Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:10])[C:4](=[O:9])[CH2:5][CH:6]([CH3:8])[CH3:7].CO[CH:13](OC)[N:14]([CH3:16])[CH3:15].O.[C:20]1(C)C=CC(S(O)(=O)=O)=CC=1>>[CH2:1]([O:2][C:3](=[O:10])[C:4](=[O:9])[C:5]([CH:6]([CH3:8])[CH3:7])=[CH:13][N:14]([CH3:16])[CH3:15])[CH3:20]
Reactant: COC(=O)C(=O)CC(C)C
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: COC(OC)N(C)C
Solvent: O
Product: CCOC(=O)C(=O)C(=CN(C)C)C(C)C
Temperature: 80 °C
Reaction time: 8 h

Procedure:
To a solution of 4-methyl-2-oxo-pentanoic acid methyl ester (3.8 g, 26 mmol) in N,N-dimethylformamide dimethyl acetal (7 mL, 52 mmol) is added p-toluenesulfonic acid monohydrate (30 mg). The mixture is stirred at 80° C. overnight. The reaction mixture is concentrated under reduced pressure to give 3-isopropyl-4-dimethylamino-2-oxo-but-3-enoic acid ethyl ester as an orange oil. To a solution of 3-isopropyl-4-dimethylamino-2-oxo-but-3-enoic acid ethyl ester and 2,6-dichlorophenylhydrazine hydrochloride (2.8 g, 13 mmol) in EtOH (40 mL) is added concentrated HCl (0.5 mL). The mixture is stirred at ambient temperature for 2 h followed by refluxing overnight. The reaction mixture is concentrated and the residue is partitioned between EtOAc and 1N HCl. The organic phase is dried (Na2SO4) and concentrated to a residue. The residue is purified by column chromatography (0-15% EtOAc in hexanes) to give the title compound as an oil (2.2 g, 52%). 1H NMR (CDCl3): δ 7.76 (s, 1H), 7.43 (d, 2H), 7.34 (dd, 1H), 3.75 (s, 3H), 3.48 (m, 1H), 1.32 (d, 6H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[Cl:10].[C:11](Cl)(=[O:18])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]>>[C:11]([NH:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[Cl:10])(=[O:18])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: CCCCCCC(=O)Cl
Reactant: NCCc1ccccc1Cl
Product: CCCCCCC(=O)NCCc1ccccc1Cl

Procedure:
1-Amino-2-(2-chlorophenyl)ethane and n-heptanoyl chloride were reacted in the same way as in step (a) of Example 13 to afford 1-n-heptanoylamino-2-(2-chlorophenyl)ethane as an oil. The product was successively reacted in the same way as in steps (b), (c), (d), (e), (f), (g) and (h) of Example 13 to afford 1-n-hexylisoquinoline-5-acetonitrile.
Reaction SMILES: [Na].C(OC(=O)C)(=O)C.C([O-])(=O)C.[K+].[CH3:14][Si:15]([CH3:46])([CH3:45])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][NH:30][C:31]1[CH:36]=[CH:35][C:34]([CH:37](O)[CH2:38][C:39]([O:41][CH2:42][CH3:43])=[O:40])=[CH:33][CH:32]=1>C(OCC)(=O)C>[CH3:46][Si:15]([CH3:14])([CH3:45])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][NH:30][C:31]1[CH:32]=[CH:33][C:34]([CH:37]=[CH:38][C:39]([O:41][CH2:42][CH3:43])=[O:40])=[CH:35][CH:36]=1
Reactant: CCOC(=O)CC(O)c1ccc(NCCCCCCCCCCCCCC[Si](C)(C)C)cc1
Agent: CC(=O)[O-]
Agent: [K+]
Agent: [Na]
Solvent: CCOC(C)=O
Solvent: CC(=O)OC(C)=O
Product: CCOC(=O)C=Cc1ccc(NCCCCCCCCCCCCCC[Si](C)(C)C)cc1

