Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([CH:20]2[S:24](=[O:26])(=[O:25])[NH:23][C:22](=[O:27])[CH2:21]2)=[C:16]([F:28])[CH:15]=1)[C:10](O)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.Cl.[NH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][O:72][C:73]1[CH:82]=[CH:81][CH:80]=[C:79]([OH:83])[C:74]=1[C:75]([O:77][CH3:78])=[O:76]>CN(C=O)C>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([CH:20]2[S:24](=[O:25])(=[O:26])[NH:23][C:22](=[O:27])[CH2:21]2)=[C:16]([F:28])[CH:15]=1)[C:10]([NH:66][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][O:72][C:73]1[CH:82]=[CH:81][CH:80]=[C:79]([OH:83])[C:74]=1[C:75]([O:77][CH3:78])=[O:76])=[O:11])=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: COC(=O)c1c(O)cccc1OCCCCCN
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(C2CC(=O)NS2(=O)=O)c(F)c1)C(=O)O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)c1c(O)cccc1OCCCCCNC(=O)[C@H](Cc1ccc(C2CC(=O)NS2(=O)=O)c(F)c1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 68.3 %

Procedure:
(2S)-2-[(tert-Butoxycarbonyl)amino]-3-[4-(1,1-dioxido-3-oxoisothiazolidin-5-yl)-3-fluorophenyl]propanoic acid (16.7 mg, 0.0400 mmol) in DMF (2.00 mL) was treated with benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (19.5 mg, 0.044 mmol). After five minutes N,N-diisopropylethylamine (20.9 μL, 0.120 mmol) and methyl 2-[(5-aminopentyl)oxy]-6-hydroxybenzoate hydrochloride (14.5 mg, 0.050 mmol) were added and the solution stirred at rt for 1 h. The product was directly purified by preparative LCMS to afford product as a white solid (17.8 mg, 68%). 1H NMR (400 MHz, CD3OD): δ 7.45–7.42 (m, 1H), 7.24–7.21 (m, 1H), 7.16–7.10 (m, 2H), 6.50–6.45 (m, 2H), 5.37–5.34 (m, 1H), 4.27–4.24 (m, 1H), 3.97 (t, J=6.3 Hz, 2H), 3.87 (s, 3H), 3.42–3.05 (m, 7H), 2.99–2.94 (m, 1H), 1.79–1.75 (m, 2H), 1.47–1.40 (m, 4H), 1.36 (s, 9H). LCMS found for C30H39FN3O10S (M+H)+: m/z=652.
Reaction SMILES: Br[CH2:2][CH2:3][C:4]#[N:5].BrCC1C=CC=C(C#N)C=1.[NH:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:18]2([C:28]3=[CH:29][C:30]4[O:34][CH2:33][O:32][C:31]=4[CH:35]=[C:27]3[O:26][CH2:25]2)[C:17]1=[O:36]>>[O:36]=[C:17]1[C:18]2([C:28]3=[CH:29][C:30]4[O:34][CH2:33][O:32][C:31]=4[CH:35]=[C:27]3[O:26][CH2:25]2)[C:19]2[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:16]1[CH2:2][CH2:3][C:4]#[N:5]
Reactant: N#CCCBr
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCO3
Agent: N#Cc1cccc(CBr)c1
Product: N#CCCN1C(=O)C2(COc3cc4c(cc32)OCO4)c2ccccc21

