Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:8]([NH:10][C@@H:11]([CH2:15][CH:16]([CH3:18])[CH3:17])[C:12]([OH:14])=O)=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:19]([O:23][C:24](=[O:36])[C@@H:25]([NH2:35])[CH2:26][C:27]1[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=1)([CH3:22])([CH3:21])[CH3:20]>>[C:19]([O:23][C:24](=[O:36])[CH:25]([NH:35][C:12](=[O:14])[CH:11]([NH:10][C:8]([N:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1)=[O:9])[CH2:15][CH:16]([CH3:18])[CH3:17])[CH2:26][C:27]1[CH:28]=[CH:29][C:30]([O:33][CH3:34])=[CH:31][CH:32]=1)([CH3:20])([CH3:22])[CH3:21]
Reactant: COc1ccc(C[C@H](N)C(=O)OC(C)(C)C)cc1
Reactant: CC(C)C[C@H](NC(=O)N1CCCCCC1)C(=O)O
Product: COc1ccc(CC(NC(=O)C(CC(C)C)NC(=O)N2CCCCCC2)C(=O)OC(C)(C)C)cc1
Yield: 86.4 %

Procedure:
A solution of the product from Example Z (2(S)-[(azepane-1-carbonyl)-amino]-4-methyl-pentanoic acid) (0.20 g, 0.78 mmol) and 2(S)-amino-3-(4-methoxy-phenyl)-propionic acid tert-butyl ester (Bachem, 0.216 g, 0.86 mmol) were coupled according to the procedure described in Example 3. The residue was purified by crystallization from hexane to give the title compound as a white solid (0.33 g, 87%), mp 105-106° C.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:17]([NH:19][C@@H:20]([CH2:41][OH:42])[C@@H:21]([OH:40])[C@@H:22]([OH:39])[C@H:23]([OH:38])[C:24]([NH:26][C@H:27]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[CH2:28][C:29]([OH:31])=[O:30])=[O:25])=[O:18])[CH2:13][CH:14]([CH3:16])[CH3:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N12CCCN=C1CCCCC2.[C:54]([O:60][CH2:61]I)(=[O:59])[C:55]([CH3:58])([CH3:57])[CH3:56].O>CN(C)C=O>[CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:17]([NH:19][C@@H:20]([CH2:41][OH:42])[C@@H:21]([OH:40])[C@@H:22]([OH:39])[C@H:23]([OH:38])[C:24]([NH:26][C@H:27]([C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)[CH2:28][C:29]([O:31][CH2:61][O:60][C:54](=[O:59])[C:55]([CH3:58])([CH3:57])[CH3:56])=[O:30])=[O:25])=[O:18])[CH2:13][CH:14]([CH3:15])[CH3:16])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)C[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@@H](CO)[C@@H](O)[C@@H](O)[C@H](O)C(=O)N[C@@H](CC(=O)O)c1ccccc1
Reactant: CC(C)(C)C(=O)OCI
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)C[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@@H](CO)[C@@H](O)[C@@H](O)[C@H](O)C(=O)N[C@@H](CC(=O)OCOC(=O)C(C)(C)C)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 45.4 %

Procedure:
To a solution of (S)-3-[(2S,3R,4R,5S)-5-(N-benzyloxycarbonyl-L-leucyl)amino-2,3,4,6-tetrahydroxyhexanoyl]amino-3-phenylpropionic acid (295 mg) and 1,8-diazabicyclo[5.4.0]undec-7-ene (0.082 ml) in dimethylformamide (2 ml) was added a solution of iodomethyl pivalate (139 mg) in dimethylformamide (1 ml) and the mixture was stirred at room temperature for 1 hour. After addition of water, the reaction mixture was extracted with ethyl acetate and the extract was washed with 10% aqueous citric acid solution, saturated aqueous sodium hydrogencarbonate solution andsaturated brine respectively. The organic solution was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was passed through a column of silica gel, followed by elution with ethyl acetate:methanol (10:1). The effective fractions were combined and concentrated under reduced pressure. Recrystallization from chloroform provided the title compound (160 mg).
Reaction SMILES: Cl[CH2:2][CH:3]([OH:19])[CH2:4][C:5]1[CH:6]=[C:7]([CH:16]=[CH:17][CH:18]=1)[CH:8]([OH:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(O)C.[C-:23]#[N:24].[K+]>O>[C:23]([CH2:2][CH:3]([OH:19])[CH2:4][C:5]1[CH:6]=[C:7]([CH:16]=[CH:17][CH:18]=1)[CH:8]([OH:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)#[N:24]
Reactant: OC(CCl)Cc1cccc(C(O)c2ccccc2)c1
Reactant: [C-]#N
Agent: [K+]
Solvent: CCO
Solvent: O
Product: N#CCC(O)Cc1cccc(C(O)c2ccccc2)c1
Yield: 71.4 %

