Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C@@H:2]1[C@@H:6]([CH2:7][O:8][C:9](=[O:52])[CH:10]([O:27][C:28](=[O:51])[C@H:29]([CH:48]([CH3:50])[CH3:49])[NH:30]C(OCC2C3C(=CC=CC=3)C3C2=CC=CC=3)=O)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[O:5][C@@H:4]([N:53]2[C:63]3[N:62]=[C:60]([NH2:61])[NH:59][C:57](=[O:58])[C:56]=3[N:55]=[CH:54]2)[CH2:3]1.C1CCN2C(=NCCC2)CC1.C(O)(=O)C>CN(C=O)C>[F:1][C@@H:2]1[C@@H:6]([CH2:7][O:8][C:9](=[O:52])[CH:10]([O:27][C:28](=[O:51])[C@H:29]([CH:48]([CH3:50])[CH3:49])[NH2:30])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[O:5][C@@H:4]([N:53]2[C:63]3[N:62]=[C:60]([NH2:61])[NH:59][C:57](=[O:58])[C:56]=3[N:55]=[CH:54]2)[CH2:3]1
Reactant: CCCCCCCCCCCCCCCCC(OC(=O)[C@@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(C)C)C(=O)OC[C@H]1O[C@@H](n2cnc3c(=O)[nH]c(N)nc32)C[C@@H]1F
Solvent: CC(=O)O
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: CCCCCCCCCCCCCCCCC(OC(=O)[C@@H](N)C(C)C)C(=O)OC[C@H]1O[C@@H](n2cnc3c(=O)[nH]c(N)nc32)C[C@@H]1F
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of 2′,3′-dideoxy-3′-fluoro-5′-O-[2-(N-FMOC-L-valyloxy) stearoyl]guanosine (800 mg, 0.89 mmole) in 15 ml DMF was added DBU (1.35 g, 8.9 mmole) and the mixture was stirred for 5 minutes at room temperature. Acetic acid (2 ml) was added and the mixture was evaporated under reduced pressure. Water (20 ml) were added and the mixture was extracted three times with dichloromethane. The organic phase was dried with sodium sulfate and evaporated under reduced pressure. The product was isolated by silica gel column chromatography. Yield: 165 mg
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[N+:20]([O-])=O)=[C:4]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:5]([CH3:7])[CH:6]=1>O1CCCC1.[Ni]>[NH2:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[NH:13][C:3]1[C:2]([Cl:1])=[CH:6][N:5]([CH3:7])[C:4]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CCOC(=O)c1c(Nc2ccccc2[N+](=O)[O-])c(Cl)cn1C
Agent: [Ni]
Solvent: C1CCOC1
Product: CCOC(=O)c1c(Nc2ccccc2N)c(Cl)cn1C
Reaction time: 13 h

Procedure:
A solution of ethyl 4-chloro-1-methyl-3-[(2-nitrophenyl) amino]-1H-pyrrole-2-carboxylate (35.6 g, 0.11 mol) in tetrahydrofuran (700 ml) is hydrogenated for 10 hours under a hydrogen pressure of 10 bar and at a temperature of 40° C. after the addition of Raney nickel (10 g). After a further Raney nickel (10 g) had been added, hydrogenation is continued for a further 13 hours under the same conditions, after which no further starting material is detected in the mixture by thin layer chromatography. The catalyst is filtered off, the filtrate is concentrated in vacuo and the syrupy residue is recrystallized once from tert.butyl methyl ether and once from methanol. The colorless crystals (27.5 g) melted at 104° to 105° C.
Reaction SMILES: [NH2:1][CH:2]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=1)[CH:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1)[OH:4].[C:23]1([CH2:29][CH2:30][C:31](Cl)=[O:32])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(=O)([O-])O.[Na+]>C(OCC)(=O)C.O>[F:11][C:8]1[CH:9]=[CH:10][C:5]([CH:3]([OH:4])[CH:2]([NH:1][C:31](=[O:32])[CH2:30][CH2:29][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:20])[F:21])=[CH:15][CH:14]=2)=[CH:6][CH:7]=1
Reactant: O=C(Cl)CCc1ccccc1
Reactant: NC(Cc1ccc(C(F)(F)F)cc1)C(O)c1ccc(F)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(CCc1ccccc1)NC(Cc1ccc(C(F)(F)F)cc1)C(O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.3 %

