Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](Cl)(=[O:5])[O:2][CH2:3][CH3:4].Cl.[C:8](=[N:16][OH:17])([NH2:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C(Cl)(Cl)Cl>[CH2:3]([O:2][C:1]([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[C:8](=[N:16][OH:17])[NH2:15])=[O:5])[CH3:4]
Reactant: NC(=NO)c1ccccc1
Reactant: CCOC(=O)Cl
Agent: Cl
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1ccccc1C(N)=NO
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Following the known process [Ber, 18, 2467 (1875)], a solution of 13.4 ml (0.14 mol) of ethyl chlorocarbonate in 100 ml of chloroform was added dropwise to a solution of 38.2 g (0.28 mol) of benzamidoxime hydrochloride in 380 ml of chloroform. After completion of the dropwise addition, the reaction mixture was stirred at room temperature for 3 hours. The benzamidoxime thus precipitated was filtered off and the filtrate was concentrated under reduced pressure. The residue was dissolved in 100 ml of ethyl alcohol, to which 30 ml, of water were added. Most ethyl alcohol was then distilled off under reduced pressure. Crystals thus formed were collected by filtration, washed with water and then dried under reduced pressure, whereby the title compound was obtained as colorless crystals.
Reaction SMILES: C[O:2][C:3](=[O:38])[CH:4]([C:13]1[CH:18]=[CH:17][C:16](/[CH:19]=[CH:20]/[C:21](=[O:37])[NH:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[NH:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])=[CH:15][CH:14]=1)[CH2:5][CH:6]1[CH2:11][CH2:10][N:9]([CH3:12])[CH2:8][CH2:7]1.[Li+].[OH-].Cl>CO.O>[C:33]([O:32][C:30]([NH:29][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1[NH:22][C:21](/[CH:20]=[CH:19]/[C:16]1[CH:15]=[CH:14][C:13]([CH:4]([CH2:5][CH:6]2[CH2:7][CH2:8][N:9]([CH3:12])[CH2:10][CH2:11]2)[C:3]([OH:38])=[O:2])=[CH:18][CH:17]=1)=[O:37])=[O:31])([CH3:36])([CH3:35])[CH3:34]
Reactant: COC(=O)C(CC1CCN(C)CC1)c1ccc(/C=C/C(=O)Nc2ccccc2NC(=O)OC(C)(C)C)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CN1CCC(CC(C(=O)O)c2ccc(/C=C/C(=O)Nc3ccccc3NC(=O)OC(C)(C)C)cc2)CC1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of (E)-2-{4-[2-(2-tert-butoxycarbonylamino-phenylcarbamoyl)-vinyl]-phenyl}-3-(1-methyl-piperidin-4-yl)-propionic acid methyl ester (52.1 mg, 10 mmol) in MeOH/H2O (4:1) (2 mL), LiOH (24 mg, 100 mmol.) was added. After the solution was stirred at room temperature for 5 h, the solution was neutralized with 2N HCl to pH 5-6. The mixture was evaporated to dryness under reduced pressure, then EtOAc (10 mL) was added. The organic layer was washed with brine, dried with Na2SO4, filtered, and evaporated to obtain a yellow solid product without further purification. MS: calc'd 508 (MH+), exp 508 (MH+).
Reaction SMILES: [N+:1]([C:4]1[C:5]([N:22]2[CH2:27][CH2:26][CH2:25][C@H:24]([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[CH2:23]2)=[C:6]2[CH:12]=[CH:11][N:10]([S:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)(=[O:15])=[O:14])[C:7]2=[N:8][CH:9]=1)([O-])=O.[NH4+].[Cl-].CCO>[Fe].O>[NH2:1][C:4]1[C:5]([N:22]2[CH2:27][CH2:26][CH2:25][C@H:24]([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:33])([CH3:32])[CH3:34])[CH2:23]2)=[C:6]2[CH:12]=[CH:11][N:10]([S:13]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)(=[O:15])=[O:14])[C:7]2=[N:8][CH:9]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCN(c2c([N+](=O)[O-])cnc3c2ccn3S(=O)(=O)c2ccccc2)C1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)N[C@H]1CCCN(c2c(N)cnc3c2ccn3S(=O)(=O)c2ccccc2)C1
Temperature: 80 °C
Reaction time: 2 h
Yield: 72.7 %