Procedure:
The [4-(trialkylsilylalkylamino)phenyl]alkenoic acids may be prepared by condensation of the appropriate aldehydes or by dehydration of the corresponding substituted-phenyl-hydroxyalkanoic acids. For example, ethyl 5-[4-[14-(trimethylsilyl)tetradecylamino]phenyl]-2,4-pentadienoate is obtained by the Wittig reaction of 4-[14-(trimethylsilyl)tetradecylamino]benzaldehyde with the Wittig reagent, triethyl 4-phosphonocrotonate. Alternatively, these alkenoic acids are obtained by heating 4-[N-trialkylsilylalkyl-N-(methyl or acetyl)amino]benzaldehydes with the sodium salt of the carbanion of ethyl acetate or with a mixture of ethyl acetate, acetic anhydride and potassium acetate. The second method is illustrated by dehydration of ethyl 3-[4-[14-(trimethylsilyl)tetradecylamino]phenyl]-3-hydroxypropionate to yield ethyl 4-[14-(trimethylsilyl)tetradecylamino]cinnamate.
Reaction SMILES: [CH2:1]1[CH2:10][O:9][C:8]2[CH:7]=[CH:6][C:5]([NH:11][NH2:12])=[CH:4][C:3]=2[O:2]1.[CH:13](=O)[CH3:14]>CCOCC>[CH2:1]1[CH2:10][O:9][C:8]2[CH:7]=[CH:6][C:5]([NH:11][N:12]=[CH:13][CH3:14])=[CH:4][C:3]=2[O:2]1
Reactant: NNc1ccc2c(c1)OCCO2
Reactant: CC=O
Solvent: CCOCC
Product: CC=NNc1ccc2c(c1)OCCO2
Reaction time: 2 h
Yield: 78.3 %

Procedure:
To a solution of 17 g of 3,4-ethylenedioxyphenylhydrazine in 100 ml of ether was added dropwise 11 g of 80 % acetaldehyde at 5° - 10° C over a period of 30 minutes. After stirring for an additional two hours at 5° - 10° C, the ethereal solution was separated, and dried over anhydrous sodium sulfate. The ether was evaporated, and the resultant residue was distilled to give 15.4 g of acetaldehyde-3,4-ethylenedioxyphenylhydrazone having a boiling point of 139° - 142° C (0.15 mmHg).
Reaction SMILES: [C:1]([NH:14][C@H:15]([CH2:41][O:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH3:58])[CH2:16][S:17][CH2:18][C@@H:19]([C:38]([OH:40])=O)[NH:20][C:21](=[O:37])[O:22][CH2:23][CH:24]1[C:36]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[C:30]2[C:25]1=[CH:26][CH:27]=[CH:28][CH:29]=2)(=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.Cl.[NH2:93][C:94]1([CH2:97][OH:98])[CH2:96][CH2:95]1>C(Cl)Cl>[C:1]([NH:14][C@H:15]([CH2:41][O:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH3:58])[CH2:16][S:17][CH2:18][C@H:19]([NH:20][C:21](=[O:37])[O:22][CH2:23][CH:24]1[C:36]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[C:30]2[C:25]1=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:38]([NH:93][C:94]1([CH2:97][OH:98])[CH2:96][CH2:95]1)=[O:40])(=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCCCCCCOC[C@H](CSC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O)NC(=O)CCCCCCCCCCC
Reactant: NC1(CO)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCCCCCCCCCCCCCCCOC[C@H](CSC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)NC1(CO)CC1)NC(=O)CCCCCCCCCCC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (5R,9R)-9-dodecanamido-1-(9H-fluoren-9-yl)-3-oxo-2,11-dioxa-7-thia-4-azaheptacosane-5-carboxylic acid (1 eq) and HBTU (1.2 eq) in DCM (0.06 M) was added DIEA (3.5 eq), followed by (1-aminocyclopropyl)methanol hydrochloride (1.2 eq). The reaction was stirred at room temperature for 2 hr. The crude mixture was purified by flash chromatography on a COMBIFLASH® system (ISCO) using 30-50% EtOAc/Hex to give (9H-fluoren-9-yl)methyl(R)-3-((R)-2-dodecanamido-3-(hexadecyloxy)propylthio)-1-(1-(hydroxymethyl)cyclopropylamino)-1-oxopropan-2-ylcarbamate.
Reaction SMILES: [CH3:1][CH:2]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]([CH3:12])[CH3:11])[C:5]=1[NH:13][C:14]([NH:16][S:17](Cl)(=[O:19])=[O:18])=[O:15])[CH3:3].[CH:21]([NH2:34])([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(N(CC)CC)C>CCOCC>[CH3:1][CH:2]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]([CH3:12])[CH3:11])[C:5]=1[NH:13][C:14]([NH:16][S:17]([NH:34][CH:21]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)(=[O:19])=[O:18])=[O:15])[CH3:3]
Reactant: CC(C)c1cccc(C(C)C)c1NC(=O)NS(=O)(=O)Cl
Reactant: NC(c1ccccc1)c1ccccc1
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CC(C)c1cccc(C(C)C)c1NC(=O)NS(=O)(=O)NC(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 33.9 %

