Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:9]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)[C:7]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:6][C:3]=1[C:4]#[N:5].C1C(=O)N(Br)C(=O)C1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.[O:49]=[C:50]1[N:54]([CH:55]2[CH2:60][CH2:59][NH:58][CH2:57][CH2:56]2)[C:53]2[CH:61]=[CH:62][CH:63]=[CH:64][C:52]=2[NH:51]1.C(N(C(C)C)CC)(C)C>C(Cl)(Cl)Cl>[Cl:1][C:2]1[N:9]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][N:58]3[CH2:57][CH2:56][CH:55]([N:54]4[C:53]5[CH:61]=[CH:62][CH:63]=[CH:64][C:52]=5[NH:51][C:50]4=[O:49])[CH2:60][CH2:59]3)=[CH:12][CH:11]=2)[C:7]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: Cc1ccc(-c2nc(Cl)c(C#N)cc2-c2ccccc2)cc1
Reactant: O=c1[nH]c2ccccc2n1C1CCNCC1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Agent: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1cc(-c2ccccc2)c(-c2ccc(CN3CCC(n4c(=O)[nH]c5ccccc54)CC3)cc2)nc1Cl
Reaction time: 8 h

Procedure:
A mixture of 2-chloro-6-(4-methylphenyl)-5-phenylnicotinonitrile (11-4) (1.78 g, 5.84 mmol), NBS (1.14 g, 6.42 mmol) and benzoylperoxide (0.28 g, 1.17 mmol) in chloroform (25 mL) was heated to reflux for 24 h. Concentrated in vacuo and the residue was dissolved in MeOH (15 mL) and THF (15 mL). To this solution was added 4-(2-keto-1-benzimidazolinyl)-piperidine (1.39 g, 6.42 mmol) and diisopropylethylamine (3.8 g, 29.2 mmol). The mixture was stirred overnight and concentrated. The residue was treated with Na2CO3 (20 mL, 2M) and extracted with CH2Cl2. The combined organic layers was dried, filtered and concentrated in vacuo. The solid was purified by silicon gel chromatography (2–4% MeOH in CH2Cl2) to give 2-chloro-6-(4-{[4-(2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)piperidin-1-yl]methyl}phenyl)-5-phenylnicotinonitrile (11-5). 1H NMR (CDCl3) δ 8.70 (s, 1H), 7.98 (s, 1H), 7.37–7.25 (m, 7H), 7.17–7.19 (m, 2H), 7.03–7.09 (m, 4H), 4.31–4.37 (m, 1H), 3.54 (s, 2H), 2.98 (m, 2H), 2.41–2.46 (m, 2H), 2.13–2.18 (m, 2H), 1.78–1.80 (m, 2H). LRMS m/z (M+H) Calcd: 520.0, found: 520.2.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[CH:9]=[CH:8][C:7]=1[NH:15][C:16](=[O:18])[CH3:17].[NH:19]1[CH:23]=[CH:22][N:21]=[CH:20]1>CN(C)C=O>[N:19]1([CH2:2][CH2:3][CH2:4][O:5][C:6]2[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[CH:9]=[CH:8][C:7]=2[NH:15][C:16](=[O:18])[CH3:17])[CH:23]=[CH:22][N:21]=[CH:20]1
Reactant: c1c[nH]cn1
Reactant: CC(=O)Nc1ccc([N+](=O)[O-])cc1OCCCCl
Solvent: CN(C)C=O
Product: CC(=O)Nc1ccc([N+](=O)[O-])cc1OCCCn1ccnc1

Procedure:
54.5 g (0.2 mol) of N-[2-(3-chloropropoxy)-4-nitrophenyl]acetamide, the preparation of which was described in step a) of Example 6 above, and 40.8 g (0.6 mol) of 1H imidazole in 150 ml of dimethylformamide were heated on a boiling water bath for 4 hours.
Reaction SMILES: [N+:1]([CH:3](S(C1C=CC(C)=CC=1)(=O)=O)[CH2:4][CH3:5])#[C-:2].[Br:16][C:17]1[CH:24]=[CH:23][C:20]([CH:21]=[O:22])=[CH:19][CH:18]=1.C([O-])([O-])=O.[K+].[K+]>CO>[Br:16][C:17]1[CH:24]=[CH:23][C:20]([C:21]2[O:22][CH:2]=[N:1][C:3]=2[CH2:4][CH3:5])=[CH:19][CH:18]=1
Reactant: O=Cc1ccc(Br)cc1
Reactant: [C-]#[N+]C(CC)S(=O)(=O)c1ccc(C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CCc1ncoc1-c1ccc(Br)cc1
Temperature: 25 °C

