Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[CH3:9])=[CH:4][CH:3]=1.Cl[C:17]1[CH:18]=[CH:19][C:20]2[N:21]([C:23]([CH:26]([F:28])[F:27])=[N:24][N:25]=2)[N:22]=1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([N:10]2[CH2:11][CH2:12][N:13]([C:17]3[CH:18]=[CH:19][C:20]4[N:21]([C:23]([CH:26]([F:27])[F:28])=[N:24][N:25]=4)[N:22]=3)[CH2:14][CH2:15]2)[CH3:9])=[CH:4][CH:3]=1
Reactant: C[C@H](c1ccc(Br)cc1)N1CCNCC1
Reactant: FC(F)c1nnc2ccc(Cl)nn12
Product: C[C@H](c1ccc(Br)cc1)N1CCN(c2ccc3nnc(C(F)F)n3n2)CC1
Yield: 75 %

Procedure:
A mixture of (R)-1-[1-(4-bromophenyl)ethyl]piperazine and 6-chloro-3-difluoromethyl-[1,2,4]-triazolo[4,3-b]pyridazine was allowed to react by an analogous method to Example 269 to give 6-[4-[(1R)-1-(4-bromophenyl)ethyl]piperazin-1-yl]-3-(difluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine in 75% yield.
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][CH2:4][C@H:3]1[C:7]1[CH:8]=[C:9]([CH2:13][CH2:14][CH2:15][NH:16][C:17]([C@H:19]2[CH2:24][CH2:23][C@H:22]([NH:25]C(=O)OC(C)(C)C)[CH2:21][CH2:20]2)=[O:18])[CH:10]=[N:11][CH:12]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:25][C@H:22]1[CH2:21][CH2:20][C@H:19]([C:17]([NH:16][CH2:15][CH2:14][CH2:13][C:9]2[CH:10]=[N:11][CH:12]=[C:7]([C@@H:3]3[CH2:4][CH2:5][CH2:6][N:2]3[CH3:1])[CH:8]=2)=[O:18])[CH2:24][CH2:23]1
Reactant: CN1CCC[C@H]1c1cncc(CCCNC(=O)[C@H]2CC[C@H](NC(=O)OC(C)(C)C)CC2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN1CCC[C@H]1c1cncc(CCCNC(=O)[C@H]2CC[C@H](N)CC2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of tert-butyl {trans-4-[(3-{5-[(2S)-1-methylpyrrolidin-2-yl]pyridin-3-yl}propyl)carbamoyl]cyclohexyl}carbamate (preparation 13) (130 mg, 0.29 mmol) in DCM (3 mL) was treated with trifluoroacetic acid (1 mL). The resulting solution was stirred at ambient temperature for 2 hours after which time it was concentrated in vacuo. The residue was dissolved in MeOH and applied to an SCX-2 cartridge and eluted with MeOH followed by ammonia in MeOH (2M). The fractions containing product were concentrated in vacuo to give the title compound as a colourless gum (98 mg, 97%).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.I[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C([O-])(=O)C.[K+]>CN(C)C(=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:7]1([C:5]2[S:1][CH:2]=[N:3][CH:4]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: c1cscn1
Reactant: Ic1ccccc1
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CC(=O)N(C)C
Product: c1ccc(-c2cncs2)cc1
Temperature: 100 °C

Procedure:
A solution of thiazole (10.0 g), iodobenzene (2.63 ml), tetrakis(triphenylphosphine)palladium (0) (1.36 g) and potassium acetate (3.46 g) in N,N-dimethylacetamide (100 ml) was stirred under heating at 100° C. overnight. The solvent was evaporated under reduced pressure, and added to the residue was ethyl acetate. The mixture was washed successively with water and brine, and dried over sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=100:0-90:10) to give 5-phenylthiazole (1.50 g) as a pale yellow solid. APCI-Mass m/Z 162 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])(=[O:12])=[O:11])[CH2:7][N:6]1[C:20](=S)[CH2:21][C:22](=O)[CH3:23])=[O:4].Cl.Cl.[CH2:28]([NH:35][NH2:36])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])(=[O:11])=[O:12])[CH2:7][N:6]1[C:20]1[N:35]([CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[N:36]=[C:22]([CH3:23])[CH:21]=1)=[O:4]
Reactant: NNCc1ccccc1
Reactant: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2Cl)CN1C(=S)CC(C)=O
Agent: Cl
Product: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2Cl)CN1c1cc(C)nn1Cc1ccccc1