Procedure:
To a solution of (1RS,2SR)-2-amino-1-(4-fluorophenyl)-3-(4-(trifluoromethyl)phenyl)-1-propanol (450 mg, 1.44 mmol) in ethyl acetate (20 ml) were added 3-phenylpropionyl chloride (320 ml, 2.15 mmol) and saturated aqueous sodium hydrogen carbonate (20 ml) and the mixture was stirred overnight at room temperature. The reaction solution was diluted with water (100 ml), and extracted with ethyl acetate (100 ml×2). The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give the title compound (560 mg, 88%).
Reaction SMILES: C(OC([NH:11][C@H:12]1[CH2:15][CH2:14][C@H:13]1[C:16]([O:18][CH3:19])=[O:17])=O)C1C=CC=CC=1.[ClH:20]>[C].[Pd].CO>[ClH:20].[NH2:11][C@H:12]1[CH2:15][CH2:14][C@H:13]1[C:16]([O:18][CH3:19])=[O:17]
Reactant: COC(=O)[C@@H]1CC[C@@H]1NC(=O)OCc1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: COC(=O)[C@@H]1CC[C@@H]1N
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of methyl rel-(1R,2S)-2-{[(benzyloxy)carbonyl]amino}cyclobutanecarboxylate (1.0 g), methanol (20 ml) and 1 M hydrochloric acid (4.0 ml) was added palladium-carbon (4.0 g) at room temperature, followed by stirring at room temperature for 2 hours under a hydrogen atmosphere. The insolubles in the reaction mixture were separated by filtration through Celite and the filtrate was concentrated under reduced pressure. To the residue were added ethyl acetate and acetonitrile, the solid precipitated was separated by filtration, and the filtrate was concentrated to obtain methyl rel-(1R,2S)-2-aminocyclobutanecarboxylate hydrochloride (0.70 g). Methyl rel-(1R,2S)-2-({N5-[(benzyloxy)carbonyl]-N2-[(1-methyl-1H-indol-2-yl)carbonyl]-L-ornithyl}amino)cyclobutanecarboxylate (0.45 g) was obtained by using methyl rel-(1R,2S)-2-aminocyclobutanecarboxylate hydrochloride (0.31 g) in the same method as for Production Process A1.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([CH2:15][C:16]([C:18]2[CH:23]=[CH:22][C:21](CO)=[CH:20][CH:19]=2)=[O:17])[C:11](=[O:26])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC1C=CNC(=O)C=1)C1C=CC=CC=1.[C:42]([O:46][C:47]([N:49]1[CH2:58]CC2[C:51](=CC=C(C(=O)CBr)C=2)[CH2:50]1)=[O:48])([CH3:45])([CH3:44])[CH3:43]>>[C:42]([O:46][C:47]([N:49]1[CH2:50][CH2:51][C:22]2[C:21](=[CH:20][CH:19]=[C:18]([C:16](=[O:17])[CH2:15][N:12]3[CH:13]=[CH:14][C:9]([O:8][CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[CH:10][C:11]3=[O:26])[CH:23]=2)[CH2:58]1)=[O:48])([CH3:45])([CH3:44])[CH3:43]
Reactant: CC(C)(C)OC(=O)N1CCc2cc(C(=O)CBr)ccc2C1
Reactant: O=C(Cn1ccc(OCc2ccccc2)cc1=O)c1ccc(CO)cc1
Agent: O=c1cc(OCc2ccccc2)cc[nH]1
Product: CC(C)(C)OC(=O)N1CCc2cc(C(=O)Cn3ccc(OCc4ccccc4)cc3=O)ccc2C1

