Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[CH2:4][N:5]1[CH2:11][CH:10]=[CH:9][CH2:8][CH:7]([NH:12]C(OC(C)(C)C)=O)[C:6]1=[O:20].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:21])[CH2:4][N:5]1[CH2:11][CH:10]=[CH:9][CH2:8][CH:7]([NH2:12])[C:6]1=[O:20]
Reactant: COC(=O)CN1CC=CCC(NC(=O)OC(C)(C)C)C1=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)CN1CC=CCC(N)C1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution containing (3-tert-butoxycarbonylamino-2-oxo-2,3,4,7-tetrahydroazepin-1-yl) acetic acid methyl ester, 2, (0.57 g, 2.0 mmol) in 10 mL of CH2Cl2 is treated with 2.5 mL of wet TFA and stirred at room temperature for 30 minutes. The solution is concentrated in vacuo and treated with saturated NaHCO3. Solid NaCl is added to the resulting aqueous solution and the solution is extracted with EtOAc. The organic layer was dried (MgSO4) and concentrated in vacuo to afford the desired intermediate which can be used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:12][C:11]2[C:10]([C:13]3[N:14](C(OC(C)(C)C)=O)[C:15]4[C:20]([CH:21]=3)=[CH:19][C:18]([C:22](=[O:24])[CH3:23])=[CH:17][CH:16]=4)=[N:9][N:8](C(OC(C)(C)C)=O)[C:7]=2[CH:6]=1)=[O:4].Cl.C([O-])([O-])=O.[Na+].[Na+]>O1CCCC1>[CH3:1][O:2][C:3]([C:5]1[S:12][C:11]2[C:10]([C:13]3[NH:14][C:15]4[C:20]([CH:21]=3)=[CH:19][C:18]([C:22](=[O:24])[CH3:23])=[CH:17][CH:16]=4)=[N:9][NH:8][C:7]=2[CH:6]=1)=[O:4]
Reactant: COC(=O)c1cc2c(s1)c(-c1cc3cc(C(C)=O)ccc3n1C(=O)OC(C)(C)C)nn2C(=O)OC(C)(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)c1cc2[nH]nc(-c3cc4cc(C(C)=O)ccc4[nH]3)c2s1
Temperature: 70 °C
Yield: 20.8 %

Procedure:
A solution of 3-(5-acetyl-1-tert-butoxycarbonyl-1H-indol-2-yl)-thieno[3,2-c]pyrazole-1,5-dicarboxylic acid 1-tert-butyl ester 5-methyl ester (115 mg, 0.213 mmol, Example 35) in tetrahydrofuran (5 mL) is treated with 2N hydrochloric acid (aqueous, 3 mL) and heated at 70° C. for 17 hours. The reaction is cooled to room temperature and neutralized with Na2CO3 (aqueous). The aqueous phase is extracted three times with ether (10 mL). Combined ether phases are washed with brine and dried over sodium sulfate. Purification by chromatography on 10 g silica gel cartridge (50-70% ethyl acetate gradient in heptane) afforded 3-(5-acetyl-1H-indol-2-yl)-1H-thieno[3,2-c]pyrazole-5-carboxylic acid methyl ester (15 mg, Example 36) as white solid; 1H NMR [(CD3)2SO)]: δ 13.82 (1H, s), 12.13 (1H, s), 8.34 (1H, s), 7.97 (1H, s), 7.78 (1H, d), 7.50 (1H, d), 6.90 (1H, s), 3.91 (3H, s), 2.61 (3H, s); LC/MS: 340 (M+H).
Reaction SMILES: [CH2:1]([O:3][CH:4]([N:6]1[CH:10]=[C:9](I)[CH:8]=[N:7]1)[CH3:5])[CH3:2].[CH:12]([C:14]1[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=1)=[CH2:13].[Br-].C([O-])(=O)C.C(=O)([O-])[O-].[K+].[K+]>>[CH2:1]([O:3][CH:4]([N:6]1[CH:10]=[C:9](/[CH:13]=[CH:12]/[C:14]2[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=2)[CH:8]=[N:7]1)[CH3:5])[CH3:2]
Reactant: CCOC(C)n1cc(I)cn1
Reactant: C=Cc1ccc(C#N)cc1
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Br-]
Product: CCOC(C)n1cc(/C=C/c2ccc(C#N)cc2)cn1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 67.6 %

Procedure:
1-(1-Ethoxyethyl)-4-iodo-1H-pyrazole obtained in Step 1 (162.0 mg) was suspended in N,N-methylformamide (5.0 mL), and added thereto were 4-vinylbenzonitrile (157.3 mg), tetrabutylamonuim bromide (19.6 mg), paladium acetate (41.0 mg) and potassium carbonate (210.4 mg). The mixture was stirred at room temperature for 10 minutes, and subjected to microwave irradiation at 140° C. for 20 minutes. After completion of the reaction, the resulting mixture was filtered through silica gel, and extracted with ethyl acetate (15 mL). The extract was washed successively with saturated ammonium chloride (15 mL) and brine (15 mL). The organic layer was dried over anhydrous magnesium sulfate and concentrated by evaporation under a reduced pressure. The resulting residue was purified by silica gel chromatography to obtain the title compound (0.11 g, yield 61%).
Reaction SMILES: ClCCl.Cl[C:5]1[C:6]2[CH:13]=[CH:12][NH:11][C:7]=2[N:8]=[CH:9][N:10]=1.[CH3:14][Mg]Br>C1(C)C=CC=CC=1.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]>[CH3:14][C:5]1[C:6]2[CH:13]=[CH:12][NH:11][C:7]=2[N:8]=[CH:9][N:10]=1
Reactant: Clc1ncnc2[nH]ccc12
Reactant: C[Mg]Br
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: Cc1ncnc2[nH]ccc12
Temperature: 60 °C
Reaction time: 0.17 h
Yield: 15.9 %

Procedure:
Into a round bottom flask the catalyst [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), 1:1 complex with dichloromethane (70.0 mg, 0.09 mmol), is placed under nitrogen with 15 mL of toluene along with a stir bar. A suspension of 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (1, 1.47 g, 9.57 mmol) in 15 mL of toluene is added at room temperature. After stirring for 10 minutes, methylmagnesium bromide (17.00 mL, 3.00 M in ether, 51.00 mmol) is added dropwise. The solution is slowly heated to 60° C. and stirred for 3 hrs at 60° C., then overnight at room temperature. The resulting dark orange reaction mixture is quenched with 1 N hydrochloric acid and adjusted to pH ˜5, then extracted with ethyl acetate and water saturated with sodium chloride. The organic layer is washed with water and brine, dried over magnesium sulfate, filtered and the filtrate concentrated under vacuum. The resulting material is purified by silica gel column chromatography eluting with ethyl acetate and hexane. Appropriate fractions are combined and concentrated under vacuum to provide the desired compound as a yellow solid (8, 202 mg). 1H-NMR (dmso-d6) is consistent with the desired compound. MS (ESI) [M+H+]+=134.3.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16](F)=[C:17]([N+:20]([O-:22])=[O:21])[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:6]=[CH:7][CH:8]=1)#[CH:2].[CH2:24]([OH:26])[CH3:25]>>[CH2:24]([O:26][C:16]1[CH:15]=[C:14]2[C:19]([C:10]([NH:9][C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([C:1]#[CH:2])[CH:4]=3)=[N:11][CH:12]=[N:13]2)=[CH:18][C:17]=1[N+:20]([O-:22])=[O:21])[CH3:25]
Reactant: CCO
Reactant: C#Cc1cccc(Nc2ncnc3cc(F)c([N+](=O)[O-])cc23)c1
Product: C#Cc1cccc(Nc2ncnc3cc(OCC)c([N+](=O)[O-])cc23)c1
Temperature: 80 °C
Reaction time: 4 h
Yield: 93.4 %

Procedure:
Na (1.4 g, 0.060 mol) was carefully dissolved in 80 ml of anhydrous ethanol to form a clear solution, then N-(3-ethynylphenyl)-7-fluoro-6-nitroquinazolin-4-amine (8 g, 0.025 mol) was added and stirred for 4 hours at 80° C. The solution was concentrated under reduced pressure to remove excess ethanol, and 50 ml H2O was added. The resulting solid precipitate was filtered and dried under vacuum to get 7-ethoxy-N-(3-ethynylphenyl)-6-nitroquinazolin-4-amine as yellow solid 8.1 g (93.4% yield).
Reaction SMILES: [C-:1]#[N:2].[Na+].COS([O-])(=O)=O.CO[N+:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[C:14]([CH3:19])[CH:13]=1>O>[C:1]([C:13]1[C:14]([CH3:19])=[CH:15][C:16]([CH3:18])=[CH:17][N:12]=1)#[N:2]
Reactant: CO[n+]1cc(C)cc(C)c1
Reactant: [C-]#N
Agent: COS(=O)(=O)[O-]
Agent: [Na+]
Solvent: O
Product: Cc1cnc(C#N)c(C)c1
Yield: 91.7 %

Procedure:
Cool a solution of sodium cyanide (49.0 g, 0.999 mol, 3.0 eq.) in 135 mL of water to 0° C., (air free) and drip 1-methoxy-3,5-dimethyl pyridinium methyl sulfate (83.0 g, 0.33 mol) in 100 mL water (air free) over 11/4 hr., keeping the temperature below 3° C. Filter the mixture and wash with water to give 40 g of the title compound which may be recrystallized from isopropyl ether and pentane (4:1) (m.p. 61°-62° C.).
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH:5]=[CH:6]1)[CH2:3][CH:2]2[NH:8][C:9]([NH:11][NH2:12])=[S:10].[N+:13]([C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=1)[CH:19]=O)([O-:15])=[O:14]>>[CH:1]12[CH2:7][CH:4]([CH:5]=[CH:6]1)[CH2:3][CH:2]2[NH:8][C:9](=[S:10])[NH:11][N:12]=[CH:19][C:18]1[CH:21]=[CH:22][CH:23]=[C:16]([N+:13]([O-:15])=[O:14])[CH:17]=1
Reactant: NNC(=S)NC1CC2C=CC1C2
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Product: O=[N+]([O-])c1cccc(C=NNC(=S)NC2CC3C=CC2C3)c1

Procedure:
The title compound was prepared from a mixture of N1-bicyclo[2.2.1]hept-5-en-2-ylhydrazine-1-carbothioamide (100 mg, 0.56 mmol) and 3-nitrobenzaldehyde (85 mg, 0.56 mmol) similar to Example 3 and isolated as a yellow solid (68 mg, 38%). 1H NMR (CDCl3): 9.82 (s, 1H), 8.48 (t, J=1.8 Hz, 1H), 8.28-8.25 (m, 1H), 7.96 (s, 1H), 7.93 (s, 1H), 7.56 (t, J=8.1 Hz, 1H), 7.47 (d, J=7.2 Hz, 1H), 6.26-6.16 (m, 2H), 4.32-4.25 (m, 1H), 3.09 (s, 1H), 3.00 (s, 1H), 1.97-1.90 (m, 1H), 1.70 (d, J=9.0 Hz, 1H), 1.53 (d, J=9.3 Hz, 1H), 1.49-1.43 (m, 1H).
Reaction SMILES: [CH2