Procedure:
A mixture of 11.97 g of 3-(3'-chloro-2'-hydroxypropyl)-benzhydrol, 120 ml of ethanol, 2.4 ml of water and 2.66 g of potassium cyanide was refluxed for 3 hours and then evaporated to dryness. The residue was taken up in 200 ml of methylene chloride and the organic phase was washed with water, dried over sodium sulfate, treated with activated carbon, filtered and evaporated to dryness. The residue was chromatographed over silica and was eluted with a 75-25 methylene chloride-ethyl acetate mixture which was evaporated to obtain 7.8 g of 3-(3'-cyano-2'-hydroxypropyl)-benzhydrol in the form of an orange amorphous solid soluble in chloroform and insoluble in water.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[O:12].[N+:13]([O-])([OH:15])=[O:14]>OS(O)(=O)=O>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([N+:13]([O-:15])=[O:14])[CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[O:12]
Reactant: O=[N+]([O-])O
Reactant: O=C1Nc2ccc(F)cc2C1=O
Agent: O=S(=O)(O)O
Product: O=C1Nc2c(cc(F)cc2[N+](=O)[O-])C1=O
Reaction time: 1 h
Yield: 94.3 %

Procedure:
To a solution of 5-fluoro-1H-indole-2,3-dione (2.5 g, 15.0 mmol) in conc. H2SO4 (9 mL) was added very slowly fuming nitric acid (1.5 mL) at −5 to 0° C. The reaction mixture was stirred at the same temperature for one hour. After completion of the reaction, the reaction mixture was poured onto crushed ice and the resulting precipitate was filtered, washed with water (2-3 times) and dried under vacuum to obtain the title compound as yellow solid (3 g, 94.30%) which was used for the next step directly.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([N:8]2[C:12]3[CH:13]=[CH:14][C:15]([Cl:17])=[CH:16][C:11]=3[N:10]=[C:9]2[C:18]([OH:21])([CH3:20])[CH3:19])[CH2:4][CH2:3]1.[F:22][C:23]([F:36])([F:35])[C:24]1[CH:25]=[C:26]2[C:30](=[CH:31][CH:32]=1)[CH2:29][CH:28]([CH:33]=O)[CH2:27]2>>[Cl:17][C:15]1[CH:14]=[CH:13][C:12]2[N:8]([C@H:5]3[CH2:4][CH2:3][C@@H:2]([NH:1][CH2:33][CH:28]4[CH2:27][C:26]5[C:30](=[CH:31][CH:32]=[C:24]([C:23]([F:22])([F:35])[F:36])[CH:25]=5)[CH2:29]4)[CH2:7][CH2:6]3)[C:9]([C:18]([OH:21])([CH3:19])[CH3:20])=[N:10][C:11]=2[CH:16]=1
Reactant: CC(C)(O)c1nc2cc(Cl)ccc2n1[C@H]1CC[C@@H](N)CC1
Reactant: O=CC1Cc2ccc(C(F)(F)F)cc2C1
Product: CC(C)(O)c1nc2cc(Cl)ccc2n1[C@H]1CC[C@@H](NCC2Cc3ccc(C(F)(F)F)cc3C2)CC1

