
Reaction time: 0.5 h
Yield: 86.7 %

Procedure:
At 5° C. 12.7 g of sodium methylate was added portionwise to a solution of 18.9 g of dimethyl-2-(o-methoxyphenoxy)malonate in 450 ml of methanol. Upon completion of the addition stirring was continued at room temperature for 30 min followed by the addition of 6 g of formamidine hydrochloride. The mixture was stirred at room temperature for 72 h. Eventually, the solvent was removed under reduced pressure and the remaining residue was suspended in diethyl ether. The solid material was filtered off and dissolved in 100 ml of water. The solution was acidified with conc. hydrochloric acid. A white precipitate formed. The precipitate was collected, washed with water and dried to give 15.1 g of 5-(o-methoxyphenoxy)-4,6-dihydroxy-pyrimidine (or a tautomer) as a white powder.