Procedure:
6-[2-(4-Benzyloxy-2-oxo-2H-pyridin-1-yl)-acetyl]-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester is prepared following preparation 15b (DMSO as solvent; purification via HPLC) from 214 mg (1.06 mmol) 4-benzyloxy-1H-pyridin-2-one and 580 mg (1.06 mmol) 6-(2-bromoacetyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (preparation 29c).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:13]2[CH2:17][CH2:16][CH2:15][N:14]2[C:18]2[CH:23]=[CH:22][N:21]3[N:24]=[CH:25][C:26]([C:27]([O:29]CC)=[O:28])=[C:20]3[N:19]=2)[CH:5]=[C:6]([O:8][CH2:9][CH2:10][O:11][CH3:12])[CH:7]=1>[OH-].[Na+].CO>[F:1][C:2]1[CH:3]=[C:4]([C@H:13]2[CH2:17][CH2:16][CH2:15][N:14]2[C:18]2[CH:23]=[CH:22][N:21]3[N:24]=[CH:25][C:26]([C:27]([OH:29])=[O:28])=[C:20]3[N:19]=2)[CH:5]=[C:6]([O:8][CH2:9][CH2:10][O:11][CH3:12])[CH:7]=1
Reactant: CCOC(=O)c1cnn2ccc(N3CCC[C@@H]3c3cc(F)cc(OCCOC)c3)nc12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COCCOc1cc(F)cc([C@H]2CCCN2c2ccn3ncc(C(=O)O)c3n2)c1
Temperature: 25 °C
Yield: 106.5 %

Procedure:
(R)-ethyl 5-(2-(3-fluoro-5-(2-methoxy ethoxy)phenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylate (178 mg, 0.415 mmol) was suspended in a mixture of 1N NaOH (5 mL) and MeOH (5 mL). The reaction mixture was stirred at ambient temperature until complete and quenched with 2N HCl (25 mL). The mixture was extracted with ethyl acetate and the combined organic fractions were concentrated to give the title compound (177 mg, 100% yield). MS (apci) m/z=401.0 (M+H).
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[N:18]=[C:17]3[N:11]([CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21](O)[N:20]=[CH:19][C:16]=43)[CH:10]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2].Cl.[F:25][C:26]1([F:34])[CH2:30][NH:29][C@H:28]([C:31]([NH2:33])=[O:32])[CH2:27]1.CCN(C(C)C)C(C)C.C(#N)C>O>[F:25][C:26]1([F:34])[CH2:30][N:29]([C:21]2[N:20]=[CH:19][C:16]3[C:17]4[N:11]([CH:10]=[C:9]([C:8]5[N:4]([CH:1]([CH3:2])[CH3:3])[N:5]=[CH:6][N:7]=5)[N:18]=4)[CH2:12][CH2:13][O:14][C:15]=3[CH:22]=2)[C@H:28]([C:31]([NH2:33])=[O:32])[CH2:27]1
Reactant: NC(=O)[C@@H]1CC(F)(F)CN1
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1cnc(O)cc1OCC2
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CC#N
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1cnc(N3CC(F)(F)C[C@H]3C(N)=O)cc1OCC2
Yield: 11 %

Procedure:
Following the procedures of Example 339, 2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a,9-triaza-benzo[e]azulen-8-ol from Example 93 and 4,4-difluoro-L-prolinamide hydrochloride with added DIPEA (2.2 eq.) were reacted and the crude product subjected to RPHPLC (C18 column, gradient 5 to 95% acetonitrile in water+0.1% HCO2H) then recrystallisation from IMS to give 381 as a white solid (24 mg, 11%). LCMS: RT=3.21 min, [M+H]+=445. 1H NMR 400 MHz (DMSO-d6) δ: 9.11 (1H, s), 7.90 (1H, d, J=0.64 Hz), 7.87 (1H, s), 7.53 (1H, br), 7.14 (1H, br), 6.08 (1H, s), 5.99-5.91 (1H, m), 4.61 (1H, dd, J=9.53, 4.24 Hz), 4.58-4.49 (4H, m), 4.00-3.98 (2H, m), 2.91-2.90 (1H, m), 2.45 (1H, dd, J=13.51, 4.18 Hz), 1.49 (6H, dd, J=6.59, 3.35 Hz)
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([CH2:12][CH3:13])=[CH:8][C:7]=2[C:14]2[C:15]3[N:22]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[C:21]([CH3:31])=[C:20]([C:32](O)=[O:33])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:3][CH2:2]1.[NH2:35][C@H:36]1[CH2:41][CH2:40][C@H:39]([NH:42][C:43](=[O:49])[O:44][C:45]([CH3:48])([CH3:47])[CH3:46])[CH2:38][CH2:37]1>>[C:45]([O:44][C:43](=[O:49])[NH:42][C@H:39]1[CH2:38][CH2:37][C@H:36]([NH:35][C:32]([C:20]2[C:16]3[N:17]=[CH:18][N:19]=[C:14]([C:7]4[CH:8]=[C:9]([CH2:12][CH3:13])[CH:10]=[CH:11][C:6]=4[O:5][CH2:4][CH:1]4[CH2:3][CH2:2]4)[C:15]=3[N:22]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:28])([CH3:29])[CH3:30])[C:21]=2[CH3:31])=[O:33])[CH2:41][CH2:40]1)([CH3:48])([CH3:46])[CH3:47]
Reactant: CCc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)O)c(C)n(COCC[Si](C)(C)C)c23)c1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](N)CC1
Product: CCc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@H]4CC[C@H](NC(=O)OC(C)(C)C)CC4)c(C)n(COCC[Si](C)(C)C)c23)c1