Procedure:
Following the procedure as described in PREPARATION 44 and making non-critical variations using 3-bromopropionitrile to replace α-bromo-m-tolunitrile, and spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one to replace 5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2″(1′H)-one, 3-(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)propanenitrile was obtained (86%) as a colorless solid: mp 200-202° C.; 1H NMR (300 MHz, DMSO-d6) δ7.32 (ddd, J=7.6, 7.4, 1.2 Hz, 1H), 7.24 (d, J=7.6 Hz, 1H), 7.15 (d, J=6.7 Hz, 1H), 7.04 (ddd, J=7.4, 7.4, 1.0 Hz, 1H), 6.66 (s, 1H), 6.24 (s, 1H), 5.89 (d, J=2.2 Hz, 2H), 4.69 (ABq, J=9.3 Hz, 2H), 4.10-3.88 (m, 2H), 2.95 (t, J=6.5 Hz, 2H); 13C NMR (75 MHz, DMSO-d6) δ177.1, 155.8, 148.8, 142.2, 141.9, 132.3, 129.3, 124.1, 123.7, 120.1, 119.1, 109.8, 103.6, 101.9, 93.7, 80.3, 57.9, 35.9, 16.2; MS (ES+) m/z 335.1 (M+1).
Reaction SMILES: [CH3:1]C1C=C2C(C(C=O)=CN2)=CC=1.C(O[C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[N:22]([C:26]([NH2:28])=[O:27])[CH:21]=[C:20]2[N:29]=[C:30]=[O:31])C=C>>[CH3:1][C:25]1[CH:24]=[C:23]2[C:19]([C:20]([N:29]=[C:30]=[O:31])=[CH:21][N:22]2[C:26]([NH2:28])=[O:27])=[CH:18][CH:17]=1
Reactant: Cc1ccc2c(C=O)c[nH]c2c1
Reactant: C=CCOc1ccc2c(c1)c(N=C=O)cn2C(N)=O
Product: Cc1ccc2c(N=C=O)cn(C(N)=O)c2c1

Procedure:
was prepared from 6-methyl-1H-indole-3-carbaldehyde using the protocol described for steps C, D and E in scheme A4 for the preparation of 5-allyloxy-3-isocyanato-indole-1-carboxylic acid amide.
Reaction SMILES: [NH2:1][C:2]([CH:9]([CH3:11])[CH3:10])=[C:3]([C:7]#[N:8])[C:4](=[S:6])[NH2:5].C(O)C.OO>O>[NH2:5][C:4]1[S:6][N:1]=[C:2]([CH:9]([CH3:11])[CH3:10])[C:3]=1[C:7]#[N:8]
Reactant: CC(C)C(N)=C(C#N)C(N)=S
Agent: OO
Solvent: O
Solvent: CCO
Product: CC(C)c1nsc(N)c1C#N
Temperature: 25 °C
Reaction time: 17.75 h
Yield: 97.2 %

Procedure:
To a stirred mixture of 444.3 g of 3-amino-2-cyano-4-methyl-2-pentenethioamide (from part B) and 1315 ml of ethanol were added dropwise 298 g of 30% hydrogen peroxide (containing 89.4 g of active H2O2) during 1.25 hours. The reaction temperature was maintained at 30°-35° with an ice bath. The reaction mixture was stirred an additional 17.5-18 hours in an ambient temperature water bath. The reaction mixture was poured into 5100 ml of cold water with stirring. The water was cooled in an ice-water bath during addition of the reaction mixture. The mixture was stirred for one hour at 5°-10° and filtered. The filter cake was washed with 2 liters of water and allowed to dry on the suction filter. After air-drying over a weekend, 426.5 g of 5-amino-4-cyano-3-isopropylisothiazole, mp 130°-132° was obtained.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[CH:11]1(/[CH:17]=[C:18](\B2OC(C)(C)C(C)(C)O2)/[CH2:19][OH:20])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1.[F-].[Cs+]>O1CCOCC1.C(OCC)(=O)C.C1(P([Pd-4](P(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(P(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)P(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH:11]1(/[CH:17]=[C:18](\[C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=2)/[CH2:19][OH:20])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: O=[N+]([O-])c1ccc(Br)cc1
Reactant: CC1(C)OB(/C(=C\C2CCCCC2)CO)OC1(C)C
Agent: c1ccc([PH](c2ccccc2)(c2ccccc2)[Pd-4]([PH](c2ccccc2)(c2ccccc2)c2ccccc2)([PH](c2ccccc2)(c2ccccc2)c2ccccc2)[PH](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Agent: [F-]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1ccc(/C(=C\C2CCCCC2)CO)cc1
Temperature: 25 °C
Yield: 68.2 %