Procedure:
This compound was prepared from the hydrochloride salt of cis-2-[1-(4-amino-cyclohexyl)-5-chloro-1H-benzoimidazol-2-yl]-propan-2-ol and 5-trifluoromethyl-indan-2-carbaldehyde. 1H-NMR is consistent with the assigned structure, LC-MS showed a single peak, C27H31ClF3N3O (m/e) calcd 505.2108, obsd 506.1 (M+H).
Reaction SMILES: Br[C:2]1[C:3]([O:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]([C:17]3[N:21]([CH3:22])[C:20]4[CH:23]=[CH:24][CH:25]=[CH:26][C:19]=4[N:18]=3)=[O:16])=[CH:11][CH:10]=2)=[N:4][CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.[CH3:34][Si:35]([C:38]#[CH:39])([CH3:37])[CH3:36]>CN(C=O)C.C(Cl)Cl.[Cu](I)I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:22][N:21]1[C:20]2[CH:23]=[CH:24][CH:25]=[CH:26][C:19]=2[N:18]=[C:17]1[C:15]([C:12]1[CH:13]=[CH:14][C:9]([O:8][C:3]2[C:2]([C:39]#[C:38][Si:35]([CH3:37])([CH3:36])[CH3:34])=[CH:7][CH:6]=[CH:5][N:4]=2)=[CH:10][CH:11]=1)=[O:16]
Reactant: C#C[Si](C)(C)C
Reactant: Cn1c(C(=O)c2ccc(Oc3ncccc3Br)cc2)nc2ccccc21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cn1c(C(=O)c2ccc(Oc3ncccc3C#C[Si](C)(C)C)cc2)nc2ccccc21

Procedure:
A solution of (4-(3-bromopyridin-2-yloxy)phenyl)(1-methyl-1H-benzo[d]imidazol-2-yl)methanone (0.18 g, 0.44 mmol), triethylamine (0.12 mL, 0.88 mmol), copper iodide (0.0084 g, 0.044 mmol), dichlorobis(triphenyl-phosphine)palladium (0.015 g, 0.022 mmol), trimethylsilylacetylene (0.093 mL, 0.66 mmol) in 1 mL DMF was heated to 110° C. overnight. The reaction mixture was diluted with DCM and then washed with water and brine. The organic layer was purified by silica gel chromatography (0-10% MeOH/DCM) to afford (1-methyl-1H-benzo[d]imidazol-2-yl)(4-(3-(2-(trimethylsilyl)ethynyl)pyridin-2-yloxy)phenyl)-methanone.
Reaction SMILES: [OH:1][C:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][C:4]([C:12]([OH:14])=[O:13])([CH2:5]3)[CH2:3]1)[CH2:9]2.[CH2:15](O)[CH2:16][CH2:17][CH3:18].S(=O)(=O)(O)O>C1(C)C=CC=CC=1>[OH:1][C:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][C:4]([C:12]([O:14][CH2:15][CH2:16][CH2:17][CH3:18])=[O:13])([CH2:5]3)[CH2:3]1)[CH2:9]2
Reactant: CCCCO
Reactant: O=C(O)C12CC3CC(CC(O)(C3)C1)C2
Agent: O=S(=O)(O)O
Solvent: Cc1ccccc1
Product: CCCCOC(=O)C12CC3CC(CC(O)(C3)C1)C2
Yield: 94.1 %

Procedure:
To 900 ml of toluene were added 300 mmol of the obtained 3-hydroxy-1-adamantanecarboxylic acid, 450 mmol of n-butanol, and 15 mmol of sulfuric acid, and the resultant mixture was stirred under reflux of toluene for 5 hours. The reaction mixture was concentrated and then subjected to column chromatography on a silica gel to give n-butyl 3-hydroxy-1-adamantanecarboxylate (yield: 94.1%). The conversion rate from 3-hydroxy-1-adamantanecarboxylic acid was 99%.
Reaction SMILES: [CH2:1]([N:3]1[C:9]2[CH:10]=[C:11]([NH2:14])[CH:12]=[CH:13][C:8]=2[O:7][CH2:6][CH2:5][CH2:4]1)[CH3:2].Cl[C:16]1[N:21]=[C:20]([NH:22][C:23]2[C:32]([F:33])=[CH:31][C:30]([C:34]3[CH:35]=[N:36][N:37]([CH3:39])[CH:38]=3)=[CH:29][C:24]=2[C:25]([NH:27][CH3:28])=[O:26])[C:19]([Cl:40])=[CH:18][N:17]=1>>[Cl:40][C:19]1[C:20]([NH:22][C:23]2[C:32]([F:33])=[CH:31][C:30]([C:34]3[CH:35]=[N:36][N:37]([CH3:39])[CH:38]=3)=[CH:29][C:24]=2[C:25]([NH:27][CH3:28])=[O:26])=[N:21][C:16]([NH:14][C:11]2[CH:12]=[CH:13][C:8]3[O:7][CH2:6][CH2:5][CH2:4][N:3]([CH2:1][CH3:2])[C:9]=3[CH:10]=2)=[N:17][CH:18]=1
Reactant: CCN1CCCOc2ccc(N)cc21
Reactant: CNC(=O)c1cc(-c2cnn(C)c2)cc(F)c1Nc1nc(Cl)ncc1Cl
Product: CCN1CCCOc2ccc(Nc3ncc(Cl)c(Nc4c(F)cc(-c5cnn(C)c5)cc4C(=O)NC)n3)cc21