Procedure:
To a vial containing tert-butyl {(3S)-1-[5-nitro-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]piperidin-3-yl}carbamate (719.5 mg, 1.434 mmol), iron powder (793.6 mg, 14.21 mmol) and NH4Cl (1147.6 mg, 21.454 mmol), EtOH (10.00 mL) was added followed by water (2.00 mL). The mixture was stirred at 80° C. for 2 h. The reaction mixture was then filtered through a pad of diatomaceous earth. The pad was eluted with 10% aq. K3PO4 (50 mL) and EtOAc (50 mL). The organic layer was washed with brine (50 mL), then dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (0-100% EtOAc in hexanes) to give the sub-title compound as a dark solid (491.8 mg, 73%). LCMS calc. for C23H30N5O4S (M+H)+: m/z=472.2. found 472.2.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][N:5]=[C:6]2[C:13]=1[C:12]1[C@@H:11]([CH2:14][CH:15]([OH:18])[C:16]#[N:17])[CH2:10][CH2:9][C:8]=1[S:7]2.[C:19]([Si:23](Cl)([CH3:25])[CH3:24])([CH3:22])([CH3:21])[CH3:20].N1C=CN=C1>CN(C=O)C.C(Cl)Cl>[Si:23]([O:18][CH:15]([CH2:14][C@H:11]1[CH2:10][CH2:9][C:8]2[S:7][C:6]3[C:13](=[C:2]([Cl:1])[N:3]=[CH:4][N:5]=3)[C:12]1=2)[C:16]#[N:17])([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:25])[CH3:24]
Reactant: N#CC(O)C[C@H]1CCc2sc3ncnc(Cl)c3c21
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OC(C#N)C[C@H]1CCc2sc3ncnc(Cl)c3c21
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.2 %

Procedure:
To a solution of 3-[(3R)-12-chloro-7-thia-9,11-diazatricyclo[6.4.0.0^[2,6]]dodeca-1(12),2(6),8,10-tetraen-3-yl]-2-hydroxypropanenitrile (170 mg, 0.61 mmol, 1.00 equiv) in 5 mL of distilled DMF was added tert-butyl(chloro)dimethylsilane (138 mg, 0.92 mmol, 1.50 equiv) and imidazole (124 mg, 1.82 mmol, 3.00 equiv) at room temperature under nitrogen. The resulting solution was stirred for 2 h at ambient temperature and diluted with DCM (30 mL), washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum to give 236 mg (99%) of 2-[(tert-butyldimethylsilyl)oxy]-3-[(3R)-12-chloro-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(12),2(6),8,10-tetraen-3-yl]propanenitrile as a white solid. MS: m/z 395 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:14]([CH2:15][O:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:13]=[C:12]([C:24]#[C:25][CH2:26][CH2:27][OH:28])[C:4]=2[N:5]=[C:6]([CH2:8][CH2:9][CH2:10][CH3:11])[N:7]=1>C(OCC)(=O)C.C(O)C.[Pd]>[NH2:1][C:2]1[C:3]2[N:14]([CH2:15][O:16][CH2:17][C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:13]=[C:12]([CH2:24][CH2:25][CH2:26][CH2:27][OH:28])[C:4]=2[N:5]=[C:6]([CH2:8][CH2:9][CH2:10][CH3:11])[N:7]=1
Reactant: CCCCc1nc(N)c2c(n1)c(C#CCCO)cn2COCc1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCCCc1nc(N)c2c(n1)c(CCCCO)cn2COCc1ccccc1