Procedure:
Add tetrakis(triphenylphosphino)palladium(0) (0.60 g, 0.52 mmol) to a solution of 1-bromo-4-nitro-benzene (0.76 g, 3.76 mmol) and (E)-3-cyclohexyl-2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-prop-2-en-1-ol (1.13 g, 4.24 mmol) in dioxane (20 mL). Add cesium fluoride (1.75 g, 12 mmol) and stir the reaction mixture for 12 h at 80° C. Allow the reaction mixture to cool to r.t. Dilute the reaction mixture with ethyl acetate and wash with water. Separate the layers. Dry the organic phase over sodium sulfate, filter and concentrate. Purify the residue via silica gel chromatography, eluting with a gradient from 95:5 to 7:3 hexanes:ethyl acetate to obtain the title compound (0.67 g). 1H-NMR (CDCl3) δ=1.05-1.72 (m, 10 H), 1.89-2.04 (m, 1H), 4.28-4.36 (m, 2H), 5.61-5.69 (m, 1H), 7.34-7.43 (m, 2H), 8.18-8.26 (m, 2H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[N:10]=[N:11][C:12]([CH2:23][C:24]2[CH:29]=[CH:28][C:27](F)=[CH:26][CH:25]=2)=[CH:13][C:14]=1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC1N=NC([Cl:53])=CC=1OCC1C=CC=CC=1)C1C=CC=CC=1.[Cl-].ClC1C=CC=CC=1C[Zn+]>>[CH2:1]([O:8][C:9]1[N:10]=[N:11][C:12]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[Cl:53])=[CH:13][C:14]=1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Clc1cc(OCc2ccccc2)c(OCc2ccccc2)nn1
Reactant: Fc1ccc(Cc2cc(OCc3ccccc3)c(OCc3ccccc3)nn2)cc1
Agent: Clc1ccccc1C[Zn+]
Agent: [Cl-]
Product: Clc1ccccc1Cc1cc(OCc2ccccc2)c(OCc2ccccc2)nn1
Yield: 38 %

Procedure:
Prepared as described for 3,4-bis(benzyloxy)-6-[(4-fluorophenyl)methyl]pyridazine (Intermediate 51) from 3,4-bis(benzyloxy)-6-chloropyridazine (Intermediate 1) and (2-chlorobenzyl)zinc(II) chloride in 38% yield.
Reaction SMILES: [O:1]=[C:2]1[NH:6][C@@H:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:4][CH2:3]1.CN(C=O)C.Br[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:25]([F:28])([F:27])[F:26].C([O-])([O-])=O.[K+].[K+].C1OCCOCCOCCOCCOCCOC1>O>[CH2:10]([O:9][C:7]([C@H:5]1[CH2:4][CH2:3][C:2](=[O:1])[N:6]1[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:25]([F:26])([F:27])[F:28])=[O:8])[CH3:11]
Reactant: CCOC(=O)[C@H]1CCC(=O)N1
Reactant: FC(F)(F)c1ccccc1CBr
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)[C@H]1CCC(=O)N1Cc1ccccc1C(F)(F)F
Temperature: 80 °C
Yield: 14.7 %