Procedure:
A mixture of 1-(1-isocyanopropylsulfonyl)-4-methylbenzene (1.21 g, 5.40 mmol), 4-bromobenzaldehyde (1 g, 5 mmol), and K2CO3 (0.896 g, 6.49 mmol) in MeOH (27 mL) was heated at reflux overnight. The reaction was cooled to ambient temperature and the solvent was evaporated at reduced pressure. The residue was partitioned between water and EtOAc. The separated organic phase was washed with water and brine, dried (Na2SO4), filtered, and concentrated in vacuo. The crude product was dissolved in minimal toluene, loaded on silica gel, and eluted with 2 column volumes of hexane, then 10% to 50% EtOAc/hexanes. The result was 1.27 g (93%) of the title compound. 1H NMR (300 MHz, CDCl3) δ 7.84 (s, 1H), 7.60-7.54 (m, 2H), 7.49-7.43 (m, 2H), 2.78 (q, J=7.5, 2H), 1.32 (t, J=7.6, 3H). MS (DCI+) m/z 252/254 (M+H).
Reaction SMILES: [CH:1]([C@@H:3]1[CH:20]2[C@:15]([CH3:22])([CH2:16][CH2:17][C:18](=[O:21])[CH2:19]2)[C@@H:14]2[C@H:5]([C@H:6]3[C@@:10]([CH2:12][CH2:13]2)([CH3:11])[C:9](=[O:23])[CH2:8][CH2:7]3)[CH2:4]1)=[O:2].[O-:24][Mn](=O)(=O)=O.[K+]>>[C:1]([C@@H:3]1[CH:20]2[C@:15]([CH3:22])([CH2:16][CH2:17][C:18](=[O:21])[CH2:19]2)[C@@H:14]2[C@H:5]([C@H:6]3[C@@:10]([CH2:12][CH2:13]2)([CH3:11])[C:9](=[O:23])[CH2:8][CH2:7]3)[CH2:4]1)([OH:24])=[O:2]
Reactant: C[C@]12CCC(=O)CC1[C@@H](C=O)C[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Reactant: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Product: C[C@]12CCC(=O)CC1[C@@H](C(=O)O)C[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Reaction time: 0.08 h

Procedure:
To a stirred suspension of 6α-formylandrostane-3,17-dione (1.77 g) in t-ButOH (35 mL) and 5% aqueous Na2HPO4 solution (21.5 mL), 1N aqueous KMnO4 (35 mL) was added. After 5 minutes at room temperature, the mixture was quenched by addition of 40% aqueous NaHSO3 solution. The suspension was filtered, washed with H2O and the filtrate was freeze-dried. The residue was taken up with H2O (50 mL) and extracted with EtOAc (4×70 mL). The combined organic extracts were dried over Na2SO4 and evaporated to dryness to give the title compound II-aq (1.80 g, 96%). 1H-NMR (300 MHz, acetone-d6, ppm from TMS): δ 11.99 (bb, 1H), 2.46-0.73 (m, 21H), 1.01 (s, 3H), 0.79 (s, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([OH:15])[CH:13]=2)[CH:8]=[CH:7]1)[CH3:2].[CH3:17][C:18]1[C:23]([CH2:24]O)=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=[C:20]([C:30]2[CH:35]=[CH:34][C:33]([O:36][C:37]([F:40])([F:39])[F:38])=[CH:32][CH:31]=2)[N:19]=1.C(P(CCCC)CCCC)CCC.CN(C)C(N=NC(N(C)C)=O)=O>>[CH2:1]([O:3][C:4](=[O:16])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][CH2:24][C:23]3[C:18]([CH3:17])=[N:19][C:20]([C:30]4[CH:31]=[CH:32][C:33]([O:36][C:37]([F:39])([F:38])[F:40])=[CH:34][CH:35]=4)=[CH:21][C:22]=3[C:26]([F:27])([F:29])[F:28])[CH:13]=2)[CH:8]=[CH:7]1)[CH3:2]
Reactant: CCOC(=O)Cn1ccc2ccc(O)cc21
Reactant: Cc1nc(-c2ccc(OC(F)(F)F)cc2)cc(C(F)(F)F)c1CO
Agent: CCCCP(CCCC)CCCC
Agent: CN(C)C(=O)N=NC(=O)N(C)C
Product: CCOC(=O)Cn1ccc2ccc(OCc3c(C(F)(F)F)cc(-c4ccc(OC(F)(F)F)cc4)nc3C)cc21

