Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]3[O:15][C:14]4[CH:16]=[CH:17][C:18]([Cl:20])=[CH:19][C:13]=4[C:7]=3[N:8]=[C:9]2O)=[CH:4][CH:3]=1.[Cl:21]C1C=C2C(C3OC4C=CC=CC=4C=3N=C2O)=CC=1>>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]3[O:15][C:14]4[CH:16]=[CH:17][C:18]([Cl:20])=[CH:19][C:13]=4[C:7]=3[N:8]=[C:9]2[Cl:21])=[CH:4][CH:3]=1
Reactant: Oc1nc2c3cc(Cl)ccc3oc2c2ccc(Cl)cc12
Reactant: Oc1nc2c3ccccc3oc2c2ccc(Cl)cc12
Product: Clc1ccc2c(c1)c(Cl)nc1c3cc(Cl)ccc3oc21

Procedure:
The procedure was similar to step S19C, while the starting material was 27B in stead of 19B.
Reaction SMILES: [CH3:1][N:2]([C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([NH2:9])[CH:4]=1.CCN(C(C)C)C(C)C.[Cl:25][C:26]1[CH:27]=[C:28]([CH:32]=[CH:33][CH:34]=1)[C:29](Cl)=[O:30]>C(Cl)Cl>[Cl:25][C:26]1[CH:27]=[C:28]([CH:32]=[CH:33][CH:34]=1)[C:29]([NH:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([N:2]([CH3:1])[C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)[CH:4]=1)=[O:30]
Reactant: O=C(Cl)c1cccc(Cl)c1
Reactant: CN(c1cccnc1)c1cccc(N)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CN(c1cccnc1)c1cccc(NC(=O)c2cccc(Cl)c2)c1
Reaction time: 0.08 h
Yield: 71 %

Procedure:
Compound 17 (25 mg, 0.13 mmol, 1.0 eq) was dissolved in CH2Cl2 (1 mL) and DIEA (24 μL, 0.14 mmol, 1.1 eq) was added and the reaction stirred for 5 min. 3-Chlorobenzoyl chloride (16.1 μL, 0.125 mmol, 1.00 eq) was added and the reaction was stirred until determination of completion by LCMS. The reaction was diluted with CH2Cl2, washed with water (1×), dried (MgSO4), filtered and concentrated in vacuo. Purification by flash chromatography on silica gel afforded 30 mg (71%) of the title compound as a light-yellow solid: 1H NMR (400 MHz, CDCl3) δ 10.44 (s, 1H), 8.36-8.15 (m, 2H), 7.98 (s, 1H), 7.89 (d, J=7.8 Hz, 1H), 7.76-7.72 (m, 1H), 7.71-7.60 (m, 4H), 7.56 (t, J=7.9 Hz, 1H), 7.44 (t, J=8.1 Hz, 1H), 7.02 (d, J=8.0 Hz, 1H), 3.36 (s, 3H); ES-MS [M+1]+: 338.2.
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[CH2:7][C@H:8]1[CH2:13][C@@H:12]([CH2:14][N:15]2[CH:19]=[CH:18][C:17]([N+:20]([O-])=O)=[N:16]2)[O:11][C:10]([CH3:24])([CH3:23])[O:9]1)([CH3:4])([CH3:3])[CH3:2].[H][H]>C(O)C.[Pd]>[C:1]([O:5][C:6](=[O:25])[CH2:7][C@H:8]1[CH2:13][C@@H:12]([CH2:14][N:15]2[CH:19]=[CH:18][C:17]([NH2:20])=[N:16]2)[O:11][C:10]([CH3:24])([CH3:23])[O:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)C[C@H]1C[C@@H](Cn2ccc([N+](=O)[O-])n2)OC(C)(C)O1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)C[C@H]1C[C@@H](Cn2ccc(N)n2)OC(C)(C)O1
Reaction time: 3 h
Yield: 117 %