Procedure:
A solution of 4-(4-amino-5-((benzyloxy)methyl)-2-butyl-5H-pyrrolo[3,2-d]pyrimidin-7-yl)but-3-yn-1-ol (948 mg, 2.505 mmol) in ethyl acetate (50 mL) and ethanol (50 mL) was hydrogenated using the H-cube (settings: 25° C., Full H2, 1 mL/min flow rate) and 10% Pd/C CatCart 70 as the catalyst. The reaction mixture was concentrated in vacuo at 60° C. to give the title compound as a viscous yellow oil which crystallised on standing (884 mg).
Reaction SMILES: [CH3:1][C@H:2]1[NH:7][C@@H:6]([CH3:8])[CH2:5][N:4]([C:9]2[N:10]([CH2:31][C:32]([F:35])([F:34])[F:33])[C:11]3[C:16]([N:17]=2)=[C:15]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[N:14]=[C:13]([C:24]2[CH:25]=[N:26][C:27]([NH2:30])=[N:28][CH:29]=2)[N:12]=3)[CH2:3]1.[O:36]1CCC[CH2:37]1.CN(CCS(O)(=O)=O)C>C(Cl)Cl>[NH2:30][C:27]1[N:28]=[CH:29][C:24]([C:13]2[N:12]=[C:11]3[C:16]([N:17]=[C:9]([N:4]4[CH2:3][C@@H:2]([CH3:1])[N:7]([CH:37]=[O:36])[C@@H:6]([CH3:8])[CH2:5]4)[N:10]3[CH2:31][C:32]([F:35])([F:34])[F:33])=[C:15]([N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[N:14]=2)=[CH:25][N:26]=1
Reactant: C[C@@H]1CN(c2nc3c(N4CCOCC4)nc(-c4cnc(N)nc4)nc3n2CC(F)(F)F)C[C@H](C)N1
Reactant: C1CCOC1
Agent: CN(C)CCS(=O)(=O)O
Solvent: ClCCl
Product: C[C@@H]1CN(c2nc3c(N4CCOCC4)nc(-c4cnc(N)nc4)nc3n2CC(F)(F)F)C[C@H](C)N1C=O
Reaction time: 24 h
Yield: 91 %

Procedure:
5-[8-(cis-3,5-Dimethylpiperazin-1-yl)-6-morpholin-4-yl-9-(2,2,2-trifluoroethyl)-9H-purin-2-yl]pyrimidin-2-amine (101.7 mg, 0.21 mmol) were added to a tetrahydrofuran solution (5.0 ml) of 1H-benzotriazole-1-carboxyaldehyde (33.8 mg, 0.21 mmol) at room temperature and the resulting mixture was stirred for 1 day. 1H-Benzotriazole-1-carboxyaldehyde (5.1 mg, 0.03 mmol) was added, the resulting mixture was further stirred for 1 day, and then the reaction mixture was poured into methylene chloride and washed with a 2 N aqueous sodium hydroxide solution. The organic layer was dried over anhydrous sodium sulfate, the mixture was filtrated, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by preparative thin layer silica gel chromatography (methylene chloride:methanol=10:1) to give the title compound (98.0 mg, 91%) as a pale yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:13]([CH3:14])=[CH:12][C:11]([OH:15])=[C:10]([CH:16]=O)[C:9]1=[O:18].Cl.[NH2:20][OH:21].C([O-])(=O)C.[Na+]>CO.O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:13]([CH3:14])=[CH:12][C:11]([OH:15])=[C:10]([CH:16]=[N:20][OH:21])[C:9]1=[O:18]
Reactant: Cc1cc(O)c(C=O)c(=O)n1-c1ccccc1Cl
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: Cc1cc(O)c(C=NO)c(=O)n1-c1ccccc1Cl
Temperature: 70 °C
Yield: 92.9 %

Procedure:
A mixture of 1-(2-chlorophenyl)-4-hydroxy-6-methyl-2-oxo-1,2-dihydropyridine-3-carbaldehyde obtained in Step B (3.95 g), hydroxylamine hydrochloride (2.08 g) and sodium acetate (2.46 g) in methanol/water (4:1, 75.0 mL) was heated at 70° C. for 2 hr, cooled to room temperature, and poured into ice water. The resulting solid was collected by filtration, washed with water, and dried under reduced pressure to give the title compound (3.88 g).
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[CH2:7][CH:6]([OH:8])[CH2:5][C:4]([CH3:10])([CH3:9])[NH:3]1.Br[CH2:13][CH2:14][CH2:15][CH3:16]>>[CH2:13]([N:3]1[C:4]([CH3:10])([CH3:9])[CH2:5][CH:6]([OH:8])[CH2:7][C:2]1([CH3:11])[CH3:1])[CH2:14][CH2:15][CH3:16]
Reactant: CCCCBr
Reactant: CC1(C)CC(O)CC(C)(C)N1
Product: CCCCN1C(C)(C)CC(O)CC1(C)C
Temperature: -78 °C
Yield: 46.9 %