Procedure:
2-[5-Chloro-2-(9-ethyl-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocyclohepten-2-ylamino)-pyrimidin-4-ylamino]-3-fluoro-N-methyl-5-(1-methyl-1H-pyrazol-4-yl)-benzamide was prepared from 9-ethyl-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocyclohepten-2-ylamine and 2-(2,5-dichloro-pyrimidin-4-ylamino)-3-fluoro-N-methyl-5-(1-methyl-1H-pyrazol-4-yl)-benzamide in an analogous manner to Example 1410. Product isolated as a white solid (58 mg, 30%). m.p.=253-255° C.; LCMS (m/e) 551 (M+H); 1H-NMR (CDCl3, 400 MHz) δ 9.20 (s, 1H), 8.99 (s, 1H), 8.56-8.50 (m, 1H), 8.27 (s, 1H), 8.12 (s, 1H), 8.00 (s, 1H), 7.74-7.64 (m, 2H), 7.01 (d, 1H, J=9.6 Hz), 6.89 (s, 1H), 6.50 (d, 1H, J=8.6 Hz), 3.95-3.85 (m, 5H), 3.12-2.96 (m, 4H), 2.75 (d, 3H, J=4.5 Hz), 1.87-1.78 (m, 2H), 1.05 (t, 3H, J=7.1 Hz).
Reaction SMILES: [ClH:1].[CH2:2]([C:6]1[N:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:9]=[C:8]([CH2:17][NH:18][C:19]([CH:21]2[CH:26]3[CH:22]2[CH2:23][N:24](C(OC(C)(C)C)=O)[CH2:25]3)=[O:20])[CH:7]=1)[CH:3]([CH3:5])[CH3:4].CCCCCC.C(OCC)(=O)C>CO>[ClH:1].[CH2:2]([C:6]1[N:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:9]=[C:8]([CH2:17][NH:18][C:19]([CH:21]2[CH:26]3[CH:22]2[CH2:23][NH:24][CH2:25]3)=[O:20])[CH:7]=1)[CH:3]([CH3:5])[CH3:4]
Reactant: CC(C)Cc1cc(CNC(=O)C2C3CN(C(=O)OC(C)(C)C)CC32)nn1-c1ccccc1
Agent: Cl
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)Cc1cc(CNC(=O)C2C3CNCC32)nn1-c1ccccc1
Reaction time: 3 h
Yield: 100.1 %

Procedure:
1.25 M hydrochloric acid solution (9.76 mL, 12.2 mmol) dissolved in methanol was added dropwise to the tert-butyl 6-((5-isobutyl-1-phenyl-1H-pyrazole-3-yl)methylcarbamoyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (268 mg, 0.610 mmol) prepared in Example 10 and stirred for 3 hours. The completion of the reaction was confirmed by TLC (hexane:ethyl acetate=1:2). After the reaction was completed, the reaction mixture was concentrated under reduced pressure to obtain 229 mg (100%) of the target compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=O)[C:9]1[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[CH:11][C:10]=1[N:18]1[C:22]([CH2:23][N:24]2C(=O)C3=CC=CC=C3C2=O)=[N:21][N:20]=[C:19]1[CH2:35][N:36]1[CH2:40][CH2:39][CH2:38][CH2:37]1.O.NN>C(O)C>[N+:15]([C:13]1[CH:12]=[CH:11][C:10]2[N:18]3[C:19]([CH2:35][N:36]4[CH2:40][CH2:39][CH2:38][CH2:37]4)=[N:20][N:21]=[C:22]3[CH2:23][N:24]=[C:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])[C:9]=2[CH:14]=1)([O-:17])=[O:16]
Reactant: O=C(c1ccccc1Cl)c1cc([N+](=O)[O-])ccc1-n1c(CN2CCCC2)nnc1CN1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: CCO
Solvent: O
Product: O=[N+]([O-])c1ccc2c(c1)C(c1ccccc1Cl)=NCc1nnc(CN3CCCC3)n1-2