Procedure:
In analogy to the procedure described in example 192 h, (2S,4R)-4-(2-chloro-benzenesulfonyl)-1-(3-oxo-thiobutyryl)-pyrrolidine-2-carboxylic acid methyl ester (example 253c) was reacted with benzylhydrazine dihydrochloride (CAS Reg. No. 20570-96-1) to give the title compound as orange oil. MS (ESI): m/z=474.2 [M+H]+.
Reaction SMILES: C(OC(N1CCC(C(O[C:21]2[CH:43]=[CH:42][C:24]3[C:25]4[N:29]([CH2:30][CH2:31][O:32][C:23]=3[CH:22]=2)[CH:28]=[C:27]([C:33]2[N:34]([CH:39]([CH3:41])[CH3:40])[N:35]=[C:36]([CH3:38])[N:37]=2)[N:26]=4)CC)CC1)=O)C1C=CC=CC=1.[CH3:44][O:45][C:46](=[O:52])[CH:47]([OH:51])[CH2:48][CH2:49][Br:50].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>O1CCOCC1.CCOC(C)=O>[CH3:44][O:45][C:46](=[O:52])[CH:47]([O:51][C:21]1[CH:43]=[CH:42][C:24]2[C:25]3[N:29]([CH2:30][CH2:31][O:32][C:23]=2[CH:22]=1)[CH:28]=[C:27]([C:33]1[N:34]([CH:39]([CH3:41])[CH3:40])[N:35]=[C:36]([CH3:38])[N:37]=1)[N:26]=3)[CH2:48][CH2:49][Br:50]
Reactant: COC(=O)C(O)CCBr
Reactant: CCC(Oc1ccc2c(c1)OCCn1cc(-c3nc(C)nn3C(C)C)nc1-2)C1CCN(C(=O)OCc2ccccc2)CC1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: COC(=O)C(CCBr)Oc1ccc2c(c1)OCCn1cc(-c3nc(C)nn3C(C)C)nc1-2
Temperature: 25 °C
Reaction time: 1 h
Yield: 58.3 %

Procedure:
To a solution of 2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulen-8-ol from Example 4 (2.8 g, 8.5 mmol), 4-bromo-2-hydroxybutyric acid methyl ester (2.5 g, 12.7 mmol) and triphenylphosphine (3.77 g, 14.3 mmol) in dioxane (30 mL) was added DIAD (2.8 ml, 14.3 mmol) and the reaction mixture was stirred at RT for 1 h. Additional amounts of DIAD (1.67 mL) and of triphenylphosphine (2.23 g) were added and stirring was continued for 1 h. The mixture was diluted with EtOAc and washed with aq. NaOH (1N). The aqueous phase was further extracted with EtOAc (×3). The combined organic layers were then washed with brine, dried and concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC, gradient 0-10% MeOH in EtOAc followed by Si-PCC, gradient 0-10% MeOH in DCM) affording 4-Bromo-2-[2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulen-8-yloxy]butyric acid methyl ester (2.5 g, 58%). 1H NMR (CDCl3, 400 MHz): δ 8.43 (1H, d, J=9.01 Hz), 7.57 (1H, s), 6.74 (1H, d, J=9.15 Hz), 6.55 (1H, d, J=2.56 Hz), 5.95-5.83 (1H, m), 4.92 (1H, dd, J=8.80, 3.97 Hz), 4.51-4.31 (4H, m), 3.79 (3H, s), 3.65-3.53 (2H, m), 2.58-2.36 (5H, m), 1.58-1.51 (6H, m)
Reaction SMILES: Br[CH:2]([CH2:12][Br:13])[CH2:3][P:4](=[O:11])([O:8][CH2:9][CH3:10])[O:5][CH2:6][CH3:7].CC(C)([O-])C.[K+]>C(O)(C)(C)C>[Br:13][CH2:12]/[CH:2]=[CH:3]\[P:4](=[O:11])([O:5][CH2:6][CH3:7])[O:8][CH2:9][CH3:10]
Reactant: CCOP(=O)(CC(Br)CBr)OCC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Product: CCOP(=O)(/C=C\CBr)OCC
Reaction time: 0.5 h
Yield: 0.4 %