Procedure:
A solution of [[[2,6-bis(1-methylethyl)phenyl]-amino]carbonyl]sulfamoyl chloride (1.0 g, 3.1 mmoles) in 60 mL Et2O was added dropwise to a solution of benzhydrylamine (0.56 g, 3.1 mmoles) and 0.5 mL triethylamine (3.4 mmoles) in 60 mL Et2O at -15° C. (acetone/ice bath) under an atmosphere of N2. The resulting suspension was warmed to 25° C. and stirred for 16 hours. This was then partitioned between 1N HCl and EtOAc. The EtOAc layer was dried with MgSO4, filtered, and evaporated to give an off-white solid. Chromatography (SiO2, 30% EtOAc/hexanes) gave 0.49 g (34%) of the title compound as a white solid, mp 182°-185° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[C:5]([CH:7]1[CH2:12][CH2:11][N:10]([CH3:13])[CH2:9][CH2:8]1)=[O:6].[F:17][C:18]1[CH:19]=[C:20]([CH:24]=[C:25]([F:28])[C:26]=1[F:27])[C:21](Cl)=[O:22]>>[F:17][C:18]1[CH:19]=[C:20]([CH:24]=[C:25]([F:28])[C:26]=1[F:27])[C:21]([NH:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[C:5]([CH:7]1[CH2:8][CH2:9][N:10]([CH3:13])[CH2:11][CH2:12]1)=[O:6])=[O:22]
Reactant: O=C(Cl)c1cc(F)c(F)c(F)c1
Reactant: CN1CCC(C(=O)c2cccc(N)c2)CC1
Product: CN1CCC(C(=O)c2cccc(NC(=O)c3cc(F)c(F)c(F)c3)c2)CC1
Yield: 98.2 %