Procedure:
To the solution of (R)-ethyl 5-oxo-pyrrolidine-2-carboxylate (D-pyroglutamic acid ethyl ester; 99% pure; 1403 mg, 8.84 mmol) in 20 ml of DMF 1-(bromomethyl)-2-(trifluoromethyl)benzene (96% pure; 2200 mg, 8.84 mmol), K2CO3 (3660 mg, 26.5 mmol) and a small amount of each KI and 18-crown-6 were added, and the mixture was heated at 80° C. for 6 h. Subsequently the mixture was poured into water and extracted three times with MTBE. The organic layer was washed with brine, dried over MgSO4 and the solvent removed under reduced pressure. Chromatography on silica gel using dichloromethane and dichloromethane/MeOH (99:1) resulted in (R)-5-oxo-1-(2-trifluoromethyl-benzyl)-pyrrolidine-2-carboxylic acid ethyl ester (410 mg, ESI-MS [M+H]+=316.1; yield: 12%), which was hydrolyzed to the corresponding carboxylate by stiffing overnight at room temperature in a solution of 15 ml ethanol and 1.56 mL 2N NaOH (aq). Evaporation of the solvent, followed by addition of water to the residue, extraction with ethyl acetate, subsequent acidification of the aqueous layer to pH 3 using concentrated HCl, extraction with dichloromethane, drying of the combined organic layers with MgSO4 and removal of the solvent under reduced pressure led to the desired product as a white foam.
Reaction SMILES: [N+:1]([C:4]1[O:8][C:7]([C:9](Cl)=[O:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].[NH:12]([C:14]1[S:15][C:16]2[CH:22]=[C:21]([O:23][CH3:24])[CH:20]=[CH:19][C:17]=2[N:18]=1)[NH2:13]>>[CH3:24][O:23][C:21]1[CH:20]=[CH:19][C:17]2[N:18]=[C:14]([NH:12][NH:13][C:9]([C:7]3[O:8][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=3)=[O:10])[S:15][C:16]=2[CH:22]=1
Reactant: COc1ccc2nc(NN)sc2c1
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])o1
Product: COc1ccc2nc(NNC(=O)c3ccc([N+](=O)[O-])o3)sc2c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
The compound 4c was prepared according to above described method by using 5-nitro-2-furancarboxylic acid chloride (300 mg, 1 mmol) and 2-hydrazino-6-methoxybenzothiazole (260 mg, 1 mmol) which stirred for 1 h at 0° C. and stirring continued at 25° C. for 11 h (yield 283 mg, 85%).
Reaction SMILES: [OH:1][C:2]1[C:9]([CH:10]([CH3:12])[CH3:11])=[CH:8][C:5]([CH:6]=O)=[C:4]([CH3:13])[CH:3]=1.[NH:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].OS([O-])(=O)=O.[Na+]>C(Cl)Cl.O>[CH:10]([C:9]1[CH:8]=[C:5]([CH2:6][N:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)[C:4]([CH3:13])=[CH:3][C:2]=1[OH:1])([CH3:12])[CH3:11]
Reactant: Cc1cc(O)c(C(C)C)cc1C=O
Reactant: C1CCNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: Cc1cc(O)c(C(C)C)cc1CN1CCCC1
Yield: 76.5 %