Procedure:
(1)-2 To a solution of diethyl 2,3-dibromopropylphosphonate (3.34 g.) in tert.-butanol (10 ml.) was added dropwise a solution of potassium tert.-butoxide (K: 430 mg., tert.-C4H9OH: 14 ml.) at ambient temperature in the course of 15 minutes. The reaction mixture was stirred at the same temperature for 30 minutes. The resultant mixture was concentrated under reduced pressure and then the residue was shaken with a mixture of ethyl acetate (50 ml.) and water (30 ml.). The ethyl acetate layer was separated, washed with water (30 ml.), dried over magnesium sulfate and evaporated to dryness under reduced pressure to give an oily mixture of isomeric diethyl 3-bromo-propenylphosphonates (2.13 g.). An aliquot (1.86 g.) of which was fractionated by subjecting to a column chromatography on silica gel (developing solvent: chloroform) in two fractions (i.e. fraction A and fraction B). The fraction A was evaporated to dryness under reduced pressure to give oily diethyl 3-bromo-cis-1-propenylphosphonate (10 mg.). The fraction B was evaporated to dryness under reduced pressure to give oily mixture (1.65 g.) of diethyl 3-bromo-2-propenylphosphonate and diethyl 3-bromo-trans-1-propenylphosphonate (molar ratio: ca 1:1).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:29]=[CH:28][C:9]2[NH:10][C:11]([NH:13][CH2:14][CH:15]3[CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17][CH2:16]3)=[N:12][C:8]=2[CH:7]=1)=[O:5])[CH3:2].Cl.O1CCOCC1.C(O)C>O1CCCC1>[CH2:1]([O:3][C:4]([C:6]1[CH:29]=[CH:28][C:9]2[NH:10][C:11]([NH:13][CH2:14][CH:15]3[CH2:16][CH2:17][NH:18][CH2:19][CH2:20]3)=[N:12][C:8]=2[CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ccc2[nH]c(NCC3CCN(C(=O)OC(C)(C)C)CC3)nc2c1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCO
Solvent: C1COCCO1
Product: CCOC(=O)c1ccc2[nH]c(NCC3CCNCC3)nc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
After dissolving the 2-[(1-tert-butoxycarbonyl-piperidin-4-ylmethyl)-amino]-1H-benzimidazole-5-carboxylic acid ethyl ester in tetrahydrofuran (2 ml), a 4N hydrogen chloride/1,4-dioxane solution (3 ml) was added. Since a precipitate was produced, ethanol (5 ml) was added to dissolve it and the solution was stirred at room temperature overnight. The reaction mixture was concentrated to obtain 2-[(piperidin-4-ylmethyl)-amino]-1H-benzimidazole-5-carboxylic acid ethyl ester as a red amorphous solid. The compound was identified by LC-MS.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][C:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[NH:12][CH:11]=2)[CH2:4][CH2:3]1.[CH3:19][N:20]=[C:21]=[O:22]>>[CH3:19][NH:20][C:21]([NH:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][C:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[NH:12][CH:11]=2)[CH2:4][CH2:3]1)=[O:22]
Reactant: NC1CCN(CCc2c[nH]c3ccccc23)CC1
Reactant: CN=C=O
Product: CNC(=O)NC1CCN(CCc2c[nH]c3ccccc23)CC1