Procedure:
A solution of [(4R,6S)-2,2-dimethyl-6-(3-nitro-pyrazol-1-ylmethyl)-[1,3]dioxan-4-yl]-acetic acid t-butyl ester (1.56 g 3.52 mmol) in ethanol (25 mL) was hydrogenated in a Parr hydrogenator at 50 psi hydrogen pressure, using 10% palladium on carbon (0.2 g, 0.19 mmol), for 3 h. The reaction mixture was filtered through a celite plug, and the filtrate concentrated which afforded [(4R,6S)-6-(3-amino-pyrazol-1-ylmethyl)-2,2-dimethyl-[1,3]dioxan-4-yl]-acetic acid t-butyl ester (1.34 g, 94%) as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:13]2[O:14][C:15]3[CH:21]=[C:20]([OH:22])[CH:19]=[CH:18][C:16]=3[N:17]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH:10]1[CH2:12][CH2:11]1.O[CH2:24][C@@H:25]([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[CH3:26].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(C)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:13]2[O:14][C:15]3[CH:21]=[C:20]([O:22][CH2:26][C@@H:25]([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:31])([CH3:33])[CH3:32])[CH3:24])[CH:19]=[CH:18][C:16]=3[N:17]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH:10]1[CH2:11][CH2:12]1
Reactant: Oc1ccc2nc(-c3ccc(OCC4CC4)c(Cl)c3)oc2c1
Reactant: C[C@@H](CO)NC(=O)OC(C)(C)C
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: C[C@@H](COc1ccc2nc(-c3ccc(OCC4CC4)c(Cl)c3)oc2c1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 72.8 %

Procedure:
To a solution of 2-(3-chloro-4-(cyclopropylmethoxy)phenyl)-1,3-benzoxazol-6-ol (1.00 g), tert-butyl ((2S)-1-hydroxypropan-2-yl)carbamate (0.832 g) and triphenylphosphine (1.25 g) in THF (10 mL) was added dropwise diisopropyl azodicarboxylate toluene solution (1.9 M, 2.50 mL), and the mixture was stirred at room temperature for 16 hr. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (NH, hexane/ethyl acetate) to give the title compound (1.09 g). 1H NMR (300 MHz, CDCl3) δ 0.39-0.48 (2H, m), 0.61-0.76 (2H, m), 1.14-1.37 (4H, m), 1.46 (9H, s), 3.90-4.04 (4H, m), 4.03-4.19 (1H, m), 4.77 (1H, brs), 6.95 (1H, dd, J=8.7, 2.3 Hz), 7.01 (1H, d, J=8.7 Hz), 7.10 (1H, d, J=2.3 Hz), 7.60 (1H, d, J=8.7 Hz), 8.04 (1H, dd, J=8.5, 2.1 Hz), 8.22 (1H, d, J=1.9 Hz).
Reaction SMILES: [O:1]=[C:2]1[N:10]2[C:11]([CH2:14][CH2:15][C:16]([OH:18])=[O:17])=[N:12][N:13]=[C:9]2[N:8]([CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[C:7]2[N:6]=[CH:5][NH:4][C:3]1=2.C1C(=O)N([Br:31])C(=O)C1>C1COCC1>[Br:31][C:5]1[NH:4][C:3]2[C:2](=[O:1])[N:10]3[C:11]([CH2:14][CH2:15][C:16]([OH:18])=[O:17])=[N:12][N:13]=[C:9]3[N:8]([CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[C:7]=2[N:6]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CCCCCn1c2nc[nH]c2c(=O)n2c(CCC(=O)O)nnc12
Solvent: C1CCOC1
Product: CCCCCn1c2nc(Br)[nH]c2c(=O)n2c(CCC(=O)O)nnc12
Temperature: 70 °C
Reaction time: 2 h
Yield: 23.7 %