Procedure:
4-Hydroxy-5-isopropyl-2-methyl-benzaldehyde (1.0 g, 5.6 mmol) was added in portions for 30 min to a mixture of pyrrolidine (0.58 mL, 7 mmol) and NaB(OAc)3H (1.49 g, 7 mmol) in CH2Cl2 (10 mL) under vigorous stirring and cooling with an ice bath in an atmosphere of argon. The mixture was stirred for 12 h and cooled with an ice bath. Water (25 mL) and 5N NaHSO4 (to pH 1) were added. The organic layer was separated and discarded. The aqueous one was alkalized with saturated K2CO3 to pH 6 and extracted with chloroform (2×25 mL). The combined extracts were dried with Na2SO4, and evaporated to give the title compound (1.0 g, 80%) was obtained as dark-yellow crystals. LCMS-data: (M+H)+ 234.1 and 235.1 (calculated for C15H23NO 233.4). 1H NMR data (DMSO-d6): 8.88 (br. s, 1H ArOH), 6.90 (s, 1H, Ar—H), 6.54 (s, 1H, Ar—H); 3.40 (s, 2H, ArCH2), 3.13 (m, 1H, CH(CH3)2), 2.33-2.45 (m, 4H, pyrrolidine (CH2)2N), 2.17 (s, 3H, CH3), 1.60-1.70 (m, 4H, CH2CH2CH2CH2), 1.12 (d, 6H, J=6.9 Hz, CH(CH3)2).
Reaction SMILES: [CH3:1][C:2]([O:4][C:5]([CH3:7])=[O:6])=O.[N+:8]([C:11]1[C:12]([N:21]2[CH2:26][CH2:25][CH2:24][C@H:23]([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[CH2:22]2)=[C:13]2[CH2:20]CC[C:14]2=[N+:15]([O-])[CH:16]=1)([O-:10])=[O:9]>>[C:5]([O:4][CH:2]1[C:14]2=[N:15][CH:16]=[C:11]([N+:8]([O-:10])=[O:9])[C:12]([N:21]3[CH2:26][CH2:25][CH2:24][C@H:23]([NH:27][C:28]([O:29][C:30]([CH3:33])([CH3:31])[CH3:32])=[O:34])[CH2:22]3)=[C:13]2[CH2:20][CH2:1]1)(=[O:6])[CH3:7]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCN(c2c([N+](=O)[O-])c[n+]([O-])c3c2CCC3)C1
Product: CC(=O)OC1CCc2c1ncc([N+](=O)[O-])c2N1CCC[C@H](NC(=O)OC(C)(C)C)C1
Temperature: 90 °C
Yield: 21.7 %

Procedure:
A mixture of Ac2O (0.90 g, 8.8 mmol) and tert-butyl [(3S)-1-(3-nitro-1-oxido-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)piperidin-3-yl]carbamate (270 mg, 0.714 mmol) was sealed and heated at 90° C. for 1 h, then allowed to cool to room temperature. The excess Ac2O was removed under reduced pressure. The residue was dissolved in DCM, and then poured into ice cold aq. Na2CO3. The mixture was extracted with DCM twice. The combined extracts were dried, filtered and concentrated under reduced pressure to give a crude product, which was purified by preparative LC-MS (XBridge™ preparative C18 5 μm 30×10 mm OBD™ column, flow rate 60 mL/min., eluting with a gradient of MeCN and water with 0.15% NH4OH) to provide the sub-title compound as a yellow powder (65 mg, 22%). LCMS calc. for C20H29N4O6 (M+H)+: m/z=421.2. Found: 421.3.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18]2[C:23]([NH2:24])=[CH:22][CH:21]=[CH:20][N:19]=2)=[CH:13][CH:12]=1.C(N(CC)CC)C.Cl[C:33](Cl)([O:35]C(=O)OC(Cl)(Cl)Cl)Cl>C1COCC1>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11]1[CH:12]=[CH:13][C:14]([N:17]2[C:18]3=[N:19][CH:20]=[CH:21][CH:22]=[C:23]3[NH:24][C:33]2=[O:35])=[CH:15][CH:16]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: Nc1cccnc1Nc1ccc(Nc2nc3ccccc3o2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=c1[nH]c2cccnc2n1-c1ccc(Nc2nc3ccccc3o2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 109.5 %