Procedure:
Following the procedure of Example 1 3-[2-(4-aminopiperidyl)ethyl]indole is reacted with methyl isocyanate to give the title compound which is converted to the hydrochloride.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:21]3[CH:20]=[CH:19][C:18]([CH:22]=[C:23]([C:26]#[N:27])[C:24]#[N:25])=[CH:17][C:16]=3[C:15]3[C:10]2=[CH:11][CH:12]=[CH:13][CH:14]=3)=[CH:5][CH:4]=1.[C-:28]#[N:29].[Na+].C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.[Pb+4]>CN(C)C=O.O.C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:21]3[CH:20]=[CH:19][C:18]([C:22]([C:28]#[N:29])=[C:23]([C:24]#[N:25])[C:26]#[N:27])=[CH:17][C:16]=3[C:15]3[C:10]2=[CH:11][CH:12]=[CH:13][CH:14]=3)=[CH:5][CH:4]=1
Reactant: [C-]#N
Reactant: COc1ccc(-n2c3ccccc3c3cc(C=C(C#N)C#N)ccc32)cc1
Agent: CC(=O)[O-]
Agent: [Na+]
Agent: [Pb+4]
Solvent: CN(C)C=O
Solvent: O
Solvent: ClC(Cl)Cl
Product: COc1ccc(-n2c3ccccc3c3cc(C(C#N)=C(C#N)C#N)ccc32)cc1
Reaction time: 0.17 h
Yield: 27.9 %

Procedure:
1.00 g (2.87 mmol) of N-(4-methoxyphenyl)-3-(2,2-dicyanoethenyl)carbazole and 12.5 ml of N,N-dimethylformamide as solvent were placed in a 500 ml four-necked flask with a mechanical stirrer and bulb-shaped cooler. To this was added an aqueous solution prepared from 0.15 g (2.87 mmol) of sodium cyanide and 0.5 ml of water, which was stirred for 10 minutes. Further, 1.74 g (3.93 mmol) of lead tetraacetate was added. The resultant product was subjected to the reaction for 30 minutes. After the reaction was completed, 100 ml of chloroform was added. To the resultant aqueous solution was added 100 ml of water. The resultant liquid was washed in a separatory funnel. To the washed liquid was added sodium sulfate, which was left to stand for 30 minutes and dehydrated. The dehydrated solution was concentrated in an evaporator and dried under vacuum to obtain a red solid, which was recrystallized in the presence of benzene to obtain 0.30 g of a red crystal.
Reaction SMILES: C([O:3][C:4](=O)[C:5]([C:8]1[CH2:9][CH2:10][O:11][CH2:12][CH:13]=1)([CH3:7])[CH3:6])C.[H-].[H-].[H-].[H-].[Li+].[Al+3].O.[OH-].[Na+]>O1CCCC1>[O:11]1[CH2:10][CH:9]=[C:8]([C:5]([CH3:7])([CH3:6])[CH2:4][OH:3])[CH2:13][CH2:12]1
Reactant: CCOC(=O)C(C)(C)C1=CCOCC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(CO)C1=CCOCC1
Temperature: 25 °C
Yield: 98.8 %