Procedure:
The mixture of 3-(5-oxo-9-pentyl-6,9-dihydro-5H[1,2,4]triazolo[4,3-a]purin-3-yl)propanoic acid (203 mg, 0.64 mmole) and NBS (125.8 mg, 7.0 mmol) in THF (25 ml) was stirred at 70° C. for 2 hours. After evaporation of solvent, the residue was purified by preparative LC-MS to afford 60.2 mg (23.7%) of the desired product (60.2 mg, 23.7%) as white solid. LCMS calculated for C14H18BrN6O3(M+H): 397.1; found: 371.1.
Reaction SMILES: [CH:1]([NH:3][C:4]1[S:8][N:7]=[C:6]([C:9](=[O:16])[CH:10](SC)[S:11]([CH3:13])=O)[N:5]=1)=[O:2].I([O-])(=O)(=O)=[O:18].[Na+]>C(O)(=O)C>[CH:1]([NH:3][C:4]1[S:8][N:7]=[C:6]([C:9](=[O:16])[C:10]([S:11][CH3:13])=[O:18])[N:5]=1)=[O:2]
Reactant: CSC(C(=O)c1nsc(NC=O)n1)S(C)=O
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CSC(=O)C(=O)c1nsc(NC=O)n1
Temperature: 70 °C
Reaction time: 0.75 h
Yield: 129.5 %

Procedure:
A mixture of 5-formamido-3-(2-methylthio-2-methylsulfinylacetyl)-1,2,4-thiadiazole (0.85 g) and sodium periodate (0.2 g) in glacial acetic acid (10 ml) was stirred for 45 minutes at 70° C. The reaction mixture was evaporated and the residue was dissolved in a mixture of ethyl acetate and water. The mixture was adjusted to pH 7 with an aqueous solution of sodium bicarbonate and treated with an aqueous solution of sodium thiosulfate. The organic layer was separated, dried over anhydrous magnesium sulfate and evaporated to dryness. The residue was triturated with a mixture of diethyl ether and petroleum ether to give the title compound (280 mg), mp. 186° to 187° C.
Reaction SMILES: [Cu][C:2]#[N:3].N1C=CC=CC=1.Br[C:11]1[CH:16]=[CH:15][C:14]([C:17]2[N:18]=[C:19]([N:22]3[C:26]([CH3:28])([CH3:27])[CH2:25][O:24][C:23]3=[O:29])[S:20][CH:21]=2)=[C:13]([F:30])[CH:12]=1>CC(N(C)C)=O.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>[CH3:27][C:26]1([CH3:28])[CH2:25][O:24][C:23](=[O:29])[N:22]1[C:19]1[S:20][CH:21]=[C:17]([C:14]2[CH:15]=[CH:16][C:11]([C:2]#[N:3])=[CH:12][C:13]=2[F:30])[N:18]=1
Reactant: N#C[Cu]
Reactant: CC1(C)COC(=O)N1c1nc(-c2ccc(Br)cc2F)cs1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccncc1
Solvent: CC(=O)N(C)C
Product: CC1(C)COC(=O)N1c1nc(-c2ccc(C#N)cc2F)cs1
Yield: 116.6 %

Procedure:
Copper (I) cyanide (0.09 g, 1.0 mmol) and pyridine (0.17 mL, 1.6 mmol) were added under a nitrogen atmosphere to a solution of 3-[4-(4-bromo-2-fluorophenyl)-1,3-thiazol-2-yl]-4,4-dimethyl-1,3-oxazolidin-2-one (0.4 g, 1.0 mmol), prepared in step 7 of Example 78, and tetrakis(triphenylphosphine)palladium(0) (115 mg, 0.1 mmol) in dimethylacetamide. The reaction solution was sealed and placed in a microwave reactor (200° C./1 h). LC/MS indicated the reaction was complete. The reaction was concentrated under reduced pressure. The residue was purified on silica gel using a stepwise gradient of 1-3% methanol:methylene chloride to give the title compound (370 mg, 55%) as a yellow solid, mp 237° C. (dec.).
Reaction SMILES: [CH3:1][N:2]1[C:10]([CH2:11][CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[N:9][C:8]2[C:3]1=[N:4][C:5]([N:24]1[C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=3[N:26]=[C:25]1[CH3:33])=[N:6][C:7]=2[N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1.Br[CH2:35][C:36]([NH2:38])=[O:37]>>[CH3:1][N:2]1[C:10]([CH2:11][CH:12]2[CH2:17][CH2:16][N:15]([CH2:35][C:36]([NH2:38])=[O:37])[CH2:14][CH2:13]2)=[N:9][C:8]2[C:3]1=[N:4][C:5]([N:24]1[C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=3[N:26]=[C:25]1[CH3:33])=[N:6][C:7]=2[N:18]1[CH2:19][CH2:20][O:21][CH2:22][CH2:23]1
Reactant: NC(=O)CBr
Reactant: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CC3CCNCC3)n(C)c2n1
Product: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CC3CCN(CC(N)=O)CC3)n(C)c2n1