Procedure:
Into a 400-milliliter Hastalloy pressure tube are placed 62.8 grams of 2,2,6,6-tetramethyl-4-hydroxypiperidine and 35.6 grams of 1-bromobutane. The tube and contents are cooled to -78°C., evacuated and filled with nitrogen. The tube is sealed, shaken and warmed to 100°C. for 1 hour, 120°C. for 1 hour and 150°C. for 30 hours. The tube is cooled and the solid charge is removed and placed in a Soxlet extraction apparatus. The material is extracted for 8 hours with diethyl ether. The resulting ether solution is treated with activated charcoal, filtered and concentrated under vacuum. The residue is distilled at 120°-125°C. at 1 torr to give 26 grams of 1-(1-butyl)-2,2,6,6-tetramethyl-4-hydroxypiperidine, a white solid melting at 29°-33°C.
Reaction SMILES: Br[C:2]([CH3:29])([CH3:28])[C:3]([C:5]1[C:13]2[C:8](=[CH:9][C:10]([O:14][CH3:15])=[CH:11][CH:12]=2)[N:7]([CH2:16][C:17]([N:19]([CH2:22][CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:20][CH3:21])=[O:18])[N:6]=1)=[O:4].[P:30]([O:35]C)([O:33][CH3:34])[O:31][CH3:32]>>[P:30]([O:33][CH3:34])([O:31][CH3:32])([O:4][C:3]([C:5]1[C:13]2[C:8](=[CH:9][C:10]([O:14][CH3:15])=[CH:11][CH:12]=2)[N:7]([CH2:16][C:17]([N:19]([CH2:22][CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:20][CH3:21])=[O:18])[N:6]=1)=[C:2]([CH3:29])[CH3:28])=[O:35]
Reactant: COP(OC)OC
Reactant: CCN(CCC(C)(C)C)C(=O)Cn1nc(C(=O)C(C)(C)Br)c2ccc(OC)cc21
Product: CCN(CCC(C)(C)C)C(=O)Cn1nc(C(OP(=O)(OC)OC)=C(C)C)c2ccc(OC)cc21