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-5-ethylphenyl]-6-methyl-5-{[2-(trimethylsilyl)ethoxy]methyl}-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (example D.c14) and commercially available tert-butyl trans-(4-amino-cyclohexyl)-carbamate the title compound is obtained as pale yellow foam.
Reaction SMILES: [NH2:1][C:2]1[N:11]=[C:10]([NH2:12])[C:9]2[C:4](=[N:5][CH:6]=[C:7]([CH2:13]Br)[N:8]=2)[N:3]=1.[Cl:15][CH2:16][CH2:17][NH:18][CH2:19][CH2:20][Cl:21]>CN(C)C(=O)C>[NH2:1][C:2]1[N:11]=[C:10]([NH2:12])[C:9]2[C:4](=[N:5][CH:6]=[C:7]([CH2:13][N:18]([CH2:19][CH2:20][Cl:21])[CH2:17][CH2:16][Cl:15])[N:8]=2)[N:3]=1
Reactant: Nc1nc(N)c2nc(CBr)cnc2n1
Reactant: ClCCNCCCl
Solvent: CC(=O)N(C)C
Product: Nc1nc(N)c2nc(CN(CCCl)CCCl)cnc2n1
Reaction time: 5 h

Procedure:
To a stirred solution of 2.4 g (9.4 mmol) of 2,4-diamino-6-(bromomethyl)pteridine in 50 ml of N,N-dimethylacetamide was added 6 g (0.04 mol) of bis-(2-chloroethyl)amine, and the mixture was stirred at 50°-55° C. for 5 hours and then for 18 hours at room temperature. After filtering from a small amount of dark insoluble matter, the filtrate was diluted with 200 ml of water whereupon 2,4-diamino-6-bis(2-chloroethyl)-aminomethylpteridine separated as a light tan solid which was filtered, washed thoroughly with water and air dried; yield, 0.92 g (31%).
Reaction SMILES: [C:1]([OH:20])(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[NH2:21][C@H:22]([C:24]([OH:26])=[O:25])[CH3:23]>>[C:1]([NH:21][C@H:22]([C:24]([OH:26])=[O:25])[CH3:23])(=[O:20])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)O
Reactant: C[C@H](N)C(=O)O
Product: CCCCCCCC/C=C\CCCCCCCC(=O)N[C@@H](C)C(=O)O

Procedure:
Prepared as described above in steps 2-4 using oleic acid and L-alanine. (400 MHz, MeOH-d4) δ 0.92 (t, J=5.9 Hz, 3H), 1.27-1.41 (m, 23H), 1.58-1.67 (m, 2H), 2.05 (q, J=5.9 & 12.7 Hz, 4H), 2.23 (t, J=7.8 Hz, 2H), 4.24 (q, J=6.8 & 14.2 Hz, 1H), 5.36 (t, J=4.9 Hz, 2H).
Reaction SMILES: [C:1](#[N:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[O-:10].[Na+].OO>[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC.CO>[C:1]([NH2:8])(=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[O-]
Reactant: N#Cc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: OO
Agent: [Cl-]
Solvent: CO
Product: NC(=O)c1ccccc1
Yield: 96 %