Procedure:
Following the example above and beginning with 4-[3-aminobenzoyl]-1-methylpiperidine (25 mg, 0.115 mmol) and 3,4,5-trifluorobenzoyl chloride (30 μL, 0.229 mmol), 42.5 mg (99%) of the title compound were recovered.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:10]=[C:11]([CH:19]=[CH:20][CH:21]=2)[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[N:5]2[N:22]=[CH:23][CH:24]=[C:4]2[N:3]=1.[Cl:25][C:26]1[CH:27]=[C:28]([CH:30]=[CH:31][CH:32]=1)[NH2:29].Cl.O1CCOCC1.[OH-].[Na+]>O.C(O)(C)(C)C>[Cl:25][C:26]1[CH:27]=[C:28]([NH:29][C:2]2[CH:7]=[C:6]([NH:8][C:9]3[CH:10]=[C:11]([CH:19]=[CH:20][CH:21]=3)[C:12]([O:14][C:15]([CH3:17])([CH3:18])[CH3:16])=[O:13])[N:5]3[N:22]=[CH:23][CH:24]=[C:4]3[N:3]=2)[CH:30]=[CH:31][CH:32]=1
Reactant: Nc1cccc(Cl)c1
Reactant: CC(C)(C)OC(=O)c1cccc(Nc2cc(Cl)nc3ccnn23)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)(C)O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)c1cccc(Nc2cc(Nc3cccc(Cl)c3)nc3ccnn23)c1
Temperature: 100 °C
Reaction time: 48 h
Yield: 55 %

Procedure:
To the reaction flask, tert-butyl 3-(5-chloropyrazolo[1,5-a]pyrimidin-7-ylamino)benzoate (2.9 g, 8.2 mmol) was added along with 3-chloroaniline (2.2 mL, 20.6 mmol), 4N HCl in dioxane (2.6 mL, 10.4 mmol), and t-butyl alcohol (41 mL). The reaction was stirred at 100° C. for 2 days then cooled to room temperature. The mixture was diluted with water, made basic with 3N NaOH, filtered and washed with water. The product, tert-butyl 3-(5-(3-chlorophenylamino)pyrazolo[1,5-a]pyrimidin-7-ylamino)benzoate, was collected as a solid in 55% yield after drying under vacuum overnight. LCMS (M+1=436)
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([NH2:9])=[C:4]([NH2:10])[CH:3]=1.[Cl:11][CH2:12][C:13](O)=O.C(=O)([O-])[O-].[Na+].[Na+]>Cl.O>[Cl:11][CH2:12][C:13]1[NH:9][C:5]2[CH:6]=[C:7]([CH3:8])[C:2]([CH3:1])=[CH:3][C:4]=2[N:10]=1
Reactant: O=C(O)CCl
Reactant: Cc1cc(N)c(N)cc1C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: Cc1cc2nc(CCl)[nH]c2cc1C
Temperature: 25 °C
Yield: 54.5 %

Procedure:
To a stirred solution of 4,5-dimethylphenylene-1,2-diamine (680 mg, 5 mmol) in 4N HCl (12 mL) was added chloroacetic acid (940 mg, 10 mmol). The solution was then heated to reflux for 17 hours, then cooled to room temperature. Solid sodium carbonate was then added slowly, with stirring, until the pH of the solution was approximately 9.0, at which point a beige precipitate formed. The aqueous phase was then diluted with water (10 mL) and extracted repeatedly with ethyl acetate. The combined organic fractions were then dried, concentrated and the residue was purified by column chromatography on silica gel (10% MeOH in CH2Cl2) to afford the desired 2-(chloromethyl)-5,6-dimethylbenzimidazole (530 mg, 54%). 1H NMR (CDCl3) δ 1.59 (br s, 1H), 2.31 (s, 6H), 4.83 (s, 2H), 7.42 (s, 2H).
Reaction SMILES: [NH:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4](=[O:5])[C:2]1=[O:3].[H-].[Na+].[CH2:14](Br)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CN(C)C=O>[CH2:14]([N:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4](=[O:5])[C:2]1=[O:3])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: BrCc1ccccc1
Reactant: O=C1Nc2ccccc2C1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1C(=O)N(Cc2ccccc2)c2ccccc21
Reaction time: 0.5 h
Yield: 66.7 %