Procedure:
Reaction of 2-[3-(2-bromo-2-methylpropanoyl)-6-methoxy-1H-indazol-1-yl]-N-(3,3-dimethylbutyl)-N-ethylacetamide from the above with trimethyl phosphite using the procedure as described in Method I Step B Example 1 provided the title compound following RP-HPLC using 50-100% MeCN gradient without TFA. 1H NMR (CDCl3, 500 MHz) showed two amide rotomers in about 1.3:1 ratio:o Major rotomer: 7.65 (d, 8.7 Hz, 1H), 6.83 (dd, 9.0 & 2.1 Hz, 1H), 6.805 (d, 1.9 Hz, 1H), 5.15 (s, 2H), 3.88 (s, 3H), 3.55 (d, 11.2 Hz, 6H), 3.48 (q, 7.1 Hz, 2H), 3.32˜3.35 (m, 2H), 2.01 (d, 2.5 Hz, 3H), 1.83 (d, 3.5 Hz, 3H), 1.40˜1.44 (m, 2H), 1.14 (t, 7.1 Hz, 3H), 0.91 (s, 9H). Minor rotomer: 7.66 (d, 8.7 Hz, 1H), 6.83 (dd, 9.0 & 2.1 Hz, 1H), 6.77 (d, 1.8 Hz, 1H), 5.12 (s, 2H), 3.88 (s, 3H), 3.54 (d, 11.4 HZ, 6H), 3.41˜3.44 (m, 2H), 3.38 (q, 7.2 Hz, 2H), 2.01 (d, 2.5 Hz, 3H), 1.84 (d, 3.5 Hz, 3H), 1.56˜1.60 (m, 2H), 1.12 (t, 7.1 Hz, 3H), 1.00 (s, 9H). 13C NMR (CDCl3, 125 MHz): Major rotomer: 165.85, 160.95, 142.34, 140.22, 133.82 (d, JC-P=9.6 Hz), 125.87 (d, JC-P=6.7 Hz), 122.56, 118.22, 113.71, 90.89, 55.74, 54.685 (d, JC-P=5.8 Hz), 51.96, 42.99, 42.51, 41.05, 29.99, 29.46, 20.13, 18.75, 14.51; Minor rotomer: 165.71, 159.96, 142.45, 140.22, 133.88 (d, JC-P=9.6 Hz), 125.79 (d, JC-P=7.7 Hz), 122.60, 118.27, 113.51, 90.94, 55.74, 54.685 (d, JC-P=5.8 Hz), 51.18, 44.03, 42.82, 41.50, 29.96, 29.46, 20.18, 18.75, 13.21. LC-MS: 3.67 min. (m/Z=518.3, 496.3, 370.4).
Reaction SMILES: [OH:1][C:2]1[C:11]([CH:12]=[O:13])=[C:10]([N+:14]([O-:16])=[O:15])[CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH3:18])([CH3:17])[O:7]2.[C:19]([O-])([O-])=O.[K+].[K+].CI>>[CH3:19][O:1][C:2]1[C:11]([CH:12]=[O:13])=[C:10]([N+:14]([O-:16])=[O:15])[CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH3:18])([CH3:17])[O:7]2
Reactant: CC1(C)C=Cc2c(cc([N+](=O)[O-])c(C=O)c2O)O1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Product: COc1c2c(cc([N+](=O)[O-])c1C=O)OC(C)(C)C=C2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 5-hydroxy-2,2-dimethyl-7-nitro-2H-chromene-6-carbaldehyde (2.34 g, 10 mmol), K2CO3 (4.12 g, 29.8 mmol) and MeI (2.13 g, 0.94 mL, 15 mmol in Me2CO (40 mL) is refluxed for 4 h and stirred at room temperature overnight. The mixture is concentrated, treated with water (15 mL) and extracted with dichloromethane. The combined organic layers are washed with waters dried over Na2SO4, and the solvent is removed in vacuo to afford an oil, which is chromatographed with 3% Me2CO in hexane to afford 5-methoxy-2,2-dimethyl-7-nitro-2H-chromene-6-carbaldehyde.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:11]=[C:12]([C@@H:15]([NH:23][C:24](=[O:35])[C:25]3[CH:30]=[CH:29][C:28]([C:31]#[N:32])=[CH:27][C:26]=3[CH2:33][CH3:34])[CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[NH:13][CH:14]=2)=[CH:6][CH:5]=1)(=[O:3])[NH2:2].CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.N[C@H](C1NC=C(C2C=CC(C(N)=O)=CC=2)N=1)CC1C=CC=CC=1>C1COCC1>[NH2:32][CH2:31][C:28]1[CH:29]=[CH:30][C:25]([C:24]([NH:23][C@H:15]([C:12]2[NH:13][CH:14]=[C:10]([C:7]3[CH:6]=[CH:5][C:4]([C:1](=[O:3])[NH2:2])=[CH:9][CH:8]=3)[N:11]=2)[CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[O:35])=[C:26]([CH2:33][CH3:34])[CH:27]=1
Reactant: CCc1cc(C#N)ccc1C(=O)N[C@@H](Cc1ccccc1)c1nc(-c2ccc(C(N)=O)cc2)c[nH]1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: NC(=O)c1ccc(-c2c[nH]c([C@@H](N)Cc3ccccc3)n2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCc1cc(CN)ccc1C(=O)N[C@@H](Cc1ccccc1)c1nc(-c2ccc(C(N)=O)cc2)c[nH]1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Part E: N—{(S)-1-[4-(4-Carbamoyl-phenyl)-1H-imidazol-2-yl]-2-phenyl-ethyl}-4-cyano-2-ethyl-benzamide: The product from Example 143 Part D (90 mg, 0.51 mmol), Bop reagent (265 mg, 0.61 mmol), and triethylamine (0.42 mL, 1.5 mmol) were added together with 5 mL of THF. The mixture was stirred at RT under N2 for 15 minutes and (S)-4-(2-(1-amino-2-phenylethyl)-1H-imidazol-4-yl)benzamide prepared using the methods described in Examples 2 and 28 (365 mg, 0.51 mg) was added. The resulting mixture was heated at 75° C. for 70 minutes. The THF was removed, and the residue was dissolved in EtOAc. It was washed with waster and brine, dried over MgSO4, concentrated, and purified by flash chromatography (silica, EtOAc/hexane) to give 80 mg of the desired product. MS: 464.4 (M+1)+.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:4]([C:8]([C@@H:26]3[CH2:30][CH2:29][CH2:28][NH:27]3)=[N:9][C:10]=2[C:11]2[CH:25]=[CH:24][C:14]([C:15]([NH:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)=[O:16])=[CH:13][CH:12]=2)[CH:5]=[CH:6][N:7]=1.C(N(CC)CC)C.[C:38](Cl)(=[O:41])[CH:39]=[CH2:40]>ClCCl>[C:38]([N:27]1[CH2:28][CH2:29][CH2:30][C@H:26]1[C:8]1[N:4]2[CH:5]=[CH:6][N:7]=[C:2]([NH2:1])[C:3]2=[C:10]([C:11]2[CH:25]=[CH:24][C:14]([C:15]([NH:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)=[O:16])=[CH:13][CH:12]=2)[N:9]=1)(=[O:41])[CH:39]=[CH2:40]
Reactant: Nc1nccn2c([C@@H]3CCCN3)nc(-c3ccc(C(=O)Nc4ccccn4)cc3)c12
Reactant: C=CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CC(=O)N1CCC[C@H]1c1nc(-c2ccc(C(=O)Nc3ccccn3)cc2)c2c(N)nccn12
Temperature: 0 °C
Reaction time: 2 h
Yield: 44.4 %