Procedure:
103.1 Grams of benzonitrile (II-4), 9.51 g of sodium methoxide, 291.5 g of a 35% aqueous hydrogen peroxide solution and 2.78 g of tetra-n-butylammonium chloride were mixed in 309.3 g of methanol. After the completion of the reaction, the formed precipitate was filtered out and washed with water to obtain 116.3 g of benzamide (m.p.: 130° C.) (I-4) in a yield of 96%.
Reaction SMILES: I[C:2]1[NH:6][C:5]([CH3:7])=[N:4][C:3]=1[CH:8]=[O:9].[CH3:10][C:11]1[CH:20]=[C:19]([CH3:21])[C:18](B2OC(C)(C)C(C)(C)O2)=[CH:17][C:12]=1[C:13]([O:15][CH3:16])=[O:14].C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH:8]([C:3]1[N:4]=[C:5]([CH3:7])[NH:6][C:2]=1[C:18]1[C:19]([CH3:21])=[CH:20][C:11]([CH3:10])=[C:12]([CH:17]=1)[C:13]([O:15][CH3:16])=[O:14])=[O:9]
Reactant: COC(=O)c1cc(B2OC(C)(C)C(C)(C)O2)c(C)cc1C
Reactant: Cc1nc(C=O)c(I)[nH]1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)c1cc(-c2[nH]c(C)nc2C=O)c(C)cc1C
Temperature: 80 °C
Reaction time: 8 h
Yield: 57.8 %

Procedure:
Into a 100-mL three neck round-bottom flask, which was purged and maintained with an inert atmosphere of nitrogen, was placed a solution of 5-iodo-2-methyl-1H-imidazole-4-carbaldehyde (compound 236.1, 600 mg, 2.54 mmol) in dioxane (30 mL). Methyl 2,4-dimethyl-5-(tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (compound 160.1, 800 mg, 2.76 mmol), a solution of potassium carbonate (1.8 g, 13.0 mmol) in water (10 mL), and Pd(dppf)Cl2 (400 mg, 0.55 mmol, 0.20 equiv) were added to the reaction. The reaction mixture was stirred for overnight at 80° C., then was quenched with 20 mL of water. The aqueous phase was extracted with 2×100 mL of ethyl acetate and the combined organic layers were washed with 2×50 mL of brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography with ethyl acetate/petroleum ether (3:1) as eluent to furnish 400 mg (58%) of the title compound as a light yellow solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:12])[NH:7][CH2:8][CH2:9][C:10]#[N:11])([CH3:4])([CH3:3])[CH3:2].[N:13]([Sn](CCCC)(CCCC)CCCC)=[N+:14]=[N-:15].C(Cl)Cl.CC(O)C>C1(C)C=CC=C(C)C=1>[C:1]([O:5][C:6](=[O:12])[NH:7][CH2:8][CH2:9][C:10]1[NH:15][N:14]=[N:13][N:11]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCCC#N
Reactant: CCCC[Sn](CCCC)(CCCC)N=[N+]=[N-]
Solvent: ClCCl
Solvent: CC(C)O
Solvent: Cc1cccc(C)c1
Product: CC(C)(C)OC(=O)NCCc1nnn[nH]1
Temperature: 25 °C

Procedure:
(2-Cyano-ethyl)-carbamic acid tert-butyl ester (59.5 g, 0.35 mol) is dissolved in dry m-xylene 460 ml) and stirred at room temperature. Azidotributyltin (140 g, 0.42 mol) is added and the reaction mixture is heated to 115° C. overnight. On cooling to room temperature, the reaction mixture is quenched with 2M NaOH (500 ml), the layers are separated and the aqueous phase is acidified with 6M HCl to pH 2 resulting in a thick precipitate. DCM (500 ml) is added followed by IPA (50 ml) resulting in clear layers, the organic layer is separated and the aqueous is re-extracted with 9:1 DCM/IPA (2×250 ml). The organic layers are combined, washed with brine (500 ml), dried over MgSO4, filtered and concentrated in vacuo. The resulting solid is triturated with iso-hexanes (250 ml), stirred for 1 hour at room temperature then a further 1 hour at 5-10° C., filtered and dried under vacuum to afford the title compound.
Reaction SMILES: [CH3:1][C:2]([OH:13])([CH3:12])[CH2:3][N:4]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[N:5]1.[CH3:14][Si:15](Cl)([CH3:17])[CH3:16].N1C=CN=C1>CN(C=O)C.C(OCC)(=O)C>[CH3:12][C:2]([O:13][Si:15]([CH3:17])([CH3:16])[CH3:14])([CH3:1])[CH2:3][N:4]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[N:5]1
Reactant: C[Si](C)(C)Cl
Reactant: CC(C)(O)Cn1cc([N+](=O)[O-])cn1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(Cn1cc([N+](=O)[O-])cn1)O[Si](C)(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 75.5 %