Procedure:
A solution of 44 g of isatin in 200 ml of N,N-dimethylformamide was added dropwise to a suspension of 16.0 g of sodium hydride (60%) in 100 ml of N,N-dimethylformamide at 0° C. in a nitrogen stream. After the mixture was stirred at that temperature for 30 minutes, a solution of 61.5 g of benzyl bromide in 100 ml of N,N-dimethylformamide was added thereto. The whole mixture was stirred for 1 hour and then concentrated. Chloroform was added to the residue, and the mixture was washed with saturated aqueous sodium hydrogencarbonate. The organic layer was dried over anhydrous sodium sulfate and concentrated. The resulting crude product was washed with hexane and recrystallized from ethanol to give 47.3 g (67%) of the title compound as red needles.
Reaction SMILES: [I:1][C:2]1[C:7]2[C:8](=[O:25])[N:9]3[CH2:24][CH2:23][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]([O:18][C:19]([CH3:22])(C)[CH3:20])=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH:26]1(O)[CH2:31]CCC[CH2:27]1>CCO.CCO.CCO.CCO.[Ti].[F-].[K+]>[I:1][C:2]1[C:7]2[C:8](=[O:25])[N:9]3[CH2:24][CH2:23][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]([O:18][CH:19]3[CH2:20][CH2:31][CH2:26][CH2:27][CH2:22]3)=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: OC1CCCCC1
Reactant: CC(C)(C)OC(=O)c1ncn2c1[C@@H]1CCN1C(=O)c1c(I)cccc1-2
Agent: [Ti]
Agent: [F-]
Agent: [K+]
Solvent: CCO
Product: O=C(OC1CCCCC1)c1ncn2c1[C@@H]1CCN1C(=O)c1c(I)cccc1-2

Procedure:
12 g (26.6 mmol) of tert.butyl (S)-12,12a-dihydro-8-iodo-9-oxo-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepine-1-carboxylate, 70 ml (660 mmol) of cyclohexanol and 2 g (8 mmol) of tetraethyl orthotitanate are stirred at 120° overnight, the solution is evaporated to dryness and the residue is taken up in chloroform. The solution obtained is stirred for 0.5 hour with 120 ml of a saturated potassium fluoride solution, the resulting emulsion is filtered through siliceous earth, the organic phase is separated, washed with water, dried over magnesium sulphate and evaporated. By crystallization from ethyl acetate and hexane there is obtained cyclohexyl (S)-12,12a-dihydro-8-iodo-9-oxo-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepine-1-carboxylate of melting point 124°-125°.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:16]=[C:15]([NH2:17])[N:14]=[C:13]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][C:26]4[CH:31]=[CH:30][N:29]=[C:28]([CH3:32])[CH:27]=4)=[CH:21][CH:20]=3)[CH:12]=2)=[CH:7][CH:6]=1.[NH:33]1[CH2:37][CH2:36][CH2:35][CH2:34]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH3:32][C:28]1[CH:27]=[C:26]([O:25][C:22]2[CH:23]=[CH:24][C:19]([NH:18][C:13]3[CH:12]=[C:11]([C:8]4[CH:9]=[CH:10][C:5]([O:4][CH2:3][CH2:2][N:33]5[CH2:37][CH2:36][CH2:35][CH2:34]5)=[CH:6][CH:7]=4)[N:16]=[C:15]([NH2:17])[N:14]=3)=[CH:20][CH:21]=2)[CH:31]=[CH:30][N:29]=1
Reactant: Cc1cc(Oc2ccc(Nc3cc(-c4ccc(OCCBr)cc4)nc(N)n3)cc2)ccn1
Reactant: C1CCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(Oc2ccc(Nc3cc(-c4ccc(OCCN5CCCC5)cc4)nc(N)n3)cc2)ccn1
Temperature: 65 °C
Reaction time: 8 h

