Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:9]([OH:11])=O)=[N:4][C:5]([Br:8])=[CH:6][N:7]=1.[NH2:12][C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1.C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>O.CN(C=O)C>[NH2:1][C:2]1[C:3]([C:9]([NH:12][C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)=[O:11])=[N:4][C:5]([Br:8])=[CH:6][N:7]=1
Reactant: Nc1ncc(Br)nc1C(=O)O
Reactant: Nc1cccnc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Nc1ncc(Br)nc1C(=O)Nc1cccnc1
Temperature: -2.5 °C
Reaction time: 0.25 h

Procedure:
3-Amino-6-bromopyrazine-2-carboxylic acid (1.07 kg), 3-aminopyridine (460 g), triethylamine (680 ml) and DMF (6.4 L) were charged into a reactor. The mixture was cooled to −5 to 0° C. and stirred for 15 min. Under a nitrogen flow, HATU (1.8 kg) was slowly added in many portions while maintaining the temperature below 10° C. Upon addition, thick yellow precipitate formed. After addition, the mixture was stirred at 20-25° C. for 1 h. The reaction was analysed for completion (3-Amino-6-bromopyrazine-2-carboxylic acid=0%). Water (13 L) was added under vigorous stirring. The yellow suspension was stirred at 25° C. for 30 min. The suspension was filtered and the filter cake was recharged into reactor. Water (13 L) was charged. The yellow suspension was warmed to 50° C. and stirred at this temperature for 2 h. The suspension was filtered and the filter cake was washed with water. The wet product (3-Amino-6-bromo-N-(pyridin-3-yl)pyrazine-2-carboxamide) was dried in oven at 55° C. under a flow of nitrogen. (1.14 Kg).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[NH:6][CH2:7][CH2:8][O:9][C:10]1[CH:19]=[CH:18][C:13]([C:14]([O:16]C)=[O:15])=[CH:12][CH:11]=1.[ClH:20]>>[ClH:20].[S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[NH:6][CH2:7][CH2:8][O:9][C:10]1[CH:19]=[CH:18][C:13]([C:14]([OH:16])=[O:15])=[CH:12][CH:11]=1
Reactant: COC(=O)c1ccc(OCCNc2nccs2)cc1
Agent: Cl
Product: O=C(O)c1ccc(OCCNc2nccs2)cc1

Procedure:
Ester 24-4 (180 mg, 0.65 mmol) was heated at 50° in 6 mL 6 N HCl for 16 h, then concentrated providing 24-5 as a yellow solid.
Reaction SMILES: C(OC([N:11]1[CH:16]2[CH2:17][NH:18][CH2:19][CH:12]1[CH2:13][O:14][CH2:15]2)=O)C1C=CC=CC=1.C([O-])([O-])=O.[K+].[K+].I[CH:27]([CH3:29])[CH3:28]>CN(C=O)C.CCOC(C)=O.CO.[Pd]>[CH:27]([N:18]1[CH2:17][CH:16]2[NH:11][CH:12]([CH2:13][O:14][CH2:15]2)[CH2:19]1)([CH3:29])[CH3:28]
Reactant: O=C(OCc1ccccc1)N1C2CNCC1COC2
Reactant: CC(C)I
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: CN(C)C=O
Product: CC(C)N1CC2COCC(C1)N2
Temperature: 80 °C
Reaction time: 16 h
Yield: 57 %