Procedure:
Following General Procedure C, 4-(9-methyl-2-(2-methyl-1H-benzo[d]imidazol-1-yl)-8-(piperidin-4-ylmethyl)-9H-purin-6-yl)morpholine and 2-bromoacetamide were reacted to give 558. LCMS m/z: 252.7 (2M+H+)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[C:5]([C:7]1[C:12]([C:13](OC)=[O:14])=[CH:11][CH:10]=[CH:9][N:8]=1)=O.O.[NH2:21][NH2:22]>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]2[C:7]3[N:8]=[CH:9][CH:10]=[CH:11][C:12]=3[C:13](=[O:14])[NH:22][N:21]=2)[CH:17]=[CH:18][CH:19]=1
Reactant: NN
Reactant: COC(=O)c1cccnc1C(=O)c1cccc(Cl)c1
Solvent: O
Solvent: CCO
Product: O=c1[nH]nc(-c2cccc(Cl)c2)c2ncccc12
Yield: 50.5 %

Procedure:
A solution of 2-(3-chlorobenzoyl)-3-methoxycarbonylpyridine (0.55 g, 2.0 mmoles), hydrazine hydrate (0.15 ml, 3.0 mmoles) in ethanol (50 ml) was stirred at 100° C. for 18 hours under an inert atmosphere. The solution was cooled and solid in the solution was collected, washed with ethyl ether and dried to give 0.26 g of 8-(3-chlorophenyl)pyrido-[2,3-d]pyridazin-5-one (50.5%), mp 268°-269° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([NH:12][NH2:13])[CH2:9][N:8]=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[F:20])[C:6]=2[CH:21]=1.[Cl:22][CH2:23][C:24](Cl)=O.C([O-])(=O)C.[Na+]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:24]([CH2:23][Cl:22])=[N:13][N:12]=[C:10]3[CH2:9][N:8]=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[F:20])[C:6]=2[CH:21]=1
Reactant: O=C(Cl)CCl
Reactant: NNC1=Nc2ccc(F)cc2C(c2ccccc2F)=NC1
Agent: CC(=O)[O-]
Agent: [Na+]
Product: Fc1ccc2c(c1)C(c1ccccc1F)=NCc1nnc(CCl)n1-2

Procedure:
In the manner given in Preparation 10, 7-fluoro-5(o-fluorophenyl)-3H-1,4-benzodiazepin-2-yl hydrazine is reacted with chloroacetyl chloride and after 1.5 hours with sodium acetate. The mixture is then refluxed to give 8-fluoro-1-(chloromethyl)-6-(o-fluorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine. Preparation 13 8-Chloro-1-(chloromethyl)-6-(2,6-difluorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.C([Li])CCC.CCCCCC.Br[CH2:21][CH2:22][CH2:23][O:24][CH2:25][O:26][CH3:27]>C1COCC1>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:8])[C:7]=1[CH2:21][CH2:22][CH2:23][O:24][CH2:25][O:26][CH3:27]
Reactant: COCOCCCBr
Reactant: Clc1cncc(Cl)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COCOCCCc1c(Cl)cncc1Cl
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 13.3 %