Procedure:
In analogy to the procedure described in example 5 f], (6-hydroxy-indol-1-yl)-acetic acid ethyl ester (example 6 b]) was reacted with [2-methyl-6-(4-trifluoromethoxy-phenyl)-4-trifluoromethyl-pyridin-3-yl]-methanol in the presence of tributylphosphine and N,N,N′,N′-tetramethyl azodicarboxamide to yield the title compound as colorless solid.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:18])=[C:4]([CH3:17])[C:5]2[O:10][C:9]([CH3:14])([C:11]([OH:13])=[O:12])[CH2:8][CH2:7][C:6]=2[C:15]=1[CH3:16].[CH3:19][O:20][CH2:21]Br.C(O)(=O)C>N1C=CC=CC=1>[CH3:19][O:20][CH2:21][O:1][C:2]1[C:3]([CH3:18])=[C:4]([CH3:17])[C:5]2[O:10][C:9]([CH3:14])([C:11]([OH:13])=[O:12])[CH2:8][CH2:7][C:6]=2[C:15]=1[CH3:16]
Reactant: COCBr
Reactant: Cc1c(C)c2c(c(C)c1O)CCC(C)(C(=O)O)O2
Solvent: CC(=O)O
Solvent: c1ccncc1
Product: COCOc1c(C)c(C)c2c(c1C)CCC(C)(C(=O)O)O2
Reaction time: 2 h

Procedure:
50 grams (0.2 mol) of 6-hydroxy-3,4-dihydro-2,5,7,8-tetramethyl-2H-1-benzopyran-2-carboxylic acid are dissolved in 150 cm3 of anhydrous pyridine. 16.34 cm3 (0.2 mol) of bromomethyl methyl ether are added dropwise. The mixture is stirred for 2 hours and then the solution is poured onto ice. The mixture is acidified with acetic acid and then extracted with methylene chloride. The organic phase is washed with water and dried over anhydrous sodium sulfate, then the title product is purified by passing through a column of silica gel, eluting with methylene chloride.
Reaction SMILES: [NH:1]1[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][C:2]1=[CH:8][C:9]([O:11][CH3:12])=[O:10].CC1(C)[O:19][C:18](=O)[CH:17]=[C:16]([CH3:21])O1>C1(C)C(C)=CC=CC=1>[CH3:21][C:16]1[N:1]2[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][C:2]2=[C:8]([C:9]([O:11][CH3:12])=[O:10])[C:18](=[O:19])[CH:17]=1
Reactant: COC(=O)C=C1CCCCCN1
Reactant: CC1=CC(=O)OC(C)(C)O1
Solvent: Cc1ccccc1C
Product: COC(=O)c1c2n(c(C)cc1=O)CCCCC2
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 77 %