Procedure:
To a solution of (S)-4-(8-amino-3-(pyrrolidin-2-yl)imidazo[1,5-a]pyrazin-1-yl)-N-(pyridin-2-yl)benzamide (0.626 mmol, 250 mg) in dichloromethane (25 ml) at 0° C. was added triethylamine (0.626 mmol, 0.087 ml, 63.3 mg) and, drop wise, acryloyl chloride (0.657 mmol, 0.053 ml, 59.5 mg). The resulting mixture was stirred at 0° C. for 2 hours. The mixture was washed with water, dried over magnesium sulfate. After evaporation, the residue was purified by preparative HPLC. Fractions containing product were collected and lyophilized to afford 126 mg of (S)-4-(3-(1-acryloylpyrrolidin-2-yl)-8-aminoimidazo[1,5-a]pyrazin-1-yl)-N-(pyridin-2-yl)benzamide (44.4% yield). Data: UPLC (C) Rt: 1.50 min; m/z 454.3 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[S:12](=[O:15])(=[O:14])[NH2:13])[CH2:8][CH2:7][CH2:6]2.CO[CH:18](OC)[N:19]([CH3:21])[CH3:20]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[S:12]([N:13]=[CH:18][N:19]([CH3:21])[CH3:20])(=[O:15])=[O:14])[CH2:8][CH2:7][CH2:6]2
Reactant: COC(OC)N(C)C
Reactant: COc1cc2c(cc1S(N)(=O)=O)CCC2
Product: COc1cc2c(cc1S(=O)(=O)N=CN(C)C)CCC2

Procedure:
This compound is prepared analogously to Example 1 c from 5-methoxy-6-sulfamoylindane and dimethylformamide dimethylacetal.
Reaction SMILES: [CH:1]([C:3]1[N:8]=[CH:7][CH:6]=[CH:5][N:4]=1)=[CH2:2].CC(O)=O.[CH2:13]([NH2:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CCO>[CH2:13]([NH:20][CH2:2][CH2:1][C:3]1[N:8]=[CH:7][CH:6]=[CH:5][N:4]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: C=Cc1ncccn1
Reactant: NCc1ccccc1
Solvent: CCO
Solvent: CC(=O)O
Product: c1ccc(CNCCc2ncccn2)cc1

Procedure:
To a solution of 2-vinylpyrimidine (1.55 g, 14.6 mmol) in EtOH (15 mL) at room temperature was added AcOH (2.0 mL) and benzylamine (3.14 g, 29.3 mmol) (3.2 mL). The reaction mixture was heated to reflux for 18 h, and concentrated. Diluted with EtOAc, washed with 5 M NaOH (1×), brine (1×), dried over MgSO4, filtered, and concentrated. Purification by flash column chromatography on silica gel (eluted with 2% to 10% MeOH in DCM) gave N-benzyl-2-(pyrimidin-2-yl)ethanamine.
Reaction SMILES: [C:1]([NH:4][CH2:5][C@@H:6]1[O:10][C:9](=[O:11])[N:8]([C:12]2[CH:17]=[CH:16][C:15]([NH2:18])=[C:14]([F:19])[CH:13]=2)[CH2:7]1)(=[S:3])[CH3:2].[C:20](OC(=O)C)(=[O:22])[CH3:21].N1C=CC=CC=1>ClCCl>[C:1]([NH:4][CH2:5][C@@H:6]1[O:10][C:9](=[O:11])[N:8]([C:12]2[CH:17]=[CH:16][C:15]([NH:18][C:20](=[O:22])[CH3:21])=[C:14]([F:19])[CH:13]=2)[CH2:7]1)(=[S:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: CC(=S)NC[C@H]1CN(c2ccc(N)c(F)c2)C(=O)O1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)Nc1ccc(N2C[C@H](CNC(C)=S)OC2=O)cc1F
Yield: 95 %

Procedure:
A solution of 5-(S)-thioacetamidomethyl-3-[4′-amino-3′-fluorophenyl]oxazoli-dine-2-one (0.070 g, 0.247 mmol), acetic anhydride (0.25 mL), pyridine (0.38 mL), and dichloromethane (0.75 mL) was stirred at r.t. for 4 h. Solvent was removed under vacuum and the crude product purified by PTLC (10% MeOH in DCM) to give a white solid (0.076 g, 95%). M.p. 200-1° C.; MS (m/z): (M+H)+=326.
Reaction SMILES: N([O-])=O.[Na+].N[C:6]1[CH:7]=[CH:8][C:9]2[N:15]([CH3:16])[C:14](=[O:17])[CH:13]3[CH2:18][CH2:19][CH2:20][N:12]3[CH2:11][C:10]=2[CH:21]=1.Cl.C(=O)([O-])[O-:24].[Na+].[Na+]>O>[OH:24][C:6]1[CH:7]=[CH:8][C:9]2[N:15]([CH3:16])[C:14](=[O:17])[CH:13]3[CH2:18][CH2:19][CH2:20][N:12]3[CH2:11][C:10]=2[CH:21]=1
Reactant: CN1C(=O)C2CCCN2Cc2cc(N)ccc21
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: CN1C(=O)C2CCCN2Cc2cc(O)ccc21
Reaction time: 0.33 h

Procedure:
A solution of 3.5 g. of sodium nitrite in 30 ml. of water is added over a 30 minute period at 90°-95°C. to a rapidly stirred solution of 11.5 g. of 7-amino-1,2,3,5,10,11a- hexahydro-10-methyl-11H-pyrrolo[2,1-c] [1,4]benzodiazepin-11- one in 600 ml. of 0.05N hydrochloric acid. The solution is held at this temperature for 20 minutes longer, cooled, treated with an excess of sodium carbonate and the crude product is extracted into benzene. The benzene solution is concentrated to remove the solvent and the residue is purified by partition chromatography in order to obtain the pure 1,2,3,5,10,11a- hexahydro-7-hydroxy-10-methyl-11H-pyrrolo[2,1-c] [1,4]benzodiazepin- 11-one.
Reaction SMILES: [Br:1][C:2]1[CH:12]=[CH:11][C:5]([O:6][C@@H:7]([CH3:10])[CH2:8][OH:9])=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.CS(C)=O.[N:23]1[CH:28]=[CH:27][CH:26]=[C:25]([C:29]#[CH:30])[CH:24]=1>C(N(CC)CC)C>[Br:1][C:2]1[CH:12]=[CH:11][C:5]([O:6][C@H:7]([CH3:10])[CH:8]([OH:9])[C:30]#[C:29][C:25]2[CH:24]=[N:23][CH:28]=[CH:27][CH:26]=2)=[CH:4][CH:3]=1
Reactant: C#Cc1cccnc1
Reactant: C[C@@H](CO)Oc1ccc(Br)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: C[C@@H](Oc1ccc(Br)cc1)C(O)C#Cc1cccnc1