Procedure:
To a solution of 3-oxa-7,9-diaza-bicyclo[3.3.1]nonane-9-carboxylic acid benzyl ester (Compound X) (100 mg, 0.33 mmol) in DMF (5 mL) was added K2CO3 (91 mg, 0.66 mmol) and 2-iodopropane (111 mg, 0.66 mmol). The reaction mixture was heated to 80° C. and stirred for 16 hours. The mixture was diluted with EtOAc (60 mL), and then washed with sat. NH4Cl, sat. NaHCO3 and brine (20 mL) respectively. The organic layer was dried over Na2SO4, and then concentrated to give the crude product which was dissolved in MeOH (20 mL). To the solution was added 10% Pd on carbon (20 mg). The mixture was stirred under one atmosphere pressure of H2 at room temperature. After the reaction was completed, the mixture was filtered and concentrated to give the crude 7-isopropyl-3-oxa-7,9-diaza-bicyclo[3.3.1]nonane (Compound AA) (32 mg, 57%) which was directly used for next step. MS: calc'd (MH+) 171, measured (MH+) 171.
Reaction SMILES: [NH2:1][C@H:2]([C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:13]([OH:15])=[O:14])=[CH:8][CH:7]=1)[C:3]([OH:5])=[O:4].C[Si](C([Si](C)(C)C)C(N)=O)(C)C.[F:28][C:29]1[CH:48]=[C:47]([N:49]([CH3:73])[CH:50]2[C:54]3[CH:55]=[C:56]4[C:61](=[CH:62][C:53]=3[CH2:52][CH2:51]2)[N:60]=[C:59]([CH3:63])[N:58]([CH2:64][O:65][C:66](=[O:71])[C:67]([CH3:70])([CH3:69])[CH3:68])[C:57]4=[O:72])[CH:46]=[CH:45][C:30]=1[C:31](OC1C(F)=C(F)C(F)=C(F)C=1F)=[O:32].ON1C2C=CC=CC=2N=N1>>[F:28][C:29]1[CH:48]=[C:47]([N:49]([CH3:73])[CH:50]2[C:54]3[CH:55]=[C:56]4[C:61](=[CH:62][C:53]=3[CH2:52][CH2:51]2)[N:60]=[C:59]([CH3:63])[N:58]([CH2:64][O:65][C:66](=[O:71])[C:67]([CH3:68])([CH3:69])[CH3:70])[C:57]4=[O:72])[CH:46]=[CH:45][C:30]=1[C:31]([NH:1][C@H:2]([C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:13]([OH:15])=[O:14])=[CH:8][CH:7]=1)[C:3]([OH:5])=[O:4])=[O:32]
Reactant: N[C@@H](C(=O)O)c1ccc(CC(=O)O)cc1
Reactant: Cc1nc2cc3c(cc2c(=O)n1COC(=O)C(C)(C)C)C(N(C)c1ccc(C(=O)Oc2c(F)c(F)c(F)c(F)c2F)c(F)c1)CC3
Agent: C[Si](C)(C)C(C(N)=O)[Si](C)(C)C
Agent: On1nnc2ccccc21
Product: Cc1nc2cc3c(cc2c(=O)n1COC(=O)C(C)(C)C)C(N(C)c1ccc(C(=O)N[C@@H](C(=O)O)c2ccc(CC(=O)O)cc2)c(F)c1)CC3
Yield: 70.6 %

Procedure:
A solution of (R)-α-amino-p-carboxymethylphenylacetic acid (0.1 g, 0.48 mmol) and bis trimethylsilyl acetamide (0.195 g, 0.96 mmol in 5 ml of DMF) was stirred for 20 minutes at room temperature. To the solution was then added pentafluorophenyl o-fluoro-p-[N-methyl-N-((6RS)-2-methyl-4-oxo-3-pivalyloxymethyl-3,4,7,8-tetrahydro-6H-cyclopenta[g]quinazolin-6-yl)amino]benzoate (0.213 g, 0.4 mmol), prepared as described in Example 2, followed by N-hydroxybenzotriazole (10 mg) and the stirring was maintained for a further 5 hours. The reaction mixture was then evaporated to dryness and the crude material redissolved in ether. The ether layers were extracted with NaHCO3. The aqueous layers were acidified to pH 2.5 with 2N HCl and the precipiate was filtered off, washed with water and dried under vacuum to give (2R)-2-{o-fluoro-p-[N-methyl-N-((6RS)-2-methyl-4-oxo-3-pivaloyloxymethyl-3,4,7,8-tetrahydro-6H-cyclopenta[g]quinazolin-6-yl)amino]benzamido}-2-[p-(carboxy-methyl)phenyl]acetic acid (0.19 g), 85%) as a white solid;
Reaction SMILES: C(O[C:4](=[O:19])[C:5]([C:17]#[N:18])=[CH:6][NH:7][C:8]1[CH:9]=[N:10][C:11]([O:14][CH2:15][CH3:16])=[CH:12][CH:13]=1)C.CCCCCC>C1C=CC(C2C=CC=CC=2)=CC=1.C1C=CC(OC2C=CC=CC=2)=CC=1>[CH2:15]([O:14][C:11]1[N:10]=[C:9]2[C:8](=[CH:13][CH:12]=1)[N:7]=[CH:6][C:5]([C:17]#[N:18])=[C:4]2[OH:19])[CH3:16]
Reactant: CCOC(=O)C(C#N)=CNc1ccc(OCC)nc1
Solvent: c1ccc(-c2ccccc2)cc1
Solvent: CCCCCC
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CCOc1ccc2ncc(C#N)c(O)c2n1