Procedure:
A mixture of 20.0 g of methyl α-(hexahydro-2-azepinylidene)acetate and 77 ml of xylene was gently refluxed, to which a mixture of 41.9 g of 2,2,6-trimethyl-4H-1,3-dioxin-4-one and 41 ml of xylene was dropwise added taking 45 minutes and refluxed for 2 hours, removing the by-product acetone through a Dean-Stark apparatus. The reaction mixture was cooled to room temperature. The resulting crystals were filtered, washed and dried to afford 21.4 g (Yield 77%) of methyl 2,6,7,8,9,10-hexahydro-4-methyl-2-oxo-pyrido[1,2-a]azepine-1-carboxylate.
Reaction SMILES: [C:1]([O:5][C:6](=[O:30])[NH:7][CH2:8][C:9]1[N:10]([CH2:26][CH:27]([CH3:29])[CH3:28])[C:11](=[O:25])[C:12]2[C:17]([C:18]=1[O:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:16][C:15]([OH:24])=[CH:14][CH:13]=2)([CH3:4])([CH3:3])[CH3:2].I[CH2:32][C:33]([NH2:35])=[O:34].C1CCN2C(=NCCC2)CC1.O>CN(C)C=O>[C:1]([O:5][C:6](=[O:30])[NH:7][CH2:8][C:9]1[N:10]([CH2:26][CH:27]([CH3:29])[CH3:28])[C:11](=[O:25])[C:12]2[C:17]([C:18]=1[O:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:16][C:15]([O:24][CH2:32][C:33]([NH2:35])=[O:34])=[CH:14][CH:13]=2)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCCCOc1c(CNC(=O)OC(C)(C)C)n(CC(C)C)c(=O)c2ccc(O)cc12
Reactant: NC(=O)CI
Solvent: O
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: CCCCOc1c(CNC(=O)OC(C)(C)C)n(CC(C)C)c(=O)c2ccc(OCC(N)=O)cc12
Yield: 77.8 %

Procedure:
A solution of tert-butyl(4-butoxy-6-hydroxy-2-isobutyl-1-oxo-1,2-dihydro-3-isoquinolinyl)methylcarbamate (0.42 g, 1 mmol), 2-iodoacetamide (0.27 g, 1.5 mmol) and 1,8-diazabicyclo[5.4.0]-7-undecene (0.22 mL, 1.5 mmol) in N,N-dimethylformamide (10 mL) was stirred at 80° C. for 10 h. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained crystals were recrystallized from ethyl acetate-diisopropyl ether to give tert-butyl[6-(2-amino-2-oxoethoxy)-4-butoxy-2-isobutyl-1-oxo-1,2-dihydro-3-isoquinolinyl]methylcarbamate (0.37 g, 78.7%) as crystals.
Reaction SMILES: [F:1][C:2]1[C:7]([CH2:8][OH:9])=[CH:6][CH:5]=[CH:4][C:3]=1[N:10]1[CH2:13][CH:12]([O:14][C:15]2[CH:16]=[CH:17][C:18](=[O:21])[NH:19][CH:20]=2)[CH2:11]1.CI.[C:24](=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[F:1][C:2]1[C:7]([CH2:8][OH:9])=[CH:6][CH:5]=[CH:4][C:3]=1[N:10]1[CH2:11][CH:12]([O:14][C:15]2[CH:16]=[CH:17][C:18](=[O:21])[N:19]([CH3:24])[CH:20]=2)[CH2:13]1
Reactant: O=c1ccc(OC2CN(c3cccc(CO)c3F)C2)c[nH]1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: Cn1cc(OC2CN(c3cccc(CO)c3F)C2)ccc1=O
Temperature: 60 °C
Reaction time: 2 h
Yield: 63.2 %