Procedure:
In the manner given in Example 27, 2'-chloro-5-nitro2-[3-(pyrrolidinomethyl)-5-(phthalimidomethyl)-4H-1,2,4-triazol-4-yl]benzophenone is heated in ethanol with hydrazine hydrate to give 8-nitro-1-(pyrrolidinomethyl)-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11](=[O:13])[N:10]([CH:14]3[CH2:19][CH2:18][N:17]([C:20]4[N:25]=[CH:24][N:23]=[C:22]([C:26](O)=[O:27])[CH:21]=4)[CH2:16][CH2:15]3)[CH2:9][CH2:8][C:7]=2[CH:29]=1.[NH:30]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH2:32][CH:31]1[CH2:39][OH:40].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[OH:40][CH2:39][CH:31]1[CH2:32][C:33]2[C:38](=[CH:37][CH:36]=[CH:35][CH:34]=2)[N:30]1[C:26]([C:22]1[N:23]=[CH:24][N:25]=[C:20]([N:17]2[CH2:16][CH2:15][CH:14]([N:10]3[CH2:9][CH2:8][C:7]4[CH:29]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=4[NH:12][C:11]3=[O:13])[CH2:19][CH2:18]2)[CH:21]=1)=[O:27]
Reactant: OCC1Cc2ccccc2N1
Reactant: COc1ccc2c(c1)CCN(C1CCN(c3cc(C(=O)O)ncn3)CC1)C(=O)N2
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)CCN(C1CCN(c3cc(C(=O)N4c5ccccc5CC4CO)ncn3)CC1)C(=O)N2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
100 mg (0.25 mmol) 6-[4-(7-methoxy-2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidin-1-yl]-pyrimidine-4-carboxylic acid and 45 mg (0.30 mmol) (2,3-dihydro-1H-indole-2-yl)-methanol in 50 μL (0.36 mmol) TEA and 0.90 mL DMF were combined with 85 mg (0.27 mmol) TBTU and stirred overnight at RT. Then the reaction mixture was purified by preparative HPLC-MS. The product-containing fractions were combined and partially evaporated down. The precipitate formed was suction filtered and dried.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:19][CH3:20])=[C:6]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([CH:16]3[CH2:18][CH2:17]3)=O)[CH2:10][CH2:9]2)[CH:7]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH:16]1([CH2:14][N:11]2[CH2:10][CH2:9][N:8]([C:6]3[CH:7]=[C:2]([NH2:1])[CH:3]=[CH:4][C:5]=3[O:19][CH3:20])[CH2:13][CH2:12]2)[CH2:17][CH2:18]1
Reactant: COc1ccc(N)cc1N1CCN(C(=O)C2CC2)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(N)cc1N1CCN(CC2CC2)CC1
Yield: 75 %

Procedure:
To a solution of [4-(5-amino-2-methoxy-phenyl)-piperazin-1-yl]cyclopropyl methanone (D19) (1.6 mmol) in dry THF (10 ml) under argon was added LiAlH4 (240 mg, 6.4 mmol). The resulting mixture was heated to reflux for 12 hrs and cooled before quenching with water (0.25 ml), 10% aqueous NaOH (0.25 ml) and finally water (0.75 ml). Filtration through celite and concentration in vacuo afforded the title compound (D21) in 75% yield. Found MH+ 262.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[S:11][C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[N:8]=[C:7]([N:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)[C:6]=2[CH:22]=1.C(N(CC)CC)C.[C:30](Cl)(=[O:32])[CH3:31]>C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[S:11][C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[N:8]=[C:7]([N:16]3[CH2:21][CH2:20][N:19]([C:30](=[O:32])[CH3:31])[CH2:18][CH2:17]3)[C:6]=2[CH:22]=1
Reactant: CC(=O)Cl
Reactant: Fc1ccc2c(c1)C(N1CCNCC1)=Nc1ccccc1S2
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N1CCN(C2=Nc3ccccc3Sc3ccc(F)cc32)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 87.9 %