Procedure:
A sample of 2-cyano-3-(6-ethoxy-pyridin-3-ylamino)-acrylic acid ethyl ester was heated at 257-259° C. (internal temperature) in Dowtherm for 10-12 hrs under nitrogen. After cooling, the reaction mixture was poured into n-hexane. The black solid was collected, and treated with MeOH and CH2Cl2 mixture (1:5). The title compound (or tautomer) was collected and dried. mass spectrum (electrospray, m/e): 215.9 (M+H); IR cm-1: 3063, 2226; H-NMR δ (DMSO-d6): 1.355 (3H, t, CH3), 4.412 (2H, q, CH2), 7.244 (1H, d, C7-H), 7.983 (1H, d, C8-H), 8.682 (1H, s, C2-H), 10.50 (1H, bs, OH).
Reaction SMILES: C([O:3][C:4]([CH2:6][CH2:7][C:8]1[C:13]([O:14][CH2:15][CH2:16][CH2:17][C:18]([O:20]CC)=[O:19])=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][O:29][C:30]1[CH:31]=[C:32]([C:43]([OH:45])=O)[CH:33]=[C:34]([C:36]2[CH:41]=[CH:40][CH:39]=[C:38]([F:42])[CH:37]=2)[CH:35]=1)=[O:5])C.[CH3:46][N:47]1[CH2:53][CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1>>[C:4]([CH2:6][CH2:7][C:8]1[C:9]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][O:29][C:30]2[CH:35]=[C:34]([C:36]3[CH:41]=[CH:40][CH:39]=[C:38]([F:42])[CH:37]=3)[CH:33]=[C:32]([C:43]([N:50]3[CH2:51][CH2:52][CH2:53][N:47]([CH3:46])[CH2:48][CH2:49]3)=[O:45])[CH:31]=2)=[CH:10][CH:11]=[CH:12][C:13]=1[O:14][CH2:15][CH2:16][CH2:17][C:18]([OH:20])=[O:19])([OH:3])=[O:5]
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(C(=O)O)cc(-c3cccc(F)c3)c2)c1CCC(=O)OCC
Reactant: CN1CCCNCC1
Product: CN1CCCN(C(=O)c2cc(OCCCCCCc3cccc(OCCCC(=O)O)c3CCC(=O)O)cc(-c3cccc(F)c3)c2)CC1

Procedure:
The title compound was prepared according to the general procedure described in Steps 7 and 8 of Method C starting from 5-{6-[2-(2-ethoxycarbonyl-ethyl)-3-(3-ethoxycarbonyl-propoxy)-phenyl]-hexyloxy}-3′-fluoro-biphenyl-3-carboxylic acid and 1-methyl-[1,4]diazepane (15% yield after two steps).
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=[C:4]([F:17])[CH:3]=1.[Cl:18][C:19]1[CH:24]=[C:23](B(O)O)[CH:22]=[CH:21][N:20]=1>>[Cl:18][C:19]1[CH:24]=[C:23]([C:2]2[C:10]3[N:9]4[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]4=[C:7]([CH3:16])[C:6]=3[CH:5]=[C:4]([F:17])[CH:3]=2)[CH:22]=[CH:21][N:20]=1
Reactant: Cc1c2n(c3c(Br)cc(F)cc13)CCNC2=O
Reactant: OB(O)c1ccnc(Cl)c1
Product: Cc1c2n(c3c(-c4ccnc(Cl)c4)cc(F)cc13)CCNC2=O

Procedure:
The title compound, light yellow solid (53 mg, 64%), MS (ISP) m/z=330.5 [(M+H)+], mp 254° C., was prepared in accordance with the general method of example 1 from 6-bromo-8-fluoro-10-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (intermediate 14) (74.3 mg, 0.25 mmol) and commercially available 2-chloro-pyridin-4-ylboronic acid (51.1 mg, 0.325 mmol).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH2:15]Cl)=[N:13][N:14]=[C:10]3[CH2:9][N:8]=[C:7]([C:17]3[C:22]([F:23])=[CH:21][CH:20]=[CH:19][C:18]=3[F:24])[C:6]=2[CH:25]=1.[CH:26]1([NH2:29])[CH2:28][CH2:27]1>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH2:15][NH:29][CH:26]4[CH2:28][CH2:27]4)=[N:13][N:14]=[C:10]3[CH2:9][N:8]=[C:7]([C:17]3[C:18]([F:24])=[CH:19][CH:20]=[CH:21][C:22]=3[F:23])[C:6]=2[CH:25]=1
Reactant: Fc1cccc(F)c1C1=NCc2nnc(CCl)n2-c2ccc(Cl)cc21
Reactant: NC1CC1
Solvent: C1CCOC1
Product: Fc1cccc(F)c1C1=NCc2nnc(CNC3CC3)n2-c2ccc(Cl)cc21

Procedure:
In the manner given in Example 1,potassium iodide and 8-chloro-1-(chloromethyl)-6-(2,6-difluorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine in tetrahydrofuran is treated with cyclopropylamine to give 8-chloro-1-[(cyclopropylamino)methyl]-6-(2,6-difluorophenyl)4H-s-triazolo-[4,3-a][1,4]benzodiazepine.
Reaction SMILES: [CH3:1][C:2]1[N:3]([CH2:8][CH2:9][NH2:10])[CH:4]=[C:5]([CH3:7])[N:6]=1.[F:11][C:12]([F:24])([F:23])[C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][CH:21]=O)=[CH:15][CH:14]=1>>[CH3:7][C:5]1[N:6]=[C:2]([CH3:1])[N:3]2[CH2:8][CH2:9][NH:10][CH:21]([CH2:20][CH2:19][C:16]3[CH:17]=[CH:18][C:13]([C:12]([F:11])([F:23])[F:24])=[CH:14][CH:15]=3)[C:4]=12
Reactant: O=CCCc1ccc(C(F)(F)F)cc1
Reactant: Cc1cn(CCN)c(C)n1
Product: Cc1nc(C)n2c1C(CCc1ccc(C(F)(F)F)cc1)NCC2

Procedure:
Prepared according to the previously described general procedure (GP11) by reaction of 2-(2,4-dimethyl-imidazol-1-yl)-ethylamine with 3-(4-trifluoromethyl-phenyl)-propionaldehyde. LC-MS: tR=0.64 min.; [M+H]+=324 g/mol.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:11](=[O:12])[C@H:10]([S:13][CH2:14][C:15]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)=[O:16])[C@H:9]2[C:24]2[CH:41]=[CH:40][C:27]([O:28][CH2:29][C:30]([NH:32][C@@H:33]([C:37]([OH:39])=O)[CH:34]([CH3:36])[CH3:35])=[O:31])=[CH:26][CH:25]=2)=[CH:4][CH:3]=1.Cl.C([O:47][CH2:48][C@@H:49]([C:51]([O:53]C(C)(C)C)=[O:52])[NH2:50])(C)(C)C.CN1CCOCC1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)CC)C.[BH4-].[Na+].C([O-])(=O)C.[NH4+]>C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:11](=[O:12])[C@H:10]([S:13][CH2:14][CH:15]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)[OH:16])[C@H:9]2[C:24]2[CH:41]=[CH:40][C:27]([O:28][CH2:29][C:30]([NH:32][C@@H:33]([C:37]([NH:50][C@H:49]([C:51]([OH:53])=[O:52])[CH2:48][OH:47])=[O:39])[CH:34]([CH3:35])[CH3:36])=[O:31])=[CH:26][CH:25]=2)=[CH:6][CH:7]=1
Reactant: CC(C)[C@@H](NC(=O)COc1ccc([C@@H]2[C@@H](SCC(=O)c3ccc(F)cc3)C(=O)N2c2ccc(F)cc2)cc1)C(=O)O
Reactant: CC(C)(C)OC[C@H](N)C(=O)OC(C)(C)C
Agent: CC(=O)[O-]
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CN1CCOCC1
Product: CC(C)[C@@H](NC(=O)COc1ccc([C@@H]2[C@@H](SCC(O)c3ccc(F)cc3)C(=O)N2c2ccc(F)cc2)cc1)C(=O)N[C@@H](CO)C(=O)O
Reaction time: 0.08 h

Procedure:
N-([4-((2R,3R)-1-(4-Fluorophenyl)-3-{[2-(4-fluorophenyl)-2-oxoethyl]thio}-4-oxoazetidin-2-yl)phenoxy]acetyl}-D-valine (6.9 mg, 11.8 μmol) was dissolved in DCM (3 ml). tert-Butyl O-(tert-butyl)-L-serinate hydrochloride (3.7 mg, 14.2 μmol) and N-methylmorpholine (5.5 μl, 50 μmol) were added. After 5 minutes, TBTU (4.6 mg, 14.3 μmol) was added and the reaction mixture was stirred overnight. The formation of the ester was confirmed. M/z: 780.57 (M−1). The mixture was extracted between DCM (5 ml) and aqueous KHSO4 (5 ml, pH of 2). The organic phase was washed with aqueous NaHCO3 (5 ml, pH of 9). The aqueous phase was extracted with DCM (2×5 ml). The combined organic phases were dried over Na2SO4, filtered and concentrated. Formic acid (1.5 ml) was added and the reaction mixture was stirred overnight. The formiate of the intermediate acid was obtained. The solvent was removed under reduced pressure, toluene (3×1 ml) was added and evaporated. The residue was dissolved in MeOH (1.5 ml) and triethylamine (90 μl, 0.65 mmol) was added and the reaction mixture was stirred for 1 hour. Sodium borohydride (4.0 mg, 0.11 mmol) was added and the reaction mixture was stirred for 1 hour. Ammonium acetate (15 mg) was added. The solvent was removed under reduced pressure and the residue was purified on preparative HPLC using a C8 column. A gradient from 20% to 50% MeCN in 0.1M ammonium acetate buffer was used as eluent. After lyophilisation, the title compound was obtained as a white solid (5.3 mg, 67%). HRMS calcd for C33H35F2N3O8S 671.2113, found 672.2192 [M+H]+.
Reaction SMILES: Cl.[C:2]1([C:8]2[CH:9]=[C:10]3[C:14](=[C:15]([C:17]([NH2:19])=[O:18])[CH:16]=2)[NH:13][N:12]=[C:11]3[CH:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:26]([S:29](Cl)(=[O:31])=[O:30])([CH3:28])[CH3:27].C(N(CC)CC)C>CN(C1C=CN=CC=1)C.CN(C=O)C>[CH3:27][CH:26]([S:29]([N:23]1[CH2:24][CH2:25][CH:20]([C:11]2[C:10]3[C:14](=[C:15]([C:17]([NH2:19])=[O:18])[CH:16]=[C:8]([C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)[CH:9]=3)[NH:13][N:12]=2)[CH2:21][CH2:22]1)(=[O:31])=[O:30])[CH3:28]
Reactant: CC(C)S(=O)(=O)Cl
Reactant: NC(=O)c1cc(-c2ccccc2)cc2c(C3CCNCC3)n[nH]c12
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)S(=O)(=O)N1CCC(c2n[nH]c3c(C(N)=O)cc(-c4ccccc4)cc23)CC1
Yield: 20.7 %

Procedure:
This compound was prepared in a fashion analogous to the procedure described in Example 3. Thus, 5-phenyl-3-(4-piperidinyl)-1H-indazole-7-carboxamide hydrochloride (0.057 g, 0.17 mmol) was reacted with isopropylsulfonyl chloride (0.02 mL, 0.17 mmol) in the presence of triethylamine (0.1 mL, 0.71 mmol) and DMAP (0.0021 g, 0.017 mmol) in DMF (3 mL) to give 0.015 g of a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@H:6]1[C@@H:8]([C:9](=[O:24])[NH:10][C@@H:11]([CH2:18][C:19]2[N:20]=[CH:21][S:22][CH:23]=2)[C:12](=[O:17])[NH:13][CH2:14][C:15]#[CH:16])[O:7]1)=[O:5])[CH3:2].[N:25]([C:28]1[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=1)=[N+:26]=[N-:27].CCCC[Sn](OC(C)=O)(CCCC)CCCC>CC(O)(C)C.CCO.O.[O-]S([O-])(=O)=O.[Cu+2]>[CH2:1]([O:3][C:4]([C@@H:6]1[C@@H:8]([C:9](=[O:24])[NH:10][C@@H:11]([CH2:18][C:19]2[N:20]=[CH:21][S:22][CH:23]=2)[C:12]([NH:13][CH2:14][C:15]2[N:27]=[N:26][N:25]([C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=3)[CH:16]=2)=[O:17])[O:7]1)=[O:5])[CH3:2]
Reactant: [N-]=[N+]=Nc1ccc(F)cc1
Reactant: C#CCNC(=O)[C@H](Cc1cscn1)NC(=O)[C@H]1O[C@@H]1C(=O)OCC
Agent: [Cu+2]
Agent: CCCC[Sn](CCCC)(CCCC)OC(C)=O
Agent: O=S(=O)([O-])[O-]
Solvent: CC(C)(C)O
Solvent: CCO
Solvent: O
Product: CCOC(=O)[C@H]1O[C@@H]1C(=O)N[C@@H](Cc1cscn1)C(=O)NCc1cn(-c2ccc(F)cc2)nn1
Yield: 89.6 %

Procedure:
The general click procedure was used substituting the following quantities: 37 (27.3 mg, 0.08 mmol); 1-azido-4-fluorobenzene (10.4 mg, 0.08 mmol); CuSO4 (2.0 mg, 0.01 mmol); NaAsc (6.0 mg, 0.03 mmol); TBTA (5.0 mg, 0.01 mmol); in t-BuOH/EtOH/H2O (2:1:0.5); afforded the 39 as a white solid (35 mg, 92.2%). 1H NMR (CDCl3, 400 MHz): δ 8.73-8.72 (d, 1H, J=1.91 Hz); 7.90 (s, 1H); 7.74-7.67 (m, 3H); 7.58-7.55 (t, 1H); 7.24-7.18 (t, 2H); 7.07-7.06 (d, 1H, J=1.71 Hz); 4.84-4.79 (q, 1H); 4.54-4.50 (d, 2H, J=5.90 Hz); 4.29-4.21 (m, 2H); 3.68-3.67 (d, 1H, J=1.78 Hz); 3.53-3.52 (d, 1H, J=1.78 Hz); 3.37-3.18 (m, 2H); 1.30-1.26 (t, 3H). 13C NMR (CDCl3, 100 MHz): 169.82, 166.17, 166.03, 163.28, 160.81, 152.86, 152.00, 144.94, 132.78, 122.10, 122.01, 120.48, 116.45, 116.22, 115.59, 61.91, 53.43, 52.40, 52.24, 34.55, 32.42, 13.63.
Reaction SMILES: C[Si](C)(C)N[Si](C)(C)C.[Br:10][C:11]1[CH:12]=[C:13]([C:17](=O)[CH3:18])[CH:14]=[CH:15][CH:16]=1.[C:20](#[N:24])[CH2:21][C:22]#[N:23]>C(O)(=O)C>[Br:10][C:11]1[CH:12]=[C:13]([C:17](=[C:21]([C:20]#[N:24])[C:22]#[N:23])[CH3:18])[CH:14]=[CH:15][CH:16]=1
Reactant: N#CCC#N
Reactant: CC(=O)c1cccc(Br)c1
Agent: C[Si](C)(C)N[Si](C)(C)C
Solvent: CC(=O)O
Product: CC(=C(C#N)C#N)c1cccc(Br)c1
Temperature: 70 °C
Yield: 102.4 %

Procedure:
To a stirred solution of acetic acid (30 mL) at RT was added hexamethyldisilazane (13.09 mL, 62.8 mmol) dropwise over 10 min, maintaining temperature below 40° C. The resulting solution was then added dropwise to a solution of 1-(3-bromophenyl)ethanone (6.68 mL, 50.2 mmol) and malononitrile (6.33 mL, 100 mmol) in acetic acid (30 mL) and the mixture heated to 70° C. under nitrogen overnight. The reaction mixture cooled to RT and partitioned between water and toluene (ca. 150 mL each). The aqueous layer was separated and re-extracted with toluene (ca. 100 mL). The combined organic layer was dried over MgSO4 and solvent removed in vacuo, to afford the title compound (12.7 g) which was carried over to next step without further purification. LCMS (A) m/z: 247/249 [M+1]+, Rt 1.18 min (acidic).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([OH:10])[C:3]=1[C:4]#[N:5].[C:11]([NH:18][CH2:19][CH2:20][CH2:21][CH2:22]O)([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12]>>[C:14]([O:13][C:11](=[O:12])[NH:18][CH2:19][CH2:20][CH2:21][CH2:22][O:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([OH:10])[C:3]=1[C:4]#[N:5])([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)OC(=O)NCCCCO
Reactant: N#Cc1c(O)cccc1O
Product: CC(C)(C)OC(=O)NCCCCOc1cccc(O)c1C#N

Procedure:
The title compound is prepared from 2,6-dihydroxybenzonitrile and 4-(Boc-amino)-1-butanol analogous to Example 110, step A.
Reaction SMILES: [N+:1]([C:4]1[CH:18]=[CH:17][C:7]2=[C:8]3[C:13](=[C:14]([NH2:16])[N:15]=[C:6]2[CH:5]=1)[N:12]=[CH:11][CH:10]=[CH:9]3)([O-])=O>CCO.C(Cl)Cl.[Pd]>[CH:9]1[C:8]2[C:13](=[C:14]([NH2:16])[N:15]=[C:6]3[CH:5]=[C:4]([NH2:1])[CH:18]=[CH:17][C:7]3=2)[N:12]=[CH:11][CH:10]=1
Reactant: Nc1nc2cc([N+](=O)[O-])ccc2c2cccnc12
Agent: [Pd]
Solvent: ClCCl
Solvent: CCO
Product: Nc1ccc2c(c1)nc(N)c1ncccc12
Reaction time: 8 h

Procedure:
A mixture of 8-nitrobenzo[f][1,7]naphthyridin-5-amine (from the previous step) (1.0 eq) and Pd/C (wet, 10% wt) in EtOH was stirred under H2 balloon overnight. The reaction mixture was diluted with DCM. The insoluble solid was filtered off through celite, and the filtrate was concentrated en vaccuo to obtain a crude residue. The crude material was washed with acetone to give benzo[f][1,7]naphthyridine-5,8-diamine as an off white solid: 1H NMR (methanol-d4): δ 8.73 (dd, 1H), 8.71 (dd, 1H), 8.11 (d, 1H), 7.69 (dd, 1H), 6.86 (d, 1H), 6.82 (dd, 1H). LRMS [M+H]=211.1.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Cl)=[CH:4][CH:3]=1.[C:10]([N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)#[C:11][CH3:12].C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][N:16]2[CH2:17][CH2:18][N:13]([C:10]#[C:11][CH3:12])[CH2:14][CH2:15]2)=[CH:4][CH:3]=1
Reactant: ClCc1ccc(Cl)cc1
Reactant: CC#CN1CCNCC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: CC#CN1CCN(Cc2ccc(Cl)cc2)CC1

Procedure:
A mixture of 6.44 g. of 4-chlorobenzyl chloride, 4.97 g. of N-propynyl piperazine, 8.48 g. of sodium carbonate and 50 ml. of ethanol was refluxed for 18 hours. The mixture was then filtered and the filtrate evaporated in vacuo. The residual oil was dissolved in chloroform which solution was washed with water and then dried over magnesium sulfate. The mixture was then filtered and the filtrate was evaporated under vacuum and subsequently distilled to give a yellow oil of the expected N'-(4-chlorobenzyl)-N-propynyl piperazine, b.p. 162°-5° C./1.5 mm, which produces a single spot of T.L.C. and the expected NMR and IR spectra.
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[C:5]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:6]([C:12]1[CH:17]=[CH:16][C:15]([CH:18]3[O:22][CH2:21][CH2:20][O:19]3)=[CH:14][CH:13]=1)=[N:7]2.[NH2:29][NH2:30]>O1CCOCC1>[O:22]1[CH2:21][CH2:20][O:19][CH:18]1[C:15]1[CH:16]=[CH:17][C:12]([C:6]2[C:5]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:4][C:3]3[C:8](=[CH:9][CH:10]=[N:11][C:2]=3[NH:29][NH2:30])[N:7]=2)=[CH:13][CH:14]=1
Reactant: NN
Reactant: Clc1nccc2nc(-c3ccc(C4OCCO4)cc3)c(-c3ccccc3)cc12
Solvent: C1COCCO1
Product: NNc1nccc2nc(-c3ccc(C4OCCO4)cc3)c(-c3ccccc3)cc12
Temperature: 100 °C

Procedure:
A suspension of 5-chloro-2-(4-[1,3]dioxolan-2-yl-phenyl)-3-phenyl-[1,6]naphthyridine (3-3, 5.2 g, 13.4 mmol) and anhydrous hydrazine (5 mL) in anhydrous 1,4-dioxane (15 mL) was heated at 100° C. in a microwave reactor for 5 min. The reaction mixture was cooled, concentrated and dried with toluene azotropically to give the title compound as a solid. LRMS m/z (M+1) Calcd: 385.2. Found 385.3.
Reaction SMILES: [CH2:1]([C:5]1[NH:6][C:7]([C:15]#[N:16])=[C:8]([C:10](=[O:14])[CH:11]([CH3:13])[CH3:12])[N:9]=1)[CH2:2][CH2:3][CH3:4].Br[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[C:26]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])=[CH:27][CH:28]=[CH:29][CH:30]=2)=[CH:21][CH:20]=1.[H-].[Na+]>CN(C)C(=O)C>[C:34]([O:33][C:31]([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=1[C:22]1[CH:23]=[CH:24][C:19]([CH2:18][N:6]2[C:7]([C:15]#[N:16])=[C:8]([C:10](=[O:14])[CH:11]([CH3:12])[CH3:13])[N:9]=[C:5]2[CH2:1][CH2:2][CH2:3][CH3:4])=[CH:20][CH:21]=1)=[O:32])([CH3:37])([CH3:36])[CH3:35]
Reactant: CC(C)(C)OC(=O)c1ccccc1-c1ccc(CBr)cc1
Reactant: CCCCc1nc(C(=O)C(C)C)c(C#N)[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CCCCc1nc(C(=O)C(C)C)c(C#N)n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Yield: 86.4 %

Procedure:
Following a procedure similar to that described in Example 45(a), but using 0.85 g of 2-butyl-4-isobutyrylimidazole-5-carbonitrile (prepared as described in Preparation 27), 1.34 g of t-butyl 4'-(bromomethyl)biphenyl-2-carboxylate and 170 mg of sodium hydride (as a 55% w/w dispersion in mineral oil) in 15 ml of N,N-dimethylacetamide, 1.62 g of the title compound were obtained as a viscous oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[C:4]([F:11])[CH:3]=1.[Br:12][C:13]1[CH:14]=[C:15]([CH:18]=O)[S:16][CH:17]=1.C[O-].[Na+]>CO>[Br:12][C:13]1[CH:14]=[C:15](/[CH:18]=[C:8](/[C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][C:4]=2[F:11])\[C:9]#[N:10])[S:16][CH:17]=1
Reactant: N#CCc1ccc(Cl)cc1F
Reactant: O=Cc1cc(Br)cs1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: N#C/C(=C\c1cc(Br)cs1)c1ccc(Cl)cc1F
Yield: 63.2 %

Procedure:
In a manner similar to the method described in Example 1b, 4-chloro-2-fluorophenylacetonitrile (4.05 g, 24 mmol) was reacted with 4-bromo-2-thiophenecarboxaldehyde (Aldrich) (6.08 g, 29 mmol), methanolic solution (25 wt %) of sodium methoxide (6 mL, 26 mmol) in methanol (90 mL) at 50° C. for 3 h to give (Z)-3-(4-bromo-thiophen-2-yl)-2-(4-chloro-2-fluoro-phenyl)-acrylonitrile as a light yellow solid (5.2 g, 64%).
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[NH:13][C:12](=[O:14])[O:11][C:9](=O)[C:8]=12)[CH3:2].[NH:15]1[CH2:22][CH2:21][CH2:20][C@H:16]1C(O)=O>CS(C)=O>[CH2:1]([C:3]1[C:8]2[C:9](=[O:11])[N:15]3[CH2:22][CH2:21][CH2:20][C@H:16]3[C:12](=[O:14])[NH:13][C:7]=2[CH:6]=[CH:5][CH:4]=1)[CH3:2]
Reactant: CCc1cccc2[nH]c(=O)oc(=O)c12
Reactant: O=C(O)[C@@H]1CCCN1
Solvent: CS(C)=O
Product: CCc1cccc2c1C(=O)N1CCC[C@H]1C(=O)N2

Procedure:
7.65 g (0.04 mol) of 6-ethylisatoic acid anhydride and 4.6 g (0.04 mol) of L-proline are suspended in 40 ml of dimethyl sulphoxide, heated to 70° for 2.5 hours, the solvent is removed in a high vacuum and the oil obtained is heated to 170° for 15 minutes. The crude product is purified by chromatography on silica gel using chloroform for the elution. There is obtained amorphous (S)-6-ethyl-1,2,3,11a-tetrahydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-5,11(10H)-dione.