Procedure:
A mixture of the product from Step 3 (1 equiv), pyrrolidine (2 equiv) and K2CO3 (8 equiv) in DMF is stirred at 65° C. overnight. The solvent is removed and the residue is dissolved in EtOAc. The organic solution is washed with water, dried, and evaporated to dryness. The residue is purified by chromatography on a silica column to afford the title compound.
Reaction SMILES: B1(C)OC(C2C=CC=CC=2)(C2C=CC=CC=2)[C@@H]2N1CCC2.[O:22]=[C:23]1[C:31]2[CH:30]=[CH:29][CH:28]=[C:27]([C:32]#[N:33])[C:26]=2[CH2:25][CH2:24]1>C1(C)C=CC=CC=1.B.CSC.C(Cl)Cl>[OH:22][C@@H:23]1[C:31]2[CH:30]=[CH:29][CH:28]=[C:27]([C:32]#[N:33])[C:26]=2[CH2:25][CH2:24]1
Reactant: N#Cc1cccc2c1CCC2=O
Agent: B
Agent: CB1OC(c2ccccc2)(c2ccccc2)[C@H]2CCCN12
Solvent: Cc1ccccc1
Solvent: CSC
Solvent: ClCCl
Product: N#Cc1cccc2c1CC[C@@H]2O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 78 %

Procedure:
To a 3-neck flask with an internal thermometer and an addition funnel was added (R)-(+)-2-methyl-CBS-oxazaborolidine solution in toluene (3.0 mL) and borane-dimethylsulfide (300 μL). The reaction was stirred at room temperature for 10 min then diluted with DCM (25 mL). Borane-dimethylsulfide (6.0 mL) was added and, after stirring for 5 min, the reaction was cooled to −20° C. 1-Oxo-2,3-dihydro-1H-indene-4-carbonitrile INT-1 (4.7 g, 30 mmol) in DCM (25 mL) was added dropwise by addition funnel over 20 min while maintaining the reaction at −20±5° C. The reaction was stirred for 1 h then quenched by the dropwise addition of MeOH (20 mL). After hydrogen evolution ceased, MeOH (30 mL) was added and removed by heating at atmospheric pressure. MeOH (50 mL) was added in two and removed by heating twice. All the solvent was evaporated to give a solid which was recrystallized from EA (9 mL) and hexane (22 mL). The compound was filtered and washed with 5:1 hexane/EA (30 mL) to provide 3.73 g (78%) of (S)-1-hydroxy-2,3-dihydro-1H-indene-4-carbonitrile INT-2 as a white powder. LCMS-ESI (m/z) calculated for C10H9NO: 159.1. found 160.1 [M+H]+, tR=2.39 min. 1H NMR (400 MHz, CDCl3) δ 7.62 (d, J=7.6 Hz, 1H), 7.53 (d, J=7.6 Hz, 1H), 7.32 (t, J=7.6 Hz, 1H), 5.28 (d, J=4.1 Hz, 1H), 3.23 (ddd, J=17.0, 8.7, 4.4 Hz, 1H), 3.04-2.90 (m, 1H), 2.64-2.51 (m, 1H), 2.00 (dddd, J=13.4, 8.7, 7.1, 5.7 Hz, 1H), 1.91 (d, J=5.4 Hz, 1H). Chiral HPLC: (S)-1-hydroxy-2,3-dihydro-1H-indene-4-carbonitrile was eluted in 20% IPA in hexane: >99.9% ee, tR=7.42 min. The (R)-enantiomer was obtained in an analogous fashion using (S)-(−)-2-methyl-CBS-oxazaborolidine. tR for (R)-enantiomer=6.79 min.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:34])[CH2:4][CH2:5][CH2:6]/[CH:7]=[CH:8]\[CH2:9][C@H:10]1[C@H:14]([Cl:15])[CH2:13][C@@H:12]([O:16]C2CCCCO2)[C@@H:11]1/[CH:23]=[CH:24]/[C:25](=[O:33])[C:26]([CH3:32])([CH3:31])[CH2:27][CH2:28][CH2:29][CH3:30]>C(O)(=O)C.O.O1CCCC1>[CH3:1][O:2][C:3](=[O:34])[CH:4]=[CH:5][CH2:6][CH2:7][CH2:8][CH3:9].[CH3:1][O:2][C:3](=[O:34])[CH2:4][CH2:5][CH2:6]/[CH:7]=[CH:8]\[CH2:9][C@H:10]1[C@H:14]([Cl:15])[CH2:13][C@@H:12]([OH:16])[C@@H:11]1/[CH:23]=[CH:24]/[C:25](=[O:33])[C:26]([CH3:32])([CH3:31])[CH2:27][CH2:28][CH2:29][CH3:30]
Reactant: CCCCC(C)(C)C(=O)/C=C/[C@@H]1[C@@H](C/C=C\CCCC(=O)OC)[C@H](Cl)C[C@H]1OC1CCCCO1
Solvent: O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CCCCC(C)(C)C(=O)/C=C/[C@@H]1[C@@H](C/C=C\CCCC(=O)OC)[C@H](Cl)C[C@H]1O
Product: CCCCC=CC(=O)OC
Yield: 128.9 %