Procedure:
5-({1-[2-Fluoro-3-(hydroxymethyl)phenyl]azetidin-3-yl}oxy)pyridin-2(1H)-one (160 mg) was mixed with DMF (3 ml), and methyl iodide (114 mg) and potassium carbonate (200 mg) were added thereto, followed by stirring at 60° C. for 2 hours. The reaction mixture was concentrated under reduced pressure, and to the residue were added CHCl3 and water. The organic layer was dried over Na2SO4 and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (CHCl3/MeOH) to obtain 5-({1-[2-fluoro-3-(hydroxymethyl)phenyl]azetidin-3-yl}oxy)-1-methylpyridin-2(1H)-one (106 mg).
Reaction SMILES: C([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:42][O:43][CH2:44][C:45]([O:47][CH2:48][CH3:49])=[O:46])[C:10]([NH:12][CH:13]2[C:40](=[O:41])[N:15]3[C:16]([C:37]([OH:39])=[O:38])=[C:17]([CH2:20][S:21][C:22]4[N:26]([CH2:27][CH2:28][NH:29]C(OC(C)(C)C)=O)[N:25]=[N:24][N:23]=4)[CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1)=O.Cl>C(O)C>[NH2:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:42][O:43][CH2:44][C:45]([O:47][CH2:48][CH3:49])=[O:46])[C:10]([NH:12][CH:13]2[C:40](=[O:41])[N:15]3[C:16]([C:37]([OH:39])=[O:38])=[C:17]([CH2:20][S:21][C:22]4[N:26]([CH2:27][CH2:28][NH2:29])[N:25]=[N:24][N:23]=4)[CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1
Reactant: CCOC(=O)CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(CSc3nnnn3CCNC(=O)OC(C)(C)C)CS[C@H]12)c1csc(NC=O)n1
Agent: Cl
Solvent: CCO
Product: CCOC(=O)CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(CSc3nnnn3CCN)CS[C@H]12)c1csc(N)n1
Yield: 25.5 %

Procedure:
7-[2-(2-formamidothiazol-4-yl)-2-ethoxycarbonylmethoxyiminoacetamido]-3-[1-(2-tert-butoxycarbonylaminoethyl)-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylic acid (syn isomer, 2.7 g.), conc. hydrochloric acid (1.52 g.) and ethanol (27 ml.) were treated in a similar manner to that of Example 11-(2) to give 7-[2-(2-aminothiazol-4-yl)-2-ethoxycarbonylmethoxyiminoacetamido]-3-[1-(2-aminoethyl)-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylic acid (syn isomer, 0.57 g.).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[N:6][CH:7]=1.CO[CH:14]1[CH2:18][CH2:17][CH:16](OC)O1.C(OCC)(=O)C.C(=O)([O-])[O-].[K+].[K+]>C(O)(=O)C.O>[N:1]1([C:2]2[CH:3]=[C:4]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[N:6][CH:7]=2)[CH:14]=[CH:18][CH:17]=[CH:16]1
Reactant: COC1CCC(OC)O1
Reactant: COC(=O)c1cncc(N)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: COC(=O)c1cncc(-n2cccc2)c1
Temperature: 25 °C
Yield: 57.1 %

Procedure:
A mixture of methyl 5-amino-3-pyridinecarboxylate (1.7 g) and 2.5-dimethoxytetrahydrofuran (2.2 g) in acetic acid (5 ml) was refluxed for 30 minutes. After being cooled to room temperature, the reaction mixture was poured into a mixture of ethyl acetate (50 ml) and water (50 ml) under stirring, and adjusted to pH 8.5 with 10% potassium carbonate aqueous solution. The organic layer was washed with brine and dried over magnesium sulfate. The solvent was evaporated in vacuo and the residue was recrystallized from diethyl ether-n-hexane to afford methyl 5-(pyrrol-1-yl)-3-pyridinecarboxylate (1.29 g).
Reaction SMILES: [OH:1][C:2]([CH3:38])([CH3:37])[CH2:3][C@@:4]1([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16]([C:19]3[N:24]=[N:23][C:22]([C:25]4([C:28]([OH:30])=O)[CH2:27][CH2:26]4)=[CH:21][CH:20]=3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1.[NH3:39]>>[OH:1][C:2]([CH3:37])([CH3:38])[CH2:3][C@@:4]1([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16]([C:19]3[N:24]=[N:23][C:22]([C:25]4([C:28]([NH2:39])=[O:30])[CH2:26][CH2:27]4)=[CH:21][CH:20]=3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1
Reactant: C[C@@H](c1ccc(-c2ccc(C3(C(=O)O)CC3)nn2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Reactant: N
Product: C[C@@H](c1ccc(-c2ccc(C3(C(N)=O)CC3)nn2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Yield: 50 %