Procedure:
3,5-Dichloropyridine (4.4 g, 30 mmol) is dissolved in THF (100 ml), and thereto is added a solution of n-butyl lithium in hexane (19 ml, 30 mmol) at −70° C., and the mixture is stirred for 15 minutes. 1-Bromo-3-methoxymethoxypropane (6.0 g, 33 mmol) is added to the mixture, and the mixture is warmed to 0° C. over a period of time for one hour. The reaction is quenched with a saturated brine (50 ml), and the mixture is extracted with ethyl acetate (150 ml×2). The organic layer is washed with a saturated brine (100 ml×2), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue is purified by silica gel column chromatography (eluent: ethyl acetate/hexane) to give 1-(3,5-dichloropyridin-4-yl)-3-methoxymethoxypropane (1.0 g) as an oil.
Reaction SMILES: [NH2:1][C:2](=[O:37])[C@@H:3]([NH:12][C:13](=[O:36])[C@@H:14]([NH:16][C:17](=[O:35])[C@@H:18]([NH:20][C:21]([C@@H:23]1[CH2:27][CH2:26][CH2:25][N:24]1[C:28]1[S:29][C:30]([CH:33]=[O:34])=[CH:31][N:32]=1)=[O:22])[CH3:19])[CH3:15])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.[BH4-].[Na+]>CCO.O>[NH2:1][C:2](=[O:37])[C@@H:3]([NH:12][C:13](=[O:36])[C@@H:14]([NH:16][C:17](=[O:35])[C@@H:18]([NH:20][C:21]([C@@H:23]1[CH2:27][CH2:26][CH2:25][N:24]1[C:28]1[S:29][C:30]([CH2:33][OH:34])=[CH:31][N:32]=1)=[O:22])[CH3:19])[CH3:15])[CH2:4][C:5]1[CH:6]=[CH:7][C:8]([OH:11])=[CH:9][CH:10]=1
Reactant: C[C@H](NC(=O)[C@H](C)NC(=O)[C@@H]1CCCN1c1ncc(C=O)s1)C(=O)N[C@@H](Cc1ccc(O)cc1)C(N)=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: C[C@H](NC(=O)[C@H](C)NC(=O)[C@@H]1CCCN1c1ncc(CO)s1)C(=O)N[C@@H](Cc1ccc(O)cc1)C(N)=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Following the procedure as described in Example 32, except using material from Example 81 (6.4 mg, 0.012 mmol), EtOH/H2O (4:1) (3 mL), sodium borohydride (4.2 mg, 0.111 mmol) and stirring at room temp for 2 h, the title compound is isolated (quantitative yield) that is used crude in the next step. LC/MS (Condition A): ret, T=1.54 min, (2M+Na) 1087.51.
Reaction SMILES: [F:1][C:2]1([F:33])[CH2:6][N:5]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)[C@@H:4]([C:18]([NH:20][C@H:21]([C:23]2[CH:32]=[CH:31][C:26]([C:27]([O:29]C)=[O:28])=[CH:25][CH:24]=2)[CH3:22])=[O:19])[CH2:3]1.O[Li].O>>[F:33][C:2]1([F:1])[CH2:6][N:5]([CH2:7][C:8]2[CH:9]=[CH:10][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:12][CH:13]=2)[C@@H:4]([C:18]([NH:20][C@H:21]([C:23]2[CH:24]=[CH:25][C:26]([C:27]([OH:29])=[O:28])=[CH:31][CH:32]=2)[CH3:22])=[O:19])[CH2:3]1
Reactant: COC(=O)c1ccc([C@H](C)NC(=O)[C@H]2CC(F)(F)CN2Cc2ccc(C(F)(F)F)cc2)cc1
Agent: [Li]O
Solvent: O
Product: C[C@H](NC(=O)[C@H]1CC(F)(F)CN1Cc1ccc(C(F)(F)F)cc1)c1ccc(C(=O)O)cc1
Yield: 73.6 %

Procedure:
The title compound (E45) (12 mg) was prepared according to the general procedure for esters hydrolysis (Method D) starting from methyl 4-((S)-1-((R)-4,4-difluoro-1-(4-(trifluoromethyl)benzyl)pyrrolidine-2-carboxamido)ethyl)benzoate (D166) (16.8 mg). (LiOH H2O: 3 eq; reaction time: 18 hrs)
Reaction SMILES: [CH:1]1([NH:4][C:5]2[C:10]([C:11]([O:13]CC)=[O:12])=[CH:9][N:8]=[C:7]3[N:16]([CH2:19][CH3:20])[N:17]=[CH:18][C:6]=23)[CH2:3][CH2:2]1.[OH-].[Na+].O>C(O)C>[CH:1]1([NH:4][C:5]2[C:10]([C:11]([OH:13])=[O:12])=[CH:9][N:8]=[C:7]3[N:16]([CH2:19][CH3:20])[N:17]=[CH:18][C:6]=23)[CH2:2][CH2:3]1
Reactant: CCOC(=O)c1cnc2c(cnn2CC)c1NC1CC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCn1ncc2c(NC3CC3)c(C(=O)O)cnc21
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To a solution of ethyl 4-cyclopropylamino-1-ethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylate (1 g, 0.0036 mole) in ethanol, sodium hydroxide solution (440 mg in 2 ml water) was added. The reaction mixture was stirred for about 14 hours at ambient temperature. Water was added and the reaction mixture was extracted with ethyl acetate. Aqueous layer was acidified by using hydrochloric acid (2N) to pH of about 4-5. White solid, which was obtained, was filtered and dried in vacuo.
Reaction SMILES: [Br:1][C:2]1[CH:14]=[C:13]2[C:5]([C:6]3[CH:7]=[CH:8][N:9]=[CH:10][C:11]=3[NH:12]2)=[CH:4][CH:3]=1.[OH-].[Na+].[C:17](OC(=O)C)(=[O:19])[CH3:18]>CN(C)C=O>[C:17]([C:10]1[C:11]2[NH:12][C:13]3[C:5](=[CH:4][CH:3]=[C:2]([Br:1])[CH:14]=3)[C:6]=2[CH:7]=[CH:8][N:9]=1)(=[O:19])[CH3:18]
Reactant: CC(=O)OC(C)=O
Reactant: Brc1ccc2c(c1)[nH]c1cnccc12
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CC(=O)c1nccc2c1[nH]c1cc(Br)ccc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 36.4 %

Procedure:
A solution of Example 1 (25 mg, 0.1 mmol) in dimetylformamide (DMF; 2 ml) was treated with 0.10 ml of 1 M aqueous NaOH (0.10 mmol). After stirring at RT for 30 minutes, acetic anhydride (0.010 ml, 0.095 mmol) was added and reaction stirred 18 h at RT. The reaction was partitioned in EtOAc and 5% citric acid and the organic layer washed with water, dried (brine; MgSO4), and concentrated to give 23 mg of crude product. The crude product was chromatographed (7:3 hexane-acetone) on silica gel to give 10 mg of 1-acetyl-7-bromo-β-carboline.
Reaction SMILES: [C:1]([C:5]1[CH:15]=[CH:14][C:8]([C:9]([N:11]=[C:12]=[S:13])=O)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[F:16][C:17]([F:21])([F:20])[CH2:18][NH2:19]>>[C:1]([C:5]1[CH:15]=[CH:14][C:8]([CH2:9][NH:11][C:12]([NH:19][CH2:18][C:17]([F:21])([F:20])[F:16])=[S:13])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc(C(=O)N=C=S)cc1
Reactant: NCC(F)(F)F
Product: CC(C)(C)c1ccc(CNC(=S)NCC(F)(F)F)cc1
Yield: 105.2 %

Procedure:
10.82 g of 4-t-butylbenzoyl isothiocyanate obtawined in (1) and 7.54 g of 2,2,2-trifluoroethylamine were dissolved in 20 ml of ethyl acetawte. The solution was left to stand at room temperature for 24 houirs. Ethyl acetate was evaporated under reduced prerssure. The resultilng oily product was purified by column chromatography silica gel; developing solvent hexane/ethyl acetate (4:1)) to give 15.80 g of the desired 1-(4-t-butylbenzyl)-3-(2,2,2-trifluoroethyl)thiourea.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[OH:32][CH2:33][CH2:34][NH:35][C:36]([C:38]1[CH:39]=[C:40]([C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)[C:41](=[O:51])[N:42]2[C:47]=1[C:46]1[S:48][CH:49]=[CH:50][C:45]=1[CH2:44][CH2:43]2)=O>O1CCCC1>[O:32]1[CH2:33][CH2:34][N:35]=[C:36]1[C:38]1[CH:39]=[C:40]([C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)[C:41](=[O:51])[N:42]2[C:47]=1[C:46]1[S:48][CH:49]=[CH:50][C:45]=1[CH2:44][CH2:43]2
Reactant: O=C(NCCO)c1cc(-c2ccccc2)c(=O)n2c1-c1sccc1CC2
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=c1c(-c2ccccc2)cc(C2=NCCO2)c2n1CCc1ccsc1-2
Reaction time: 24 h

Procedure:
0.94 g of diethyl azodicarboxylate and 0.71 g of triphenylphosphine were added to a solution of 1.0 g of 4,5-dihydro-N-(2-hydroxyethyl)-8-phenyl-7-oxo-7H-thieno[2,3-a]quinolizine-10-carboxamide in 27 ml of tetrahydrofuran, whereupon the reaction mixture was stirred for 24 hours. The mixture was then evaporated in vacuo, the residue was treated with water and extracted three times with methylene chloride. The organic phase was dried over sodium sulfate and evaporated in vacuo. The residue was chromatographed on silica gel with acetonitrile/diethyl ether (2:3). By recrystallization from dioxane, there was obtained 4,5-dihydro-10-(2-oxazolin-2-yl)-8-phenyl-7H-thieno[2,3-a]quinolizin-7-one of m.p. 211°-212°.
Reaction SMILES: [CH:1]1([NH:5][C:6]([C@@H:8]2[CH2:12][CH2:11][CH2:10][N:9]2[C:13](=[O:30])[CH2:14][O:15][C:16]2[N:20]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:19]=[C:18]([C:27](O)=[O:28])[CH:17]=2)=[O:7])[CH2:4][CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH2:64]([O:68][C:69](=[O:81])[NH:70][CH:71]1[CH2:76][CH2:75][N:74]([C:77](=[O:80])[CH2:78][NH2:79])[CH2:73][CH2:72]1)[CH2:65][CH2:66][CH3:67]>CN(C=O)C>[CH2:64]([O:68][C:69](=[O:81])[NH:70][CH:71]1[CH2:72][CH2:73][N:74]([C:77](=[O:80])[CH2:78][NH:79][C:27]([C:18]2[CH:17]=[C:16]([O:15][CH2:14][C:13]([N:9]3[CH2:10][CH2:11][CH2:12][C@H:8]3[C:6](=[O:7])[NH:5][CH:1]3[CH2:4][CH2:3][CH2:2]3)=[O:30])[N:20]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:19]=2)=[O:28])[CH2:75][CH2:76]1)[CH2:65][CH2:66][CH3:67]
Reactant: O=C(O)c1cc(OCC(=O)N2CCC[C@H]2C(=O)NC2CCC2)n(-c2ccccc2)n1
Reactant: CCCCOC(=O)NC1CCN(C(=O)CN)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCCCOC(=O)NC1CCN(C(=O)CNC(=O)c2cc(OCC(=O)N3CCC[C@H]3C(=O)NC3CCC3)n(-c3ccccc3)n2)CC1
Reaction time: 12 h

Procedure:
To solution of 250 mg 5-[2-((S)-2-Cyclobutylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-1-phenyl-1H-pyrazole-3-carboxylic acid in 4 ml DMF were added 231 mg HATU, 0.10 ml DIPEA and 156 mg [1-(2-Amino-acetyl)-piperidin-4-yl]-carbamic acid butyl ester. After stirring for 12 h it was concentrated and the residue dissolved in dichloromethane. It was extracted with aqueous LiCl (4% w/w), aqueous NaHCO3 and 0.1 M HCl. The organic layer was dried over MgSO4 and concentrated to furnish the crude coupling product which was further purified by preparative HPLC (C18 reverse phase column, elution with a water/MeCN gradient with 0.1% TFA) to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([C:10]2[CH:14]=[CH:13][NH:12][N:11]=2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].C([NH:22][CH2:23][C@@H:24](O)[CH3:25])(OC(C)(C)C)=O.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>>[NH2:22][CH2:23][C@@H:24]([N:12]1[CH:13]=[CH:14][C:10]([C:8]2[CH:7]=[CH:6][C:3]([C:4]#[N:5])=[C:2]([Cl:1])[CH:9]=2)=[N:11]1)[CH3:25]
Reactant: C[C@H](O)CNC(=O)OC(C)(C)C
Reactant: N#Cc1ccc(-c2cc[nH]n2)cc1Cl
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: C[C@@H](CN)n1ccc(-c2ccc(C#N)c(Cl)c2)n1