Procedure:
1 g of VIII is stirred for 24 hours at 40° C. with 25 ml of a mixture of glacial acetic acid-water-tetrahydrofuran (65/35/10). It is concentrated by evaporation in a vacuum, chromatographed on silica gel with hexane/10-50% ethyl acetate, and 720 mg of IX is obtained as oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][C:10]([N:12]2[CH2:27][CH2:26][C:15]3([CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16]3)[CH2:14][CH2:13]2)=[O:11])=[N:7][CH:8]=1.[ClH:28]>O1CCOCC1.C(OCC)(=O)C>[ClH:28].[ClH:28].[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][C:10]([N:12]2[CH2:13][CH2:14][C:15]3([CH2:18][NH:17][CH2:16]3)[CH2:26][CH2:27]2)=[O:11])=[N:7][CH:8]=1
Reactant: COc1ccc(CC(=O)N2CCC3(CC2)CN(C(=O)OC(C)(C)C)C3)nc1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COc1ccc(CC(=O)N2CCC3(CC2)CNC3)nc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 78 %

Procedure:
To a solution of tert-butyl 7-[(5-methoxypyridin-2-yl)acetyl]-2,7-diazaspiro[3.5]nonane-2-carboxylate (2-1a, 2.57 g, 6.85 mmol) in dioxane (5 mL) was added 4N HCl in dioxane (1.72 mL). The mixture was stirred at room temperature for 5 hours and heated at 45° C. overnight. The light-yellow mixture was concentrated to give a light-yellow sticky foam. The residue was suspended in ethyl acetate and evaporated to dryness (3×) to afford the title compound (2-1b, 1.86 g, 78%) MS (ES+) 276.4 (M+H)+. 1H NMR (CD3OD) δ 2.17-2.42 (m, 2H), 2.48 (d, 2H), 3.94-4.13 (m, 4H), 4.40 (d, 4H), 4.51 (s, 3H), 4.74 (s, 2H), 8.34 (d, 1H), 8.61-8.64 (m, 1H), 8.99-9.01 (m 1H).
Reaction SMILES: Br[C:2]1[C:3]2[N:4]([N:8]=[C:9]([Cl:11])[N:10]=2)[CH:5]=[CH:6][CH:7]=1.[NH2:12][C:13]1[CH:25]=[CH:24][CH:23]=[CH:22][C:14]=1[CH2:15][N:16]([CH3:21])[S:17]([CH3:20])(=[O:19])=[O:18]>>[Cl:11][C:9]1[N:10]=[C:3]2[C:2]([NH:12][C:13]3[CH:25]=[CH:24][CH:23]=[CH:22][C:14]=3[CH2:15][N:16]([CH3:21])[S:17]([CH3:20])(=[O:19])=[O:18])=[CH:7][CH:6]=[CH:5][N:4]2[N:8]=1
Reactant: CN(Cc1ccccc1N)S(C)(=O)=O
Reactant: Clc1nc2c(Br)cccn2n1
Product: CN(Cc1ccccc1Nc1cccn2nc(Cl)nc12)S(C)(=O)=O