Procedure:
To a solution of 2-methyl-1-(4-nitro-1H-pyrazol-1-yl)propan-2-ol (1 equiv) in dry DMF (0.18 M) was added trimethylsilyl chloride (1.26 equiv) at 0° C. and imidazole (2.55 equiv) under an atmosphere of nitrogen. The resulting mixture was stirred at room temperature for 4 h and then diluted with ethyl acetate. The organic solution was washed with water and brine, dried over sodium sulfate and concentrated under reduced pressure to afford the title compound as a yellow oil (75.5% yield). 1H NMR (400 MHz, CHLOROFORM-d1) δ ppm (9.06 (bs, 1H), 7.91 (s, 1H), 4.13 (s, 3H), 3.79 (s, 2H), 1.70 (s, 9H), 1.68 (s, 6H). MS (ESI) m/z 258.1 [M+H]+.
Reaction SMILES: [F:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([N+:11]([O-:13])=[O:12])=[C:4](F)[CH:3]=1.[OH-:15].[Na+]>O>[F:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([N+:11]([O-:13])=[O:12])=[C:4]([OH:15])[CH:3]=1
Reactant: [OH-]
Reactant: O=[N+]([O-])c1cc([N+](=O)[O-])c(F)cc1F
Agent: [Na+]
Solvent: O
Product: O=[N+]([O-])c1cc([N+](=O)[O-])c(F)cc1O

Procedure:
0.41 g of 1,3-difluoro-4,6-dinitrobenzene was dissolved in 8 ml of 0.5 N aqueous sodium hydroxide solution and refluxed for 2 hours. After cooling, it was diluted with water and extracted three times with diethyl ether. The aqueous phase was made acidic by adding 1N hydrochloric acid and extracted with diethyl ether. The organic phase was dried on sodium sulfate and concentrated by evaporation in a vacuum.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[CH:9][S:10][C:3]=12.[OH:11][C:12]1[CH:25]=[CH:24][C:15]2[C:16]([C:20]([O:22][CH3:23])=[O:21])=[C:17]([CH3:19])[O:18][C:14]=2[CH:13]=1.C([O-])([O-])=O.[Cs+].[Cs+]>>[CH3:19][C:17]1[O:18][C:14]2[CH:13]=[C:12]([O:11][C:2]3[CH:7]=[CH:6][N:5]=[C:4]4[CH:8]=[CH:9][S:10][C:3]=34)[CH:25]=[CH:24][C:15]=2[C:16]=1[C:20]([O:22][CH3:23])=[O:21]
Reactant: COC(=O)c1c(C)oc2cc(O)ccc12
Reactant: Clc1ccnc2ccsc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: COC(=O)c1c(C)oc2cc(Oc3ccnc4ccsc34)ccc12

Procedure:
This material was prepared by the reaction of 7-chloro-thieno[3,2-b]pyridine with methyl 6-hydroxy-2-methylbenzofuran-3-carboxylate 89c and Cs2CO3 in a manner as previously described. 1H NMR (CDCl3) δ8.48 (1H, d, J=5.3 Hz), 7.99 (1H, d, J=8.3 Hz), 7.74 (1H, d, J=5.6 Hz), 7.56 (1H, d, J=5.3 Hz), 7.29 (1H, d, J=2.0 Hz), 7.16 (1H, dd, J=8.6, 2.3 Hz), 6.53 (1H, d, J=5.3 Hz), 3.96 (3H, s), 2.79 (3H, s).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12][C:4]=2[CH:5]=[C:6]2[C:11]=1[NH:10][CH2:9][CH2:8][CH2:7]2.C=O.[C:26]([BH3-])#N.[Na+].C(O)(=O)C>C(#N)C.O>[Cl:1][C:2]1[C:3]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12][C:4]=2[CH:5]=[C:6]2[C:11]=1[N:10]([CH3:26])[CH2:9][CH2:8][CH2:7]2
Reactant: CC(C)(C)OC(=O)N1CCc2cc3c(c(Cl)c2CC1)NCCC3
Reactant: [BH3-]C#N
Agent: C=O
Agent: [Na+]
Solvent: O
Solvent: CC#N
Solvent: CC(=O)O
Product: CN1CCCc2cc3c(c(Cl)c21)CCN(C(=O)OC(C)(C)C)CC3
Temperature: 25 °C
Yield: 45 %