Procedure:
To a mixture of N2-[4-(1,3-benzoxazol-2-ylamino)phenyl]pyridine-2,3-diamine (0.080 g) and triethylamine (0.0638 g) in THF (1.5 mL) at 0° C., was added dropwise a solution of triphosgene (0.030 g) in THF (0.6 ml). The reaction mixture was stirred at 0° C. for 0.5 h. The cold bath was removed and the stirring continued at ambient temperature for another 0.5 h. After this time, a saturated aqueous solution of sodium bicarbonate was added. The organic layer was extracted with ethyl acetate (3×100 mL). The combined organic extracts were washed with brine (50 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue obtained was purified by chromatography (silica, methylene chloride to 0.3:5:95 ammonium hydroxide/methanol/methylene chloride) to afford 3-[4-(1,3-benzoxazol-2-ylamino)phenyl]-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (0.038 g) as a white solid.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3](=O)[CH2:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=1)=O.[CH2:20]([O:22][C:23]([C:25]1[N:26]=[CH:27][NH:28][C:29]=1[NH2:30])=[O:24])[CH3:21]>C(O)(=O)C>[CH2:20]([O:22][C:23]([C:25]1[N:26]=[CH:27][N:28]2[C:3]([C:2]([F:19])([F:18])[F:1])=[CH:4][C:5]([C:7]3[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=3)=[N:30][C:29]=12)=[O:24])[CH3:21]
Reactant: CCOC(=O)c1nc[nH]c1N
Reactant: O=C(CC(=O)C(F)(F)F)c1ccc(C(F)(F)F)cc1
Solvent: CC(=O)O
Product: CCOC(=O)c1ncn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Yield: 43.5 %

Procedure:
A mixture of 4,4,4-trifluoro-1-(4-trifluoromethyl-phenyl)-butane-1,3-dione (10.0 g, 35.2 mmol) and 5-amino-1H-imidazole-4-carboxylic acid ethyl ester (5.0 g, 32.2 mmol) in acetic acid (120 mL) was refluxed for 24 h and evaporated. The crude product was further purified by column chromatography on silica gel (ethyl acetate/heptane) and crystallization (diethyl acetate/hexane) to yield 4-trifluoromethyl-2-(4-trifluoromethyl-phenyl)-imidazo[1,5-a]pyrimidine-8-carboxylic acid ethyl ester (5.65 g, 43%) as a yellow solid. MS (EI) 403.1 [(M)+]; mp 243° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:12][CH3:13])[C:5]([O:10][CH3:11])=[C:6]([O:8][CH3:9])[CH:7]=1.[CH3:14][Si:15]([C:18]#[CH:19])([CH3:17])[CH3:16].C(N(C(C)C)CC)(C)C.[Cl-]>ClCCl>[CH3:14][Si:15]([CH3:17])([CH3:16])[C:18]#[C:19][C:2]1[CH:3]=[C:4]([O:12][CH3:13])[C:5]([O:10][CH3:11])=[C:6]([O:8][CH3:9])[CH:7]=1
Reactant: C#C[Si](C)(C)C
Reactant: COc1cc(Br)cc(OC)c1OC
Agent: [Cl-]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1cc(C#C[Si](C)(C)C)cc(OC)c1OC
Temperature: 80 °C
Reaction time: 1 h

Procedure:
1 g 5-bromo-1,2,3-trimethoxybenzene, 1.14 mL of trimethylsilylacetylene, 1.4 mL of diisopropylethylamine (DIPEA) and 290 mg of triphenylphosphinpalladium(II) chloride and 39 mg Cu(I)iodide were placed in a dried flask under argon. The mixture was stirred for 1 h at 80° C., after cooling diluted with dichloromethane (DCM) and filtered through a plug of silica. The filtrate was extracted with aqueous ammonia, saturated brine and concentrated. The residue was purified via flash chromatography (SiO2:cyclohexane→cyclohexane/ethylacetate 9:1) to give trimethyl((3,4,5-trimethoxyphenyl)ethynyl)silane.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:8]2[C:12]([C:13]3[O:22][C:21](=[O:23])[C:20]4[C:15](=[C:16]([CH3:27])[CH:17]=[C:18]5[CH:26]=[N:25][NH:24][C:19]5=4)[N:14]=3)=[CH:11][C:10]([O:28][CH3:29])=[N:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.Cl.[C:31]1([NH2:37])([CH:34]2[CH2:36][CH2:35]2)[CH2:33][CH2:32]1.C(N(CC)CC)C>CN(C)C=O>[C:31]1([NH:37][C:21]([C:20]2[C:15]([NH:14][C:13]([C:12]3[N:8]([C:3]4[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][N:4]=4)[N:9]=[C:10]([O:28][CH3:29])[CH:11]=3)=[O:22])=[C:16]([CH3:27])[CH:17]=[C:18]3[C:19]=2[NH:24][N:25]=[CH:26]3)=[O:23])([CH:34]2[CH2:36][CH2:35]2)[CH2:33][CH2:32]1
Reactant: COc1cc(-c2nc3c(C)cc4cn[nH]c4c3c(=O)o2)n(-c2ncccc2Cl)n1
Reactant: NC1(C2CC2)CC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1cc(C(=O)Nc2c(C)cc3cn[nH]c3c2C(=O)NC2(C3CC3)CC2)n(-c2ncccc2Cl)n1
Temperature: 70 °C
Reaction time: 16 h