Procedure:
Step C To a solution of 2-(3,6-dihydro-2H-pyran-4-yl)-2-methyl-propionic acid ethyl ester (6 g, 30 mmol) in anhydrous tetrahydrofuran (75 mL) at 0° C. was added a tetrahydrofuran solution (1 M) of LiAlH4 (100 mL, 100 mmol) under nitrogen. The reaction mixture was heated at reflux for 3 h, then cooled to room temperature. Water and aqueous NaOH solution (2N) was added. The mixture was filtered to remove the precipitate, and the filtrate was concentrated. Water was added, and the mixture was extracted with ethyl acetate. The organic layer were separated, washed with water, aqueous HCl solution, brine, dried over MgSO4, and concentrated to give 2-(3,6-dihydro-2H-pyran-4-yl)-2-methyl-propan-1-ol as a brown oil (4.63 g, 98%).
Reaction SMILES: N#N.[Si:3]([O:10][CH2:11][C:12]1[O:13][CH:14]=[C:15]([C:17]2([OH:20])[CH2:19][CH2:18]2)[N:16]=1)([C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:5])[CH3:4].[C:21](Cl)(=[O:26])[C:22]([CH3:25])([CH3:24])[CH3:23].[NH4+].[Cl-]>N1C=CC=CC=1.CC(=O)OCC>[C:21]([O:20][C:17]1([C:15]2[N:16]=[C:12]([CH2:11][O:10][Si:3]([C:6]([CH3:9])([CH3:7])[CH3:8])([CH3:5])[CH3:4])[O:13][CH:14]=2)[CH2:18][CH2:19]1)(=[O:26])[C:22]([CH3:25])([CH3:24])[CH3:23]
Reactant: CC(C)(C)C(=O)Cl
Reactant: CC(C)(C)[Si](C)(C)OCc1nc(C2(O)CC2)co1
Agent: N#N
Agent: [Cl-]
Agent: [NH4+]
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CC(C)(C)C(=O)OC1(c2coc(CO[Si](C)(C)C(C)(C)C)n2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of 1-(2-(((tert-butyldimethylsilyl)oxy)methyl)oxazol-4-yl)cyclopropanol (509 mg, 1.89 mmol) in pyridine (2.0 mL) was treated with pivaloyl chloride (0.28 mL, 2.27 mmol) and the reaction mixture was stirred at rt overnight. Sat. aq. NH4Cl (10 mL) was added followed by EA (10 mL). The org. layer was washed with a CuSO4 sol. (2×15 mL) followed by brine (10 mL). The layers were separated and the org. layer was dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC (9:1 hept-EA) gave the title compound as a colorless oil: TLC: rf (9:1 hept-EA)=0.35. LC-MS-conditions 06: tR=1.19 min, [M+H]+=354.18.
Reaction SMILES: [CH3:1][N:2]1[C:6]([S:7][CH3:8])=[C:5]([CH3:9])[C:4]([C:10]2[CH:15]=[CH:14][C:13]([O:16]C(C)C)=[C:12]([CH3:20])[CH:11]=2)=[N:3]1.S(=O)(=O)(O)O>>[CH3:1][N:2]1[C:6]([S:7][CH3:8])=[C:5]([CH3:9])[C:4]([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[C:12]([CH3:20])[CH:11]=2)=[N:3]1
Reactant: CSc1c(C)c(-c2ccc(OC(C)C)c(C)c2)nn1C
Agent: O=S(=O)(O)O
Product: CSc1c(C)c(-c2ccc(O)c(C)c2)nn1C
Temperature: 0 °C
Yield: 95.9 %

Procedure:
A mixture of 1,4-dimethyl-3-(4-isopropoxy-3-methyl-phenyl)-5-methylthio-1H-pyrazole (described in Reference Preparation example 104) 8.9 g and 30% aqueous sulfuric acid solution 120 ml was stirred with heating under reflux for twenty hours. The reaction mixture was cooled to 0° C. and thereto was added ice water 50 ml. The resulting precipitates were filtered and were washed with cool water and hexane, and were concentrated under reduced pressure to give 4-(1,4-dimethyl-5-methylthio-1H-pyrazol-3-yl)-2-methyl-phenol 7.3 g.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([CH2:12][N:13]1[C:19](=[O:20])[C@@H:18]([NH:21]C(=O)OC(C)(C)C)[CH2:17][O:16][C:15]3[CH:29]=[CH:30][CH:31]=[CH:32][C:14]1=3)=[C:7]([O:33][CH3:34])[CH:6]=[CH:5]2.[ClH:35]>O1CCOCC1>[ClH:35].[NH2:21][C@H:18]1[CH2:17][O:16][C:15]2[CH:29]=[CH:30][CH:31]=[CH:32][C:14]=2[N:13]([CH2:12][C:8]2[C:9]3[C:4](=[CH:3][C:2]([Br:1])=[CH:11][CH:10]=3)[CH:5]=[CH:6][C:7]=2[O:33][CH3:34])[C:19]1=[O:20]
Reactant: COc1ccc2cc(Br)ccc2c1CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)COc2ccccc21
Agent: Cl
Solvent: C1COCCO1
Product: COc1ccc2cc(Br)ccc2c1CN1C(=O)[C@@H](N)COc2ccccc21
Yield: 89 %