Procedure:
2-Chloro-4-(1H-pyrazol-3-yl)benzonitrile (0.91 g, 3.80 mmol) was reacted with N-Boc-(S)-1-amino-2-propanol (1.00 g, 5.71 mmol) in the presence of triphenylphosphine and DIAD using the method of Example 99. After Boc-deprotection 0.30 g (30%) of the title compound was obtained. 1H-NMR (400 MHz; d6-DMSO): δ 1.43 (d, 3H), 2.91-3.40 (m, 1H), 4.29-4.39 (m, 1H), 4.71-4.85 (m, 1H), 7.97 (d, 1H), 7.89 (d, 1H), 7.96 (d, 1H), 7.97 (d, 1H), 8.11 (dd, 1H). m/z [260.7+1].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1.[N+:11]([CH3:14])([O-:13])=[O:12].[OH-].[Na+].Cl.O>CO>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[CH:14][N+:11]([O-:13])=[O:12])=[CH:5][CH:4]=1
Reactant: C[N+](=O)[O-]
Reactant: COc1ccc(C=O)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1ccc(C=C[N+](=O)[O-])cc1
Temperature: 0 °C

Procedure:
p-Methoxybenzaldehyde (11.19 g, 82.2 mmol) and nitromethane (5.0 g, 82.2 mmol) were dissolved in methanol (20 mL) in a two-necked flask equipped with a thermometer and a pressure-equalizing dropping funnel. NaOH (4.27 g, 0.107 mol) in ice/water (10 mL) was added dropwise to the solution keeping the temperature below 15° C. A fine slurry formed during addition and additional methanol was added to allow efficient stirring. After the addition the reaction mixture was diluted with ice/water and the resulting clear solution was added dropwise to a solution of HCl/H2O (40 mL/60 mL); a yellow precipitate formed during the addition. The precipitate was filtered on a buchner funnel and crystallized from methanol obtaining 4-methoxy-β-nitrostirene (10.66 g, 72%). Yellow needles. M.p. 57-58° C. ESI-MS: 180 (MH+); (Calc. for C9H9NO3: 179 u.m.a.).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11](=[O:14])[CH:10]([CH3:15])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.OS(O)(=O)=O.[N-:21]=[N+]=[N-].[Na+].[OH-].[Na+]>C(Cl)(Cl)Cl.O>[CH2:1]([N:8]1[CH2:13][CH2:12][C:11](=[O:14])[NH:21][CH:10]([CH3:15])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [N-]=[N+]=[N-]
Reactant: CC1CN(Cc2ccccc2)CCC1=O
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: O
Product: CC1CN(Cc2ccccc2)CCC(=O)N1
Temperature: 0 °C
Reaction time: 2 h
Yield: 90.5 %

Procedure:
1-Benzyl-3-methyl-piperidin-4-one (5.00 g, 24.6 mmol) was dissolved in CHCl3 (50 mL), the reaction mixture was cooled to 0° C. and conc H2SO4 (12 mL) was added dropwise. NaN3 (3.20 g, 49.2 mmol) was added portionwise over 10 min and the reaction mixture was stirred at room temperature for 18 h and at 50° C. for 2 h. Iced water (120 mL) was added and the reaction mixture was neutralized with NaOH, extracted with DCM (2×50 mL), dried (MgSO4) and concentrated in vacuo to give the crude title compound (4.86 g, 91%) as an off-white solid. LCMS (ES+): 219.3 [MH]+.