Procedure:
To a solution of 500 mg of the above 7-[2-(3-chloro-pyridin-2-yl)-5-methoxy-2H-pyrazol-3-yl]-5-methyl-1H-8-oxa-1,2,6-triaza-cyclopenta[a]naphthalen-9-one in 8 mL of N,N-dimethylformamide is added 244 mg (1.83 mmol) of bicyclopropyl-1-ylamine hydrochloride and 340 μL (2.44 mmol) of triethylamine. The reaction is stirred at 70° C. for 16 hours and then concentrated in vacuo. The residue is taken-up with water and ethyl acetate. The phases are separated and the aqueous layer is washed with ethyl acetate. The combined organic layers are washed several times with brine, dried over MgSO4 and concentrated in vacuo. Purification of the residue by flash chromatography (SiO2, hexanes/ethyl acetate 3:7) affords 90 mg (15% over two steps) of product as a pale yellowish solid; LC/MS:506/508 (M+H)+, m.p.: 150-154° C.
Reaction SMILES: [C:1](=[O:4])([O-])[O-].[Cs+].[Cs+].[Br:7][C:8]1[CH:9]=[C:10]([N+:15]([O-:17])=[O:16])[C:11](O)=[N:12][CH:13]=1.IC>CN(C)C=O>[Br:7][C:8]1[CH:9]=[C:10]([N+:15]([O-:17])=[O:16])[C:1](=[O:4])[N:12]([CH3:11])[CH:13]=1
Reactant: O=C([O-])[O-]
Reactant: O=[N+]([O-])c1cc(Br)cnc1O
Agent: [Cs+]
Solvent: CI
Solvent: CN(C)C=O
Product: Cn1cc(Br)cc([N+](=O)[O-])c1=O
Reaction time: 18 h

Procedure:
Cesium carbonate (44.6 g, 137 mmol) was added to a solution of 5-bromo-2-hydroxy-3-nitropyridine (20.0 g, 91.3 mmol) and iodomethane (19.4 g, 137 mmol) in N,N-dimethylformamide (500 mL). After 18 h, the reaction mixture was quenched with water. The mixture was extracted with ethyl acetate (3×), and the combined organic extracts were washed with water, saturated brine, dried over sodium sulfate, filtered and concentrated. MS 233.1 (MI).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][C:8](=[O:13])[C:9](C)([CH3:11])[CH3:10])[CH:2]=1.CN(C)CCN(C)C.C([Li])CCC.[I:27]I>O1CCCC1.CCCCCC>[CH3:10][CH:9]([CH3:11])[C:8]([NH:7][C:3]1[CH:2]=[N:1][CH:6]=[CH:5][C:4]=1[I:27])=[O:13]
Reactant: CC(C)(C)C(=O)Nc1cccnc1
Reactant: II
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(C)C(=O)Nc1cnccc1I
Temperature: 0 °C
Reaction time: 1 h
Yield: 50.7 %