Procedure:
Prepared according to the method described in Example 1c) from (2S)-2-(4-bromophenoxy)propan-1-ol (9.24 g, Example 4b)), oxalyl chloride (4.38 ml), dimethyl sulfoxide (4.4 ml), triethylamine (22.4 ml), 3-pyridylacetylene (6.3 g) andn-butyllithium (2.5M in hexanes, 24 ml) to give the sub-title compound as an oil and as a 4:1 mixture of diastereomers (8.31 g).
Reaction SMILES: S(=O)(=O)(O)O.[Cl:6][CH:7]([CH3:18])[CH2:8][CH2:9][C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:11].[N+:19]([O-])([OH:21])=[O:20]>[S]>[Cl:6][CH:7]([CH3:18])[CH:8]([N+:19]([O-:21])=[O:20])[CH2:9][C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:11]
Reactant: CC(Cl)CCC(=O)c1ccccc1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Agent: [S]
Product: CC(Cl)C(CC(=O)c1ccccc1)[N+](=O)[O-]

Procedure:
50 ml of concentrated sulphuric acid are treated, while stirring, with 9.9 g of 4-chloro-valerophenone, while cooling with an ice/sodium chloride mixture. The bulk of the product dissolves, a slightly exothermic reaction taking place, and a yellow suspension forms, which is treated, while stirring vigorously and at a temperature of -10° to -5°, with a mixture of 20 ml of concentrated sulphur acid and 10.4 ml of concentrated nitric acid (d = 1.52), in the course of 10 minutes. After a reaction time of five minutes, the mixture is poured onto ice and the aqueous mixture is extracted with chloroform. The organic extract is washed once with an aqueous solution of sodium carbonate and with water, dried over sodium sulphate and filtered through silica gel. 4-Chloro-3-nitro-valerophenone is obtained as an oily residue after evaporating the filtrate.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[NH:12][C:11](=[O:13])[CH2:10][O:9][C:8]=2[CH:14]=1)([O-:3])=[O:2].Cl.Cl[CH2:17][CH2:18][N:19]1[CH2:23][CH2:22][CH2:21][CH2:20]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[N:12]([CH2:17][CH2:18][N:19]3[CH2:23][CH2:22][CH2:21][CH2:20]3)[C:11](=[O:13])[CH2:10][O:9][C:8]=2[CH:14]=1)([O-:3])=[O:2]
Reactant: O=C1COc2cc([N+](=O)[O-])ccc2N1
Reactant: ClCCN1CCCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1COc2cc([N+](=O)[O-])ccc2N1CCN1CCCC1
Temperature: 100 °C
Reaction time: 18 h
Yield: 65.3 %

Procedure:
A suspension of 7-nitro-2H-benzo[b][1,4]oxazin-3(4H)-one (0.5 g, 2.575 mmol), 1-(2-chloroethyl)pyrrolidine hydrochloride (0.43 g, 2.575 mmol) and K2CO3 (1.06 g, 7.726 mmol) in dry DMF (5 mL) was stirred at 100° C. overnight (18 hours). The reaction was brought to room temperature, diluted with water (100 mL), and the product was extracted into ethyl acetate (2×25 mL). The combined ethyl acetate layers were washed with brine (20 mL) and dried (Na2SO4). The solvent was evaporated, and the crude material was purified by column chromatography (3:97 (2M NH3 in MeOH):CH2Cl2) to obtain the title compound (0.49 g, 65%) as a solid. 1H NMR (DMSO-d6) δ 1.62-1.70 (m, 4H), 2.46-2.54 (m, 4H, merged with DMSO-d6 resonance), 2.60 (t, 2H, J=6.9 Hz), 4.08 (t, 2H, J=6.9 Hz), 4.80 (s, 2H), 7.44 (d, 1H, J=9.3 Hz), 7.80 (d, 1H, J=2.4 Hz), 7.96 (dd, 1H, J=2.7, 9.0 Hz); ESI-MS (m/z, %): 292 (MH+, 100).