Procedure:
The title compound was prepared from 1-[6-(4-{(S)-1-[(S)-6-(2-hydroxy-2-methyl-propyl)-2-oxo-6-phenyl-[1,3]oxazinan-3-yl]ethyl}-phenyl)-pyridazin-3-yl]-cyclopropanecarboxylic acid and ammonia (32% in water) following a procedure analogous to that described in Step 2 for Intermediate 5. Yield: 50% of theory; LC (method 1): tR=1.72 min; Mass spectrum (ESI+): m/z=515 [M+H]+.
Reaction SMILES: FC(F)(F)C(O)=O.C[O:9][C:10](=O)[C:11]1[CH:16]=[C:15]([C:17]2[CH:22]=[C:21]([S:23][CH2:24][CH2:25][NH:26][C:27](=[O:39])[CH2:28][CH2:29][CH2:30][NH:31]C(OC(C)(C)C)=O)[N:20]=[C:19]([NH2:40])[N:18]=2)[C:14]([CH3:41])=[CH:13][C:12]=1[O:42][CH3:43].[OH-].[Li+].Cl.C(OCC)(=O)C.ON1C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.Cl.C(N=C=NCCCN(C)C)C>ClCCl>[NH2:40][C:19]1[N:20]=[C:21]2[CH:22]=[C:17]([C:15]3[CH:16]=[C:11]([C:10](=[O:9])[NH:31][CH2:30][CH2:29][CH2:28][C:27](=[O:39])[NH:26][CH2:25][CH2:24][S:23]2)[C:12]([O:42][CH3:43])=[CH:13][C:14]=3[CH3:41])[N:18]=1
Reactant: COC(=O)c1cc(-c2cc(SCCNC(=O)CCCNC(=O)OC(C)(C)C)nc(N)n2)c(C)cc1OC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C)c2cc1C(=O)NCCCC(=O)NCCSc1cc-2nc(N)n1
Reaction time: 3.5 h
Yield: 12.5 %

Procedure:
Trifluoroacetic acid (0.5 ml) was added to a dichloromethane (2.0 ml) solution of 5-{2-amino-6-[2-(4-tert-butoxycarbonylaminobutyrylamino)ethylsulfanyl]pyrimidin-4-yl}-2-methoxy-4-methylbenzoic acid methyl ester (45 mg, 0.08 mmol) obtained in Step 2 above. The reaction solution was stirred for 3.5 hours while gradually warming from 0° C. to room temperature. The reaction solution was concentrated under reduced pressure, and then benzene (1.5 ml) was added to the resulting residue. The solution was concentrated under reduced pressure. This treatment was repeated three times. The resulting colorless syrup-like material was dissolved in tetrahydrofuran (0.7 ml), methanol (0.7 ml), and water (0.5 ml). Lithium hydroxide (18 mg, 0.43 mmol) was added to the mixture, and the resulting mixture was stirred at room temperature for 24 hours. The reaction solution was acidified by adding 4N hydrochloric acid-ethyl acetate solution (0.95 ml). The solvent was distilled off under reduced pressure. The obtained white solid material was dissolved by adding N,N-dimethylformamide (10 ml) and tetrahydrofuran (33 ml). N-Hydroxybenzotriazole (58 mg, 0.43 mmol), diisopropylethylamine (0.15 ml, 0.9 mmol), and 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride (165 mg, 0.9 mmol) were sequentially added to the solution. The resulting mixture was stirred at room temperature for 2.5 hours. The reaction solution was concentrated under reduced pressure. The resulting residue was diluted with ethyl acetate (100 ml), and sequentially washed twice with water (50 ml), and with a saturated aqueous sodium bicarbonate solution (50 ml), water (50 ml), and a saturated aqueous sodium chloride solution (50 ml). The washed ethyl acetate solution was dried over anhydrous sodium sulfate (10 g). After filtration, the filtrate was concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography with diol-silica gel (developing solvent: ethyl acetate to ethyl acetate:methanol=15:1) and amino-silica gel (developing solvent: ethyl acetate to ethyl acetate:methanol=15:1) to yield 4-amino-18-methoxy-20-methyl-7-thia-3,5,10,15-tetraazatricyclo[15.3.1.12,6]docosa-1(20),2(22),3,5,17(21),18-hexaene-11,16-dione (Compound 9) (4 mg) as a white solid material.
Reaction SMILES: [CH:1]1[C:6]2[CH2:7][NH:8][C:9]3[CH:15]=[C:14]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:13]=[CH:12][C:10]=3[O:11][C:5]=2[CH:4]=[CH:3][CH:2]=1.[C:21](Cl)(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>N1C=CC=CC=1.C(Cl)(Cl)Cl>[C:21]([N:8]1[CH2:7][C:6]2[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=2[O:11][C:10]2[CH:12]=[CH:13][C:14]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:15][C:9]1=2)(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CCOC(=O)c1ccc2c(c1)NCc1ccccc1O2
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: CCOC(=O)c1ccc2c(c1)N(C(=O)c1ccccc1)Cc1ccccc1O2
Yield: 75 %