Procedure:
A solution of 91 g (510 mmol) N-3-pyridylpivalamide and 230 ml (1.53 mol) N,N,N′,N′-tetramethylethylenediamine under argon in 2000 ml tetrahydrofuran was cooled in a dry ice bath to −78° C. Within 1 h, 153 ml (1.53 mmol) of a 10 N n-butyllithium solution in hexane were added dropwise. The reaction mixture was stirred at 0° C. for additional 2 h. After cooling again to −78° C., 380 g (1.5 mol) iodine dissolved in 300 ml tetrahydrofuran were added dropwise during 1.5 h. The dry ice bath was removed and the reaction mixture was allowed to warm up to room temperature overnight. Stirring was continued and 1000 ml water and 1000 ml saturated sodium thiosulfate pentahydrate solution were added. The aqueous layer was separated and extracted twice with 800 ml ethyl acetate. The combined organic layers were dried (magnesium sulfate) and evaporated. Chromatographical filtration gave 75 g (48%) of the title compound as brown crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]2[C:6](=[O:18])[C:7]3[C:14]([C:15]([OH:17])=[O:16])=[N:13][NH:12][C:8]=3[C:9](=[O:11])[NH:10][C:4]=2[CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH2:33](O)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.O>CN(C)C=O>[Cl:1][C:2]1[CH:20]=[CH:19][C:5]2[C:6](=[O:18])[C:7]3[C:14]([C:15]([O:17][CH2:33][C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)=[O:16])=[N:13][NH:12][C:8]=3[C:9](=[O:11])[NH:10][C:4]=2[CH:3]=1
Reactant: OCc1ccccc1
Reactant: O=C(O)c1n[nH]c2c(=O)[nH]c3cc(Cl)ccc3c(=O)c12
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: CN(C)C=O
Product: O=C(OCc1ccccc1)c1n[nH]c2c(=O)[nH]c3cc(Cl)ccc3c(=O)c12
Temperature: 55 °C
Reaction time: 0.05 h
Yield: 54.8 %

Procedure:
A solution of 7-chloro-3-(carboxy)pyrazolo[3,4-c][1]benzazepine-4,10(1H,9H)-dione (500 mg, 1.72 mmol) (compound of Example 9) and 1,1′-carbonyldiimidazole (418 mg, 2.58 mmol) in N,N-dimethylformamide (7 mL) was stirred 13 minutes. In one portion benzyl alcohol (534 μL, 5.16 mmol) was added. The solution was stirred for 17.5 hours at room temperature and 2.75 minutes at 55° C. The solution was allowed to cool to room temperature and water (10 mL) was added. The insoluble material was filtered and dried to give the title compound (360 mg, 55% yield, m.p. 254° C.).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([C:12](=[O:14])[CH3:13])[C:9]([N:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[C:21](Cl)(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(N(CC)CC)C>C(Cl)Cl>[C:21]([N:18]1[CH2:17][CH2:16][N:15]([C:9]2[C:10]([C:12](=[O:14])[CH3:13])=[CH:11][C:2]([Cl:1])=[C:3]3[C:8]=2[N:7]=[CH:6][CH:5]=[CH:4]3)[CH2:20][CH2:19]1)(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CC(=O)c1cc(Cl)c2cccnc2c1N1CCNCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)c1cc(Cl)c2cccnc2c1N1CCN(C(=O)c2ccccc2)CC1
Reaction time: 2 h
Yield: 129.5 %

Procedure:
1-(5-Chloro-8-piperazin-1-ylquinolin-7-yl)ethanone (0.030 g, 0.10 mmol, from Example 47, Step 1) was combined with benzoyl chloride (0.018 mL, 0.16 mmol) and triethylamine (0.043 mL, 0.31 mmol) in methylene chloride (1.0 mL) at room temperature and stirred for 2 hours. The reaction was diluted with dichloromethane, washed with water, dried over MgSO4 and concentrated. The resulting residue was purified on silica gel (eluting with 0 to 5% MeOH in dichloromthane) to give the desired product (51 mg). LCMS calculated for C22H21ClN3O2 (M+H)+: m/z=394.1; Found: 394.0.