Procedure:
A solution of (S)-tert-butyl 5-((6-bromo-2-methoxynaphthalen-1-yl)methyl)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-ylcarbamate (1.803 g, 3.42 mmol) in 4 M HCl in dioxane (17.1 mL) was stirred at RT for 2 h. The mixture was concentrated and the residue triturated with Et2O to provide (S)-3-amino-5-((6-bromo-2-methoxynaphthalen-1-yl)methyl)-2,3-dihydrobenzo[b][1,4]oxazepin-4(5H)-one hydrochloride (1.415 g, 89%) as an off-white solid. MS m/z 427/429 MH
Reaction SMILES: [Cl:1][C:2](Cl)([CH:5]=[C:6]([Cl:8])[Cl:7])[CH:3]=[O:4].[P:10]([O:17]CC)([O:14][CH2:15][CH3:16])[O:11][CH2:12][CH3:13]>>[P:10]([O:14][CH2:15][CH3:16])([O:11][CH2:12][CH3:13])([O:4][CH:3]=[C:2]([Cl:1])[CH:5]=[C:6]([Cl:8])[Cl:7])=[O:17]
Reactant: CCOP(OCC)OCC
Reactant: O=CC(Cl)(Cl)C=C(Cl)Cl
Product: CCOP(=O)(OC=C(Cl)C=C(Cl)Cl)OCC
Yield: 62.8 %

Procedure:
184 g of 2,2,4,4-tetrachloro-but-3-enal (prepared in accordance with Example 6) were reacted in a manner analogous to that described in Example 6 with 166 g of triethyl phosphite, and 172 g of product were obtained by distillation at 0.2 to 0.3 torr and 121° to 125° C. NMR-spectrum : δ (CH3) : 1.33 ppm, J = 7 Hz; δ (CH2) : 3.95 - 4.47 ppm; δ (C=CH-C) : 6.67 ppm; δ (CH-O-P) : 7.33 ppm, J = 6 Hz.
Reaction SMILES: [N+:1]([CH2:3][C:4]([O:6][CH3:7])=[O:5])#[C-:2].C(N(CC)CC)C.[S:15]1[CH:19]=[CH:18][CH:17]=[C:16]1[C:20](Cl)=[O:21]>O1CCCC1>[S:15]1[CH:19]=[CH:18][CH:17]=[C:16]1[C:20]1[O:21][CH:2]=[N:1][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: [C-]#[N+]CC(=O)OC
Reactant: O=C(Cl)c1cccs1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)c1ncoc1-c1cccs1
Yield: 86 %

Procedure:
29.7 g of methyl α-isocyanoacetate, 120 g of triethylamine, 450 ml of tetrahydrofuran and 48.4 g of 2-thienylcarbonyl chloride are treated in the same manner as described in Preparation 1-(1). 53.9 g of 5-(2-thienyl)-4-methoxycarbonyloxazole are thereby obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH:12]([CH3:14])[CH3:13])[C:9](O)=[O:10])=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.C[N:22](C)C=O>CCOCC>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH:12]([CH3:14])[CH3:13])[C:9]([NH2:22])=[O:10])=[CH:4][CH:3]=1
Reactant: CC(C)C(C(=O)O)c1ccc(Cl)cc1
Reactant: CN(C)C=O
Agent: O=C(Cl)C(=O)Cl
Solvent: CCOCC
Product: CC(C)C(C(N)=O)c1ccc(Cl)cc1
Temperature: 25 °C

Procedure:
To a solution of 4.25 g (20 mmol) of 2-(4-chlorophenyl)-3-methylbutanoic acid in 30 ml of ether containing one drop of N,N-dimethylformamide is added dropwise 3.81 g (30 mmol) of oxalyl chloride. The solution is stirred at RT until gas evolution ceases. The solvent and excess oxalyl chloride are removed in vacuo and the residue is taken up in 30 ml of ether. This solution is then added dropwise at 0°-5° to 4.86 g (40 mmol) of a 14% w/w aqueous solution of ammonia. After stirring the mixture for 30 minutes at 0°-5°, the aqueous layer is removed. The ethereal solution is washed with water, dried over sodium sulfate, filtered and concentrated in vacuo to obtain 2-(4-chlorophenyl)-3-methylbutyramide.
Reaction SMILES: [C:1]([CH:3]=[C:4]1[CH2:7][N:6](C(OC(C)(C)C)=O)[CH2:5]1)#[N:2].N12CCCN=C1CCCCC2.[CH2:26]([N:33]1[C:37]2[CH:38]=[CH:39][C:40]3[N:41]([C:42]([CH3:45])=[N:43][N:44]=3)[C:36]=2[CH:35]=[C:34]1[C:46]1[NH:50][N:49]=[CH:48][CH:47]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.Cl.O1CCOCC1>C(#N)C>[CH2:26]([N:33]1[C:37]2[CH:38]=[CH:39][C:40]3[N:41]([C:42]([CH3:45])=[N:43][N:44]=3)[C:36]=2[CH:35]=[C:34]1[C:46]1[CH:47]=[CH:48][N:49]([C:4]2([CH2:3][C:1]#[N:2])[CH2:5][NH:6][CH2:7]2)[N:50]=1)[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: CC(C)(C)OC(=O)N1CC(=CC#N)C1
Reactant: Cc1nnc2ccc3c(cc(-c4ccn[nH]4)n3Cc3ccccc3)n12
Agent: Cl
Solvent: CC#N
Solvent: C1COCCO1
Solvent: C1CCC2=NCCCN2CC1
Product: Cc1nnc2ccc3c(cc(-c4ccn(C5(CC#N)CNC5)n4)n3Cc3ccccc3)n12
Reaction time: 0.33 h
Yield: 44.2 %

Procedure:
tert-Butyl 3-(cyanomethylene)azetidine-1-carboxylate (59 mg, 0.30 mmol, prepared as described in WO 2009114512) and 1,8-diazabicyclo[5.4.0]undec-7-ene (23 μL, 0.15 mmol) were added to a solution of 6-benzyl-1-methyl-7-(1H-pyrazol-5-yl)-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyridine (50 mg, 0.15 mmol, from Example 62) in acetonitrile (2.0 mL). After stirring for 20 minutes, 4.0 M HCl in dioxane (0.50 mL, 2.0 mmol) was added. After a further reaction time of 22 minutes, the solvent was removed in vacuo and the residue was dissolved in MeOH. Aqueous ammonia was added to adjust pH=10. Purification via preparative HPLC-MS (C18 eluting with a gradient of MeCN and H2O containing 0.15% NH4OH) afforded product as a white solid (28 mg, 44%).
Reaction SMILES: FC(F)(F)C(O)=O.[C:8]1([CH:14]([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[CH2:15][CH2:16][N:17]([C:31]([NH:33][C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([C:40]([F:43])([F:42])[F:41])[CH:35]=2)=[O:32])[CH:18]2[CH2:23][CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20][CH2:19]2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>ClCCl>[C:44]1([CH:14]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:15][CH2:16][N:17]([CH:18]2[CH2:19][CH2:20][NH:21][CH2:22][CH2:23]2)[C:31]([NH:33][C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([C:40]([F:42])([F:41])[F:43])[CH:35]=2)=[O:32])[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1
Reactant: CC(C)(C)OC(=O)N1CCC(N(CCC(c2ccccc2)c2ccccc2)C(=O)Nc2cccc(C(F)(F)F)c2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(Nc1cccc(C(F)(F)F)c1)N(CCC(c1ccccc1)c1ccccc1)C1CCNCC1
Reaction time: 1.5 h
Yield: 97.8 %

Procedure:
1.6 ml (21 mmol, 20 eq.) of trifluoroacetic acid is added to a solution of tert-butyl 4-((3,3-diphenylpropyl){[3-(trifluoromethyl)anilino]carbonyl}amino)-1-piperidine carboxylate (600 mg, 1.04 mmol) in dichloromethane. The reaction medium is agitated for 90 minutes then concentrated. Dichloromethane is added and the organic phase is washed with a saturated solution of sodium bicarbonate, dried over magnesium sulphate, filtered and concentrated under vacuum in order to isolate 490 mg (yield=98%) of a white foam.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][CH3:9])=[N:6][CH:7]=1.C([O-])(=O)C.[Na+].[Br:15]Br>C(O)(=O)C.O>[Br:15][C:4]1[C:5]([O:8][CH3:9])=[N:6][CH:7]=[C:2]([Br:1])[CH:3]=1
Reactant: BrBr
Reactant: COc1ccc(Br)cn1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: COc1ncc(Br)cc1Br
Temperature: 80 °C
Reaction time: 3 h

Procedure:
To 5-bromo-2-methoxypyridine (0.564 g, 3.0 mmol) and sodium acetate (0.246 g, 3.0 mmol) in acetic acid (3 mL) was added bromine (0.27 mL, 5.25 mmol), and the mixture was stirred at 80° C. for 3 hours, and then at room temperature overnight. The mixture was diluted with H2O and extracted with EtOAc, and the combined organic layers were washed with saturated aqueous Na2CO3 and saturated aqueous Na2S2O3. The organic layer was concentrated and dried under high vacuum to give 3,5-dibromo-2-methoxy-pyridine.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[C:10]([CH3:11])=[CH:9][C:8]([O:12][CH2:13][CH:14]([CH3:16])[CH3:15])=[CH:7][C:6]=1[CH3:17])=O.[NH2:18][C:19]([NH2:21])=[S:20]>CCO>[CH2:13]([O:12][C:8]1[CH:9]=[C:10]([CH3:11])[C:5]([C:3]2[N:18]=[C:19]([NH2:21])[S:20][CH:2]=2)=[C:6]([CH3:17])[CH:7]=1)[CH:14]([CH3:16])[CH3:15]
Reactant: NC(N)=S
Reactant: Cc1cc(OCC(C)C)cc(C)c1C(=O)CBr
Solvent: CCO
Product: Cc1cc(OCC(C)C)cc(C)c1-c1csc(N)n1
Yield: 81.6 %

Procedure:
A mixture of 2-bromo-1-(4-isobutoxy-2,6-dimethylphenyl)ethanone (5.84 g, 19.5 mmol) and thiourea (1.49 g, 19.6 mmol) in 95% EtOH (28 mL) was heated at reflux for 60 min. The solution was concentrated and added with water (50 mL) and saturated aqueous Na2CO3 (5.0 mL). The resultant precipitate was filtered and recrystallized in toluene (30 mL). The solids were filtered and dried under vacuum to give 4-(4-isobutoxy-2,6-dimethylphenyl)thiazol-2-amine (4.4 g) as white solids in 82% yield: 1H NMR (500 MHz, CDCl3) δ 6.61 (s, 2 H), 6.24 (s, 1 H), 3.70 (d, J=6.5 Hz, 2 H), 2.15 (s, 6 H), 2.07 (m, 1 H), 1.01 (d, J=6.7 Hz, 6 H).