Procedure:
The compound of Formula I where Z is —C(═O)R1 and R1 is methyl was prepared as follows. To a solution of 2-fluoro-11-(piperazin-1-yl)dibenzo[b,f][1,4]thiazepine VI (see Scheme A) (0.05 g, 0.16 mmol) and triethylamine (0.05 mL, 0.32 mmol) in DCM (3 mL) was added acetyl chloride (0.02 mL, 0.32 mmol) dropwise at 0° C. under nitrogen. After stirring the mixture at 0° C. for 1 hour, the solvent was removed under reduced pressure. The reaction mixture was triturated with ether (1×20 mL), the insolubles filtered off and the filtrate concentrated under reduced pressure to give 1-(4-(2-fluorodibenzo[b,f][1,4]thiazepine-11-yl)piperazin-1-yl)ethanone (0.05 g, 80%) as a very pale yellow powder. m/z (ES+) M+1=356.0; HPLC tR=0.64 min. 1H NMR (300 MHz, DMSO-d6): δ 2.03 (s, 3H), 3.35-3.61 (br m, 8H), 6.90 (t, 1H, J=7.8 Hz), 7.01 (d, 1H, J=7.8 Hz), 7.22 (t, 1H, J=7.8 Hz), 7.31-7.40 (br m, 3H), 7.60 (dd, 1H, J=5.7 Hz).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:16][C@@H:15]2[C@@H:10]([N:11]([NH:18][C@@H:19]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH3:20])[C:12](=O)[CH2:13][O:14]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O.C(=O)([O-])[O-].[K+].[K+]>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[CH2:16][C@@H:15]2[C@@H:10]([N:11]([NH:18][C@@H:19]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH3:20])[CH2:12][CH2:13][O:14]2)[CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: C[C@@H](NN1C(=O)CO[C@@H]2CN(C(=O)OC(C)(C)C)C[C@@H]21)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: C[C@@H](NN1CCO[C@@H]2CN(C(=O)OC(C)(C)C)C[C@@H]21)c1ccccc1
Temperature: 5 °C
Reaction time: 72 h

Procedure:
To a solution of 191 mg of cis-8-tert-butoxycarbonyl-5-[(1R)-1-phenylethylamino]-4-oxo-2-oxa-5,8-diazabicyclo[4.3.0]nonane 13a in 6 ml of tetrahydrofuran was added 1 ml of 1M diborane tetrahydrofuran complex dropwise. The mixture was stirred at 5° C. for 3 days. To an ice-cooled reaction mixture was added 15 ml of water and 10 ml of saturated potassium carbonate aqueous solution, and the mixture was stirred. The mixture was extracted by chloroform and the organic layer was separated. The organic layer was washed by saturated sodium chloride aqueous solution. The organic layer was dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure and a residue was subjected to silica gel column chromatography. From an eluant of a mixture of hexane and ethyl acetate (3:1 by volume), the titled compound 14a weighing 103 mg was obtained.
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([CH:18]([CH3:20])[CH3:19])=[CH:14][CH:13]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:21].[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29][C:30](O)=[O:31])=[CH:25][CH:24]=1>>[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29][C:30]([NH:1][N:2]2[N:11]=[C:10]([C:12]3[CH:13]=[CH:14][C:15]([CH:18]([CH3:19])[CH3:20])=[CH:16][CH:17]=3)[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]2=[O:21])=[O:31])=[CH:25][CH:24]=1
Reactant: CC(C)c1ccc(-c2nn(N)c(=O)c3ccccc23)cc1
Reactant: O=C(O)Cc1ccc(Cl)cc1
Product: CC(C)c1ccc(-c2nn(NC(=O)Cc3ccc(Cl)cc3)c(=O)c3ccccc23)cc1