Procedure:
To a solution of ethyl 10,11-dihydrodibenz[b,f][1,4]oxazepine-8-carboxylate (1.35 g) in a mixture of pyridine (2.5 ml) and chloroform (5 ml) was added dropwise a solution of benzoyl chloride (0.7 g) in chloroform (5 ml) over 15 minutes while stirring under ice cooling. The resulting mixture was stirred at room temperature for 3 hours, washed with a diluted sodium hydroxide aqueous solution and with water, dried over anhydrous sodium sulfate and distilled under reduced pressure to remove chloroform. The residue was recrystallized from ethanol to give ethyl N-benzoyl-10,11-dihydrodibenz[b,f][1,4]oxazepine-8-carboxylate as colorless needles.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][NH2:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:10][C:11]1[CH:16]=[CH:15][N:14]=[C:13]2[CH:17]=[C:18]([C:20]([O-])=[O:21])[S:19][C:12]=12.[Li+]>>[N:1]1([CH2:7][CH2:8][NH:9][C:20]([C:18]2[S:19][C:12]3[C:13](=[N:14][CH:15]=[CH:16][C:11]=3[Cl:10])[CH:17]=2)=[O:21])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C([O-])c1cc2nccc(Cl)c2s1
Reactant: NCCN1CCCCC1
Agent: [Li+]
Product: O=C(NCCN1CCCCC1)c1cc2nccc(Cl)c2s1

Procedure:
The title compound was prepared from 2-piperidin-1-yl-ethyl amine and lithium 7-chloro-thieno[3,2-b]pyridine-2-carboxylate by a procedure analogous to Example 1B. MS: 324/326 (MH+); HPLC Rf: 3.64 min.; HPLC purity 93%.
Reaction SMILES: CO[C:3]([C:5]1[NH:9][N:8]=[C:7]([N+:10]([O-:12])=[O:11])[N:6]=1)=[O:4].[CH3:13][O:14][CH2:15][CH2:16][NH2:17]>O1CCOCC1>[CH3:13][O:14][CH2:15][CH2:16][NH:17][C:3]([C:5]1[NH:9][N:8]=[C:7]([N+:10]([O-:12])=[O:11])[N:6]=1)=[O:4]
Reactant: COCCN
Reactant: COC(=O)c1nc([N+](=O)[O-])n[nH]1
Solvent: C1COCCO1
Product: COCCNC(=O)c1nc([N+](=O)[O-])n[nH]1