Procedure:
171 c) N-[2-(2-Chloro-[1,2,4]triazolo[1,5-a]pyridin-8-ylamino)-benzyl]-N-methyl-methanesulfonamide was prepared from 8-bromo-2-chloro-[1,2,4]triazolo[1,5-a]pyridine (500.0 mg, 2.151 mmol) and N-(2-amino-benzyl)-N-methyl-methanesulfonamide (507.0 mg, 2.366 mmol) in a manner analogous to Example 2d. Product isolated as a tan foam (0.53 g, 67%). 1H NMR (400 MHz, CDCl3, δ, ppm): 8.01 (d, J=6.4 Hz, 1H), 7.48-7.41 (m, 2H), 7.38 (t, J=7.4 Hz, 1H), 7.21 (t, J=7.4 Hz, 1H), 7.10 (s, 1H), 6.90-6.81 (m, 2H), 4.36 (s, 2H), 3.02 (s, 3H), 2.76 (s, 3H). MS=366 (MH)+. 171 d) N-Methyl-N-(2-{2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-[1,2,4]triazolo[1,5-a]pyridin-8-ylamino}-benzyl)-methanesulfonamide was prepared from N-[2-(2-chloro-[1,2,4]triazolo[1,5-a]pyridin-8-ylamino)-benzyl]-N-methyl-methanesulfonamide (75.0 mg, 0.205 mmol) and 4-(4-methyl-piperazin-1-yl)-phenylamine (44.0 mg, 0.230 mmol) with 2,2′-bis-dicyclohexylphosphanyl-biphenyl (25.0 mg, 0.0457 mmol) as the ligand in a manner analogous to Example 2d. Product isolated as a brown foam (0.019 g, 18%). 1H NMR (400 MHz, CDCl3, δ, ppm): 7.94 (d, J=6.5 Hz, 1H), 7.51 (d, J=8.7 Hz, 2H), 7.45-7.39 (m, 2H), 7.35 (t, J=7.2 Hz, 1H), 7.13 (t, J=7.4 Hz, 1H), 7.00-6.94 (m, 3H), 6.81 (d, J=7.7 Hz, 1H), 6.68 (t, J=7.2 Hz, 1H), 6.60 (s, 1H), 4.36 (s, 2H), 3.18-3.13 (m, 4H), 2.91 (s, 3H), 2.78 (s, 3H), 2.62-2.57 (m, 4H), 2.36 (s, 3H). MS=521 (MH)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH2:15][CH2:16]O)=[N:13][N:14]=[C:10]3[CH2:9][N:8]=[C:7]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:6]=2[CH:24]=1.[C:25]1(=[O:35])[NH:29][C:28](=[O:30])[C:27]2=[CH:31][CH:32]=[CH:33][CH:34]=[C:26]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC)=O)=NC(OC)=O>O1CCOCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH2:15][CH2:16][N:29]4[C:25](=[O:35])[C:26]5=[CH:34][CH:33]=[CH:32][CH:31]=[C:27]5[C:28]4=[O:30])=[N:13][N:14]=[C:10]3[CH2:9][N:8]=[C:7]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:6]=2[CH:24]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: OCCc1nnc2n1-c1ccc(F)cc1C(c1ccccc1)=NC2
Agent: COC(=O)N=NC(=O)OC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: O=C1c2ccccc2C(=O)N1CCc1nnc2n1-c1ccc(F)cc1C(c1ccccc1)=NC2

Procedure:
In the manner given in Example 2, 8-fluoro-1-(2-hydroxyethyl)-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine in dioxane is treated with phthalimide, triphenylphosphine and subsequently with dimethyl azodicarboxylate to give 8-fluoro-1-(2-phthalimidoethyl)-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine.