Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([S:3][C:4]1[N:8]2[C:9]([Sn](CCCC)(CCCC)CCCC)=[CH:10][CH:11]=[CH:12][C:7]2=[CH:6][N:5]=1)[CH3:2].Br[C:27]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:30]=[CH:29][CH:28]=1.C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.[F-].[Cs+]>O1CCOCC1.C(OCC)C>[CH2:1]([S:3][C:4]1[N:8]2[C:9]([C:35]3[C:36]4[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=4)[CH:32]=[CH:33][CH:34]=3)=[CH:10][CH:11]=[CH:12][C:7]2=[CH:6][N:5]=1)[CH3:2]
Reactant: Brc1cccc2ccccc12
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccc2cnc(SCC)n12
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: [Cs+]
Agent: [F-]
Solvent: C1COCCO1
Solvent: CCOCC
Product: CCSc1ncc2cccc(-c3cccc4ccccc34)n12
Temperature: 100 °C

Procedure:
To a solution of the title C compound, 3-ethylsulfanyl-5-tributylstannyl-imidazo-[1,5-a]pyridine (550 mg, 1.18 mmol) in 1,4-dioxane (8 mL), 1-bromonaphthalene (0.18 mL, 1.29 mmol) is added followed by tris(dibenzylidineacetone)dipalladium(0) (38 mg, 0.041 mmol), tri-t-butylphosphine (80 μL, 0.329 mmol) and cesium fluoride (396 mg, 2.6 mmol). The suspension is heated at 100° C. under nitrogen in a sealed tube for two days. The mixture is cooled, diluted with ethyl ether and filtered through a short silica plug. The solvent is evaporated under reduced pressure, and the residue is purified by flash column chromatography on silica using 10% ethyl acetate in hexanes to yield 3-ethylsulfanyl-5-naphthalen-1-yl-imidazo[1,5-a]pyridine as an amber oil: 1H-NMR (CDCl3) δ 8.01 (dd, J=7.5, 1.8, 1H), 7.93 (d, J=8.1, 1H), 7.61 (s, 1H), 7.58-7.47 (m, 4H), 7.41-7.32 (m, 2H), 6.78 (dd, J=9.0, 6.6, 1H), 6.51 (dd, J=6.6, 1.2, 1H), 2.66 (q, J=7.2, 2H), 0.86 (t, J=7.2, 3H), MS (M+1)+ 305.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([N+:11]([O-:13])=[O:12])[CH:3]=1.[CH2:14]1CCN2C(=NCCC2)CC1.CI.O>CN(C=O)C>[CH3:14][O:7][C:6](=[O:8])[C:5]1[CH:9]=[CH:10][C:2]([Br:1])=[CH:3][C:4]=1[N+:11]([O-:13])=[O:12]
Reactant: O=C(O)c1ccc(Br)cc1[N+](=O)[O-]
Reactant: C1CCC2=NCCCN2CC1
Solvent: CI
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc(Br)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 72 h
Yield: 98 %

Procedure:
To a solution of 4-bromo-2-nitrobenzoic acid (25.3 g, 103 mmol) in DMF (200 mL) at 0° C. were added DBU (79.1 mL, 514.8 mmol) and MeI (32.2 mL, 515 mmol). The reaction mixture was stirred for 15 min at this temperature and for 72 h at r.t. The mixture was poured into water and extracted with EtOAc (2×). The combined organic layers were washed with water (2×), dried (Na2SO4) and the solvent was removed in vacuo. The residue was purified by flash chromatography (silica gel, 7:3 hexanes:EtOAc) to provide the title compound (26.24 g, 98%) as a yellow oil.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH2:8][CH2:7][CH2:6][CH2:5]1.[H-].[Na+].Cl[C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][C:13]=1[O:21][CH3:22]>CN(C)C=O>[CH3:22][O:21][C:13]1[CH:14]=[C:15]([N+:18]([O-:20])=[O:19])[CH:16]=[CH:17][C:12]=1[O:1][CH2:2][CH2:3][N:4]1[CH2:8][CH2:7][CH2:6][CH2:5]1
Reactant: OCCN1CCCC1
Reactant: COc1cc([N+](=O)[O-])ccc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc([N+](=O)[O-])ccc1OCCN1CCCC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of the 1-(2-hydroxyethyl)-pyrrolidine [Aldrich], (1.87 ml, 16 mmol) in dimethylformamide was added portionwise sodium hydride [60% dispersion in oil, (544 mg, 16 mmol). After stirring at room temperature for 10 minutes a solution of 1-chloro-2-methoxy-4-nitro-benzene [Avocado] (3 g, 16 mmol) in dimethylformamide (10 ml) was added dropwise. The reaction mixture was left stirring at room temperature for 16 hrs then concentrated. The residue was dissolved in ethyl acetate (200 ml) and washed with water (3×50 ml). The organic phase was dried with magnesium sulphate, evaporated and the residue purified by flash chromatography on silica gel using dichloromethane-aq. ammonia-methanol as eluent to afford 1-[2-(2-methoxy-4-nitro-phenoxy)-ethyl]-pyrrolidine as a brown oil.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH2:6][N:5]2[CH:13]([CH3:15])[CH3:14].[Cl:16][C:17]1[CH:18]=[C:19](B(O)O)[CH:20]=[CH:21][CH:22]=1.C(=O)([O-])[O-].[K+].[K+]>C(COC)OC.C(O)C.O.C1C=CC([P]([Pd]([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)=CC=1>[Cl:16][C:17]1[CH:22]=[C:21]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[NH:8][C:7](=[O:12])[CH2:6][N:5]3[CH:13]([CH3:15])[CH3:14])[CH:20]=[CH:19][CH:18]=1
Reactant: CC(C)N1CC(=O)Nc2ccc(Br)cc21
Reactant: OB(O)c1cccc(Cl)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Solvent: COCCOC
Product: CC(C)N1CC(=O)Nc2ccc(-c3cccc(Cl)c3)cc21
Temperature: 25 °C

Procedure:
A mixture of 6-bromo-4-isopropyl-3,4-dihydro-1H-quinoxalin-2-one (2 g, 75 mmol), 3-chlorophenylboronic acid (1.6 g, 10 mmol), potassium carbonate (4g, 30 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.4 g, 0.35 mmol) in dimethoxyethane (100 ml), ethanol (25 ml), and water (25 ml) was heated to reflux for 6 hrs. After cooling to room temperature the mixture was diluted with water and extracted with EtOAc (3×50 mL). The combined organic layers were washed with water, then brine, dried (MgSO4) and evaporated to give crude product (1.5 g, 66%). Recrystallization from EtOAc/hexane afforded the title compound: mp 146-150° C. 1H-NMR (DMSO-d6) δ 1.16 (d, J=6.37 Hz, 6H), 3.57 (s, 2H), 4.21 (septet, J=6.59 Hz, 1H), 6.87 (d, J=7.91 Hz, 1H), 6.98 (dd, J=7.91, 1.76 Hz, 1H), 7.02 (d, J=1.76 Hz, 1H), 7.35 (m, 1H), 7.43 (t, J=7.69 Hz, 1H), 7.57 (m, 1H), 7.66 (t, J=1.76 Hz, 1H), 10.48 (s, 1H). MS (EI) m/z 300 (M)+ + 1 chlorine.
Reaction SMILES: [CH3:1][CH:2]([CH3:13])[CH:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1)[C:4]([NH2:6])=[S:5].[CH3:14][NH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[CH2:22]=O>CO>[CH3:1][CH:2]([CH3:13])[CH:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1)[C:4]([NH:6][CH2:14][N:15]([CH3:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[S:5]
Reactant: C=O
Reactant: CC(C)C(C(N)=S)c1ccccn1
Reactant: CNc1ccccc1
Solvent: CO
Product: CC(C)C(C(=S)NCN(C)c1ccccc1)c1ccccn1
Reaction time: 12 h

Procedure:
A solution of 1.94 g. (0.01 mole) of 3-methyl-2-(2-pyridyl)thiobutanamide in 40 ml. of methanol is treated with 1.6 g. (0.015 mole) of N-methylaniline and 1.22 ml. of 37 percent formalin solution. The reaction is kept at 25°C. for 12 hours, then refluxed for four hours. The solvents are evaporated in vacuo and the residue is triturated with ethyl acetate and cooled, then filtered. The filtrate is evaporated in vacuo and the resulting oil is triturated with cold ether to give 3-methyl-N-(N-methyl-N-phenylaminomethyl)-2-(2-pyridyl)thiobutanamide, which after recrystallization from ether melts at 95°-97°C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:37])[NH:5][CH:6]1[CH2:15][CH2:14][C:13]2[C:8](=[CH:9][C:10]([CH2:16][CH2:17][NH:18]C(OCC3C=CC=CC=3)=O)=[CH:11][CH:12]=2)[CH:7]1[CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([Cl:36])[CH:31]=1)[CH3:2].Br>C(O)(=O)C.C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:37])[NH:5][CH:6]1[CH2:15][CH2:14][C:13]2[C:8](=[CH:9][C:10]([CH2:16][CH2:17][NH2:18])=[CH:11][CH:12]=2)[CH:7]1[CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([Cl:36])[CH:31]=1)[CH3:2]
Reactant: CCOC(=O)NC1CCc2ccc(CCNC(=O)OCc3ccccc3)cc2C1Cc1cccc(Cl)c1
Agent: Br
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCOC(=O)NC1CCc2ccc(CCN)cc2C1Cc1cccc(Cl)c1
Yield: 105.5 %

Procedure:
To [7-(2-benzyloxycarbonylamino-ethyl)-1-(3-chloro-benzyl)-1,2,3,4-tetrahydro-naphthalen-2-yl]-carbamic acid ethyl ester (500 mg, 0.960 mmol) was added at room temperature 8 ml of 33% HBr in acetic acid. After 2 h the mixture was diluted with CH2Cl2, washed twice with NaHCO3, dried and filtered. The solvent was evaporated to obtain the product as a yellow oil (392 mg), which was used without further purification.
Reaction SMILES: [CH3:1][NH:2][C@H:3]([C:7]([NH:9][C@H:10]([C:14]([N:16]([C@@H:18]([C@@H:57]([CH3:60])[CH2:58][CH3:59])[C@H:19]([O:55][CH3:56])[CH2:20][C:21]([N:23]1[CH2:27][CH2:26][CH2:25][C@H:24]1[C@H:28]([O:53][CH3:54])[C@@H:29]([CH3:52])[C:30](=[O:51])[NH:31][C@H:32]([C:40]1[O:41][C:42]([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)=[N:43][N:44]=1)[CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:22])[CH3:17])=[O:15])[CH:11]([CH3:13])[CH3:12])=[O:8])[CH:4]([CH3:6])[CH3:5].O=[CH:62][CH2:63][CH2:64][CH2:65][CH2:66][C:67]([OH:69])=[O:68].C(O)(=O)C.FC(F)(F)C(O)=O>CO>[C:67]([CH2:66][CH2:65][CH2:64][CH2:63][CH2:62][N:2]([CH3:1])[C@H:3]([C:7]([NH:9][C@H:10]([C:14]([N:16]([C@@H:18]([C@@H:57]([CH3:60])[CH2:58][CH3:59])[C@H:19]([O:55][CH3:56])[CH2:20][C:21]([N:23]1[CH2:27][CH2:26][CH2:25][C@H:24]1[C@H:28]([O:53][CH3:54])[C@@H:29]([CH3:52])[C:30](=[O:51])[NH:31][C@H:32]([C:40]1[O:41][C:42]([C:45]2[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=2)=[N:43][N:44]=1)[CH2:33][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)=[O:22])[CH3:17])=[O:15])[CH:11]([CH3:13])[CH3:12])=[O:8])[CH:4]([CH3:5])[CH3:6])([OH:69])=[O:68]
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@@H](Cc1ccccc1)c1nnc(-c2ccccc2)o1)OC)N(C)C(=O)[C@@H](NC(=O)[C@@H](NC)C(C)C)C(C)C
Reactant: O=CCCCCC(=O)O
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Solvent: CC(=O)O
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@@H](Cc1ccccc1)c1nnc(-c2ccccc2)o1)OC)N(C)C(=O)[C@@H](NC(=O)[C@H](C(C)C)N(C)CCCCCC(=O)O)C(C)C
Temperature: 25 °C
Reaction time: 20 h

Procedure:
25 mg (30 μmol) of N-methyl-L-valyl-N-[(3R,4S,5S)-3-methoxy-1-{(2S)-2-[(1R,2R)-1-methoxy-2-methyl-3-oxo-3-{[(1S)-2-phenyl-1-(5-phenyl-1,3,4-oxadiazol-2-yl)ethyl]amino}propyl]pyrrolidin-1-yl}-5-methyl-1-oxoheptan-4-yl]-N-methyl-L-valinamide (Intermediate 55) and 23 mg (180 μmol) of 6-oxohexanoic acid were taken up in 3 ml of methanol and acidified with acetic acid. At room temperature, 15 μl (144 μmol; 9.4M) of borane-pyridine complex were subsequently added. The reaction mixture was subsequently stirred at RT for 20 h, and acetic acid and 15 μl (144 μmol; 9.4M) of borane-pyridine complex were added again after 8 h. The reaction mixture was subsequently adjusted to pH 2 with trifluoroacetic acid and purified by means of preparative HPLC. The product fractions were combined and concentrated, and the residue was lyophilized. 21 mg (74% of theory) of the title compound were thus obtained as a foam.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH:30]2[CH2:34][CH2:33][CH2:32][C:31]2([F:36])[F:35])[C:9]([NH:11][C:12]2[CH:13]=[C:14]([CH:26]=[CH:27][C:28]=2[F:29])[CH2:15][C:16]2([C:19]([O:21]C(C)(C)C)=[O:20])[CH2:18][CH2:17]2)=[O:10])=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH:30]2[CH2:34][CH2:33][CH2:32][C:31]2([F:36])[F:35])[C:9]([NH:11][C:12]2[CH:13]=[C:14]([CH:26]=[CH:27][C:28]=2[F:29])[CH2:15][C:16]2([C:19]([OH:21])=[O:20])[CH2:17][CH2:18]2)=[O:10])=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)C1(Cc2ccc(F)c(NC(=O)C(c3ccc(Cl)cc3)C3CCCC3(F)F)c2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(Nc1cc(CC2(C(=O)O)CC2)ccc1F)C(c1ccc(Cl)cc1)C1CCCC1(F)F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
750 mg (1.44 mmol) of tert-butyl 1-(3-{[(4-chlorophenyl)(2,2-difluorocyclopentyl)acetyl]amino}-4-fluorobenzyl)cyclopropanecarboxylate (as racemic diastereomer mixture) were dissolved in 1.6 ml of dichloromethane, and 5.5 ml of TFA were added at RT. The mixture was stirred at RT for 2 h and then concentrated under reduced pressure. The residue was dried under high vacuum and then triturated with acetonitrile. The precipitated solid was filtered off. The filtrate was concentrated, the residue obtained was once more triturated with acetonitrile and a further batch of solid was isolated. This procedure was repeated once more, and all solid batches were then combined. This gave a total of 553 mg (82.6% of theory) of the title compound as a mixture of four isomers.
Reaction SMILES: F[C:2]1[CH:3]=[N+:4]([O-:11])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].[CH:12]1([NH2:21])[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][CH2:13]1>C(O)C>[CH:12]1([NH:21][C:2]2[CH:3]=[N+:4]([O-:11])[CH:5]=[CH:6][C:7]=2[N+:8]([O-:10])=[O:9])[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][CH2:13]1
Reactant: O=[N+]([O-])c1cc[n+]([O-])cc1F
Reactant: NC1CCc2ccccc21
Solvent: CCO
Product: O=[N+]([O-])c1cc[n+]([O-])cc1NC1CCc2ccccc21
Yield: 95.7 %

Procedure:
A solution of 3-fluoro-4-nitropyridine-1-oxide (5.6 g) and indan-1-amine (6 g) in 100 ml ethanol was stirred at reflux for one hour and thereafter cooled and concentrated to 12 g of solid. This solid was purified by flash chromatography (silica, 10% ethyl acetate in dichloromethane) to give 9.2 g solid, m.p. 137°-138°. An analytical sample was obtained by recrystallizing 2.7 g from ethanol to give 2.5 g crystals, m.p. 141°-142°.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([Cl:13])[C:8]=2[Cl:14])=[N:4][NH:5][CH:6]=1.[CH3:15]P(=O)(OC)OC.C([O-])(O)=O.[Na+]>>[CH3:15][N:5]1[CH:6]=[C:2]([Cl:1])[C:3]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([Cl:13])[C:8]=2[Cl:14])=[N:4]1
Reactant: Clc1c[nH]nc1-c1cccc(Cl)c1Cl
Reactant: COP(C)(=O)OC
Agent: O=C([O-])O
Agent: [Na+]
Product: Cn1cc(Cl)c(-c2cccc(Cl)c2Cl)n1

Procedure:
1.5 g of 4-chloro-3-(2,3-dichlorophenyl) pyrazole and 0.40 g of dimethyl methylphosphonate are heated at 150° C. for 1 hour. After returning to room temperature, the mixture is taken up in a saturated aqueous NaHCO3 solution and extracted with 2×50 ml of CH2Cl2. The combined organic phases are dried over Na2SO4 and concentrated under reduced pressure. The crude solid is purified by liquid chromatography on a silica column (eluent: heptane/ethyl acetate [80/20]).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([C:16]2[CH:21]=[CH:20][C:19](Br)=[CH:18][CH:17]=2)[C:9]2[CH:14]=[CH:13][C:12]([Br:15])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.C([Li])CCC.CCCCCC.CN(C)[CH:36]=[O:37]>O1CCCC1.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]([C:9]2[CH:14]=[CH:13][C:12]([Br:15])=[CH:11][CH:10]=2)[C:16]2[CH:21]=[CH:20][C:19]([CH:36]=[O:37])=[CH:18][CH:17]=2)=[CH:6][CH:7]=1
Reactant: CN(C)C=O
Reactant: Brc1ccc(N(c2ccc(Br)cc2)c2ccc(Br)cc2)cc1
Agent: [Li]CCCC
Solvent: O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=Cc1ccc(N(c2ccc(Br)cc2)c2ccc(Br)cc2)cc1
Reaction time: 0.17 h
Yield: 43.7 %

Procedure:
In an argon atmosphere, tris(4-bromophenyl)amine (964 mg, 2.00 mmol) was dissolved in tetrahydrofuran (10 mL) and cooled to −78° C. n-Butyl lithium (a 1.6 mol/L hexane solution, 1.5 mL, 2.4 mmol) and dimethylformamide (0.19 mL, 2.4 mmol) was dripped thereto at a system temperature of −60° C. or less, followed by stirring for 10 minutes. To the reaction liquid was added water and the product was extracted with ethyl acetate. The organic layer was washed with water and brine, and then dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: hexane/ethyl acetate=8/1) to give 4-[bis(4-bromophenyl)amino]benzaldehyde (377 mg, 44%).
Reaction SMILES: [C:1](NC(N)=N)#[N:2].[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]=[C:15]=[N:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[F:23])=[C:10]([O:24][Si](C(C)(C)C)(C)C)[C:9]=1[S:32]([N:35]([CH3:37])[CH3:36])(=[O:34])=[O:33].[N:38]#CN.C(N(CC)C(C)C)(C)C.[F-].[Cs+]>>[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]([C:1]#[N:2])[C:15]([NH:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[F:23])=[NH:38])=[C:10]([OH:24])[C:9]=1[S:32]([N:35]([CH3:36])[CH3:37])(=[O:34])=[O:33]
Reactant: N#CN
Reactant: N#CNC(=N)N
Reactant: CN(C)S(=O)(=O)c1c(Cl)ccc(N=C=Nc2ccccc2F)c1O[Si](C)(C)C(C)(C)C
Agent: [Cs+]
Agent: [F-]
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)S(=O)(=O)c1c(Cl)ccc(N(C#N)C(=N)Nc2ccccc2F)c1O
Yield: 40 %

Procedure:
Following the general procedure for cyanoguanidine formation outlined in example 12, N-[4-chloro-2-tert-butyldimethylsilyloxy-3-(N″,N″-dimethylaminosulfonyl)phenyl]-N′-(2-fluorophenyl)carbodiimide (350 mg, 0.72 mmol), cyanamide (121 mg, 2.88 mmol) and N,N-diisopropylethylamine (111 mg, 0.86 mmol) were reacted, followed by desilylation with Cesium fluoride (132 mg, 0.86 mmol) to form the desired product (120 mg, 40%). EI-MS m/z 412.2 (M+). 1H NMR (DMSO-d6) δ 2.86 (s, 6H), 7.20 (m, 2H), 7.27 (m, 2H), 7.40 (t, 1H), 7.52 (d, 1H), 9.06 (s, 1H), 9.20 (s, 1H), 10.51 (s, 1H).
Reaction SMILES: [CH:1]1([N:6]2[CH2:14][C:11]3([CH2:13][CH2:12]3)[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([OH:28])=O)=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.ON1C2C=CC=CC=2N=N1.F[P-](F)(F)(F)(F)F.CN(C(N(C)C)=[N+]1C2C=CC=CC=2[N+]([O-])=N1)C.C(N(C(C)C)C(C)C)C.[NH2:76][CH:77]1[CH2:82][CH2:81][N:80]([CH3:83])[CH2:79][CH2:78]1>CN(C)C=O>[CH:1]1([N:6]2[CH2:14][C:11]3([CH2:12][CH2:13]3)[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([NH:76][CH:77]5[CH2:82][CH2:81][N:80]([CH3:83])[CH2:79][CH2:78]5)=[O:28])=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC1(CC1)C(=O)N2C
Reactant: CN1CCC(N)CC1
Agent: CN(C)C(N(C)C)=[N+]1N=[N+]([O-])c2ccccc21
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C(=O)NC2CCN(C)CC2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC1(CC1)C(=O)N2C
Reaction time: 0.33 h
Yield: 55.2 %

Procedure:
To a suspension of 0.2463 g (0.000563 mole) of 4-[(9-cyclopentyl-6,7,8,9-tetrahydro-5-methyl-6-oxospiro[5H-pyrimido[4,5-b][1,4]diazepine-7,1′-cyclopropan]-2-yl)amino]-3-methoxybenzoic acid (I-53) in 15 mL of dimethylformamide was added 0.1222 g (0.00091 mole) of 1-hydroxybenzotriazole, 0.3307 g (0.00087 mole) of 1-[bis(dimethylamino)methylene]-1H-benzotriazolium 3-oxide hexafluorophosphate and 0.59 mL (0.00339 mole) of ethyldiisopropylamine. The mixture was stirred for 20 minutes and then 0.0980 g (0.00086 mole) of 4-amino-1-methylpiperidine was added. The mixture was stirred for an additional 2.5 hours and then concentrated under reduced pressure. The residue was dissolved in ethyl acetate and washed successively with 1 M sodium hydroxide, brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with dichloromethane-methanol (98:2-80:20) to give 0.166 g of 4-[(9-cyclopentyl-6,7,8,9-tetrahydro-5-methyl-6-oxospiro[5H-pyrimido[4,5-b][1,4]diazepine-7,1′-cyclopropan]-2-yl)amino]-3-methoxy-N-(1-methyl-4-piperidinyl)benzamide (I-54).
Reaction SMILES: [H-].[Na+].[N+:3]([C:6]1[CH:11]=[CH:10][C:9]([C:12]23[CH2:18][CH:16]([CH2:17]2)[C:15](=[O:19])[NH:14][C:13]3=[O:20])=[CH:8][CH:7]=1)([O-:5])=[O:4].[CH2:21](Br)[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27].C(OCC)(=O)C.CCCCCC>CN(C)C=O>[CH2:21]([N:14]1[C:15](=[O:19])[CH:16]2[CH2:17][C:12]([C:9]3[CH:8]=[CH:7][C:6]([N+:3]([O-:5])=[O:4])=[CH:11][CH:10]=3)([CH2:18]2)[C:13]1=[O:20])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: O=C1NC(=O)C2(c3ccc([N+](=O)[O-])cc3)CC1C2
Reactant: CCCCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCCCCCCN1C(=O)C2CC(c3ccc([N+](=O)[O-])cc3)(C2)C1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
0.36 g of sodium hydride is added to a solution of 2.46 of 1-(4-nitrophenyl)-3-azabicyclo[3.1.1]heptane-2,4-dione in 25 ml of N,N-dimethylformamide and the whole is stirred at room temperature for 30 minutes. 2.68 g of n-heptyl bromide dissolved in 10 ml of N,N-dimethylformamide are then added dropwise thereto. When the reaction is complete, the reaction mixture is freed of N,N-dimethylformamide. The residue is partitioned between ethyl acetate and water, and the organic phase is dried over magnesium sulphate. After concentration by evaporation and purification by chromotography over silica gel in the system ethyl acetate/hexane 2:5, the product is obtained in the form of a solid. Melting point 92°-92°. Rf (ethyl acetate/hexane 4:1)=0.63.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:23]=[C:24]([O:28][CH3:29])[C:25]=1[O:26][CH3:27])[C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH:10]([CH2:14][O:15][C:16]([N:18]([CH2:21][CH3:22])[CH2:19][CH3:20])=[O:17])[CH2:9]1)=O.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:39])=CC=1>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:23]=[C:24]([O:28][CH3:29])[C:25]=1[O:26][CH3:27])[C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH:10]([CH2:14][O:15][C:16]([N:18]([CH2:21][CH3:22])[CH2:19][CH3:20])=[O:17])[CH2:9]1)=[S:39]
Reactant: CCN(CC)C(=O)OCC1CN(C(=O)c2cc(OC)c(OC)c(OC)c2)CCN1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: C1CCOC1
Product: CCN(CC)C(=O)OCC1CN(C(=S)c2cc(OC)c(OC)c(OC)c2)CCN1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 70.6 %

Procedure:
1.7 g (3.66 mmol) of 4-(3′,4′,5′-trimethoxybenzoyl)-2-(N,N-diethylaminocarbonyloxymethyl)piperazine, prepared according to the protocol described in step 8.1 of Example 8, are dissolved in 34 ml of THF and cooled in an ice bath. 1.7 g (1 equivalent) of Lawesson's reagent are added portionwise thereto. The solution is stirred at 0° C. for 30 minutes and then at room temperature overnight. The solvent is then removed under vacuum and the residue is rapidly purified on a column of silica gel (eluents: CH2Cl2 and then 1% MeOH in CH2Cl2) to give 1.1 g of 4-(3′,4′,5′-trimethoxythiobenzoyl)-2-(N,N-diethylaminocarbonyloxymethyl)piperazine in the form of a viscous yellow product. Yield: 62.4%.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:39][C:40]1[CH:45]=[CH:44][C:43]([OH:46])=[CH:42][CH:41]=1)[CH2:10][N:11]([CH2:14][CH:15]([NH:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH2:24]C2C=CC=CC=2)=[CH:19][CH:18]=1)[CH2:12][CH3:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].[N+](=[CH2:49])=[N-]>C(OCC)C>[C:35]([O:34][C:32]([NH:31][C@@H:15]([CH2:16][C:17]1[CH:18]=[CH:19][C:20]([O:23][CH3:24])=[CH:21][CH:22]=1)[CH2:14][N:11]([CH2:10][CH:9]([NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:7])[CH2:39][C:40]1[CH:45]=[CH:44][C:43]([O:46][CH3:49])=[CH:42][CH:41]=1)[CH2:12][CH3:13])=[O:33])([CH3:37])([CH3:36])[CH3:38]
Reactant: C=[N+]=[N-]
Reactant: CCN(CC(Cc1ccc(OCc2ccccc2)cc1)NC(=O)OC(C)(C)C)C[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C
Solvent: CCOCC
Product: CCN(CC(Cc1ccc(OC)cc1)NC(=O)OC(C)(C)C)C[C@H](Cc1ccc(OC)cc1)NC(=O)OC(C)(C)C
Reaction time: 48 h
Yield: 77 %

Procedure:
The product from Example 19A (21 mg, 38 μmol) was treated with diazomethane in diethyl ether (˜0.4 M, 1 mL) at ambient temperature. After stirring for 2 days, the solvent was removed under reduced pressure. The residue was dissolved in fresh diazomethane solution and stirred at ambient temperature for an additional 2 days. This process was repeated until TLC (CHCl3:methanol, 19:1) indicated the reaction was complete. The residue was purified by column chromatography on silica gel (CH2Cl2:methanol, 99:1) to provide the title compound as a colorless amorphous solid (17 mg, 77%). 1H NMR (CDCl3) δ 7.09 (d, J=8.9 Hz, 4H), 6.82 (d, J=8.5 Hz, 4H), 4.70 (br s, 1.3H), 4.53 (br s, 0.7H), 3.83-3.78 (m, 2H), 3.78 (s, 6H), 2.85-2.68 (m, 4H), 2.60-2.27 (m, 6H), 1.41 (s, 12H), 1.38 (s, 6H), 0.94-0.84 (m, 3H); MS (APCl+) m/z 572 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([NH2:9])=[CH:5][CH:6]=[CH:7][CH:8]=1.[CH2:10]([O:12][C:13](=[O:18])[CH2:14][C:15]([CH3:17])=O)[CH3:11].[H][H]>[Pt].C1(C)C=CC(S(O)(=O)=O)=CC=1.C(O)(C)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][CH:15]([CH3:17])[CH2:14][C:13]([O:12][CH2:10][CH3:11])=[O:18]
Reactant: CCOC(=O)CC(C)=O
Reactant: [H][H]
Reactant: COc1ccccc1N
Agent: [Pt]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)O
Product: CCOC(=O)CC(C)Nc1ccccc1OC
Yield: 62.8 %

Procedure:
A mixture of 123.0 g (1 mole) of o-anisidine, 260.0 g (2 moles) of ethylacetoacetate, 400 ml of isopropyl alcohol, 10.0 g of 1% Pt/C, 2.5 g of p-toluenesulfonic acid is treated in an autoclave at 165° C., with 1000 psi of hydrogen until the uptake of hydrogen ceases. The catalyst is removed by filtration. The solution is distilled under vacuum to yield 149.0 g of ethyl 3(2'-methoxyphenylamino)butyrate.