Procedure:
The product of Example 168A and 2-(4-chlorophenyl)acetic acid were treated using a method similar to that described in Example 17C to give the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.69-11.71 (bs, 1H), 8.38-8.41 (m, 1H), 7.89-8.03 (m, 2H), 7.75-7.77 (m, 1H), 7.50-7.53 (m, 2H), 7.42-7.46 (m, 2H), 7.37-7.43 (m, 4H), 3.70 (s, 2H), 2.93-3.06 (m, 1H), 1.27 (d, J=6.9 Hz, 6H); MS (APCI+) M/Z 432 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[C:21]([N:22]=1)=[CH:20][C:7]1[CH2:8][CH2:9][N:10](C(OC(C)(C)C)=O)[CH2:11][CH2:12][C:6]=1[CH:5]=2.FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:1][C:2]1[O:3][C:4]2[C:21]([N:22]=1)=[CH:20][C:7]1[CH2:8][CH2:9][NH:10][CH2:11][CH2:12][C:6]=1[CH:5]=2
Reactant: Cc1nc2cc3c(cc2o1)CCN(C(=O)OC(C)(C)C)CC3
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1nc2cc3c(cc2o1)CCNCC3
Yield: 114.2 %

Procedure:
1,1-Dimethylethyl 2-methyl-5,6,8,9-tetrahydro-7H-[1,3]oxazolo[4,5-h][3]benzazepine-7-carboxylate (1.1 g) was exposed to trifluoroacetic acid (5 ml) in DCM (5 ml) for 90 min at 25° C. After elimination of volatiles under reduced pressure the residue was partitioned between aqueous Na2CO3 (2M) and DCM. The organic layer was collected and the aqueous phase extracted twice with DCM. The combined DCM layers were concentrated to give the title compound (0.84 g) as an off-white solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[CH:7]=[CH:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([Br:15])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2]>CO.O1CCCC1.[Pt](=O)=O>[C:1]([O:5][C:6](=[O:16])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([Br:15])[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)C=Cc1cccc(Br)c1
Agent: O=[Pt]=O
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)CCc1cccc(Br)c1
Reaction time: 10 h
Yield: 58.6 %

Procedure:
Platinum(IV) oxide (0.002 g, 0.032 mmol) was added to a solution of 3-(3-bromophenyl)acrylic acid tert-butyl ester (2.24 g, 7.90 mmol) in methanol (7 mL) and tetrahydrofuran (1 mL) at room temperature under a nitrogen atmosphere. The mixture was hydrogenated under a balloon pressure for 10 hours. The mixture was filtered and the filtrate was concentrated to dryness. Purification by flash chromatography, eluting with hexane/ethyl acetate, gave 3-(3-bromophenyl)propionic acid tert-butyl ester as a clear oil (1.32 g, 58%).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=2)=[N:5][NH:4][C:3]1=[S:13].[CH3:14]I.[OH-].[Na+].O>CC(C)=O>[CH3:1][N:2]1[C:3]([S:13][CH3:14])=[N:4][N:5]=[C:6]1[C:7]1[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=1
Reactant: Cn1c(-c2ccncc2)n[nH]c1=S
Reactant: CI
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Product: CSc1nnc(-c2ccncc2)n1C
Reaction time: 2 h
Yield: 82 %

Procedure:
To a mechanically stirred and cooled (9° C.) suspension of 4-methyl-5-pyridin-4-yl-2,4-dihydro-3H-1,2,4-triazole-3-thione (267 g) and methyl iodide (197.7 g) in acetone (2.6 L), was added a solution of sodium hydroxide (54 g in 600 mL of water) at such a rate (ca. 20 mL/min) as to maintain the temperature between 10 and 15° C. Another portion of water (50 mL) was then added and the temperature was allowed to come to 21 to 24° C. After another 2 h, the acetone was distilled off from the reaction mixture in vacuo (water-bath kept at 30° C.). Another portion of water (750 mL) was then added before cooling (17 to 18° C.) and collection of the formed precipitate by filtration. This solid was then washed with water (2×1 L) before drying at 100 mbar under a gentle stream of air for 3 days to yield 235 g of the title compound as a white powder. 1H NMR (DMSO-d6): 2.7 (s, 3H), 3.6 (s, 3H), 7.7 (m, 2H), 8.8 (d, 2H).