Procedure:
To 1 g of 3-nitro-1,2,4-triazole-5-carboxylic acid methyl ester dissolved in 5 ml of dioxane is added 1 g of methoxy ethylamine. The reaction mixture is warmed at 40°-50° C. for 2 hr with stirring.
Reaction SMILES: [CH2:1]1[CH:5]2[CH2:6][NH:7][CH2:8][CH:4]2[CH2:3][N:2]1[C:9]1[N:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[N:12]=[C:11]([N:19]([CH3:21])[CH3:20])[CH:10]=1.[F:22][C:23]1[CH:24]=[CH:25][C:26]([N:32]2[N:36]=[CH:35][CH:34]=[N:33]2)=[C:27]([CH:31]=1)[C:28](O)=[O:29].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>CN(C=O)C.C(OCC)(=O)C>[F:22][C:23]1[CH:24]=[CH:25][C:26]([N:32]2[N:36]=[CH:35][CH:34]=[N:33]2)=[C:27]([C:28]([N:7]2[CH2:6][CH:5]3[CH2:1][N:2]([C:9]4[N:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[N:12]=[C:11]([N:19]([CH3:21])[CH3:20])[CH:10]=4)[CH2:3][CH:4]3[CH2:8]2)=[O:29])[CH:31]=1
Reactant: CN(C)c1cc(N2CC3CNCC3C2)nc(C(F)(F)F)n1
Reactant: O=C(O)c1cc(F)ccc1-n1nccn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CN(C)c1cc(N2CC3CN(C(=O)c4cc(F)ccc4-n4nccn4)CC3C2)nc(C(F)(F)F)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 50.4 %

Procedure:
A mixture of [6-(hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-2-trifluoromethyl-pyrimidin-4-yl]-dimethyl-amine (50 mg, 0.17 mmol), 5-fluoro-2-[1,2,3]triazol-2-yl-benzoic acid (37.8 mg, 0.18 mmol), HATU (94.6 mg, 0.25 mmol) and DIPEA (0.09 mL, 0.50 mmol) in DMF (4.0 mL) was stirred at room temperature for 30 minutes. The reaction mixture was diluted with ethyl acetate (60.0 mL) and washed with water (2×100 mL). The organic phase was dried (Na2SO4), filtered and concentrated to dryness. The crude product was purified using Agilent HPLC (Basic system) to yield pure title compound (42.0 mg, 51.6%). MS (ESI) mass calcd. for C22H22F4N8O, 490.46; m/z found [M+H]+. 1H NMR (CDCl3): 7.96 (dd, J=9.0, 4.8, 1H), 7.80-7.66 (m, 2H), 7.25-7.18 (m, 1H), 7.16-7.10 (m, 1H), 5.22-5.11 (m, 1H), 3.90-3.30 (m, 8H), 3.13-3.06 (m, 7H), 3.00 (s, 6H).
Reaction SMILES: [H-].[Na+].[C:3]([C:5]1[CH:10]=[CH:9][N:8]2[N:11]=[CH:12][C:13]([C:14]3[N:19]=[C:18]([NH:20][C@@H:21]4[CH2:26][CH2:25][CH2:24][N:23]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:22]4)[CH:17]=[CH:16][N:15]=3)=[C:7]2[CH:6]=1)#[N:4].[CH3:34]I>CN(C)C=O>[C:3]([C:5]1[CH:10]=[CH:9][N:8]2[N:11]=[CH:12][C:13]([C:14]3[N:19]=[C:18]([N:20]([CH3:34])[C@@H:21]4[CH2:26][CH2:25][CH2:24][N:23]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:22]4)[CH:17]=[CH:16][N:15]=3)=[C:7]2[CH:6]=1)#[N:4]
Reactant: CI
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](Nc2ccnc(-c3cnn4ccc(C#N)cc34)n2)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(c1ccnc(-c2cnn3ccc(C#N)cc23)n1)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Reaction time: 0.5 h
Yield: 45.4 %

Procedure:
Sodium hydride (60% dispersion in mineral oil, 102 mg, 2.55 mmol) was added to a cooled (0° C.) solution of tert-butyl (3R)-3-{[2-(5-cyanopyrazolo[1,5-a]pyridin-3-yl) pyrimidin-4-yl]amino}piperidine-1-carboxylate (Preparation 7a, 0.83 g, 1.98 mmol) in NIP-dimethylformamide (5 mL) and the reaction mixture was stirred at the same temperature for 30 minutes. Methyl iodide (0.135 mL, 2.17 mmol) was then added and the reaction mixture was stirred at room temperature for 2 hours. The solvent was concentrated in vacuo and the residue was partitioned between water and ethyl acetate. The organic layer was separated, washed with water and brine, dried (MgSO4) and the solvent was evaporated to give the title compound (0.39 g, 80%) as a beige solid.