Procedure:
To a solution of 205 mg of t-butyl 11-chloro-1,2,3,4,6,7,9,10-octahydro-8H-azepino[4,5-g]quinoline-8-carboxylate in 3 ml of acetonitrile were added 0.077 ml of 36% formalin, 58 mg of sodium cyanoborohydride, and 0.5 ml of acetic acid, followed by stirring at room temperature. To the reaction mixture was added water, followed by extraction with EtOAc, the organic layer was dried over anhydrous sodium sulfate and then filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (elution solvent: HEX-EtOAc) to obtain 96 mg of t-butyl 11-chloro-1-methyl-1,2,3,4,6,7,9,10-octahydro-8H-azepino[4,5-g]quinoline-8-carboxylate as an orange viscous substance.
Reaction SMILES: [Br:1]Br.[C:3]([C:6]1[S:7][C:8]([Cl:11])=[CH:9][CH:10]=1)(=[O:5])[CH3:4].CCOCC.CCCCCC>C(Cl)(Cl)Cl.O>[Br:1][CH2:4][C:3]([C:6]1[S:7][C:8]([Cl:11])=[CH:9][CH:10]=1)=[O:5]
Reactant: CC(=O)c1ccc(Cl)s1
Reactant: BrBr
Solvent: CCCCCC
Solvent: CCOCC
Solvent: ClC(Cl)Cl
Product: O=C(CBr)c1ccc(Cl)s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 43.2 %

Procedure:
A solution of bromine (18.90 g, 118 mmol) in chloroform is added to a solution of 2-acetyl-5-chlorothiophene (19.00 g, 118 mmol) in chloroform at 40°-45° C. The reaction mixture is stirred at room temperature for two hours and diluted with water. The organic layer is separated, dried over MgSO4 and concentrated in vacuo to give a solid. The solid is slurried in an ether/hexane solution, filtered and dried to give the title product as a solid (12.20 g, mp 68°-70° C.).
Reaction SMILES: Cl.C(OC([NH:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18]([C@@H:20]2[CH2:22][C@H:21]2[CH3:23])=[O:19])=[CH:13][CH:12]=1)=O)(C)(C)C.C(OCC)C>O1CCOCC1>[CH3:23][C@@H:21]1[CH2:22][C@H:20]1[C:18]([NH:17][C:14]1[CH:13]=[CH:12][C:11]([CH2:10][NH2:9])=[CH:16][CH:15]=1)=[O:19]
Reactant: C[C@@H]1C[C@H]1C(=O)Nc1ccc(CNC(=O)OC(C)(C)C)cc1
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Product: C[C@@H]1C[C@H]1C(=O)Nc1ccc(CN)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81 %

Procedure:
Add 4M hydrogen chloride in dioxane (17.7 mL) to a solution of (±)-trans-N-(tert-butoxycarbonyl)-4-[(2-methyl-cyclopropanecarbonyl)-amino]-benzylamine (1.72 g, 5.65 mmol) in dioxane (35.4 mL). Stir at room temperature overnight, add diethyl ether and concentrate in vacuo several times. Partition the residue between saturated aqueous NaHCO3 (200 mL) and DCM (500 mL). Extract the aqueous phase with DCM/iso-propanol (3:1, 4×200 mL). Dry the combined organic extracts over Na2SO4, filter and concentrate in vacuo. Load the compound into a SCX column (10 g), wash the column with DCM (100 mL), and then elute with 2M ammonia in methanol/DCM (1:1, 100 mL) to afford the title compound (0.935 g, 81%) as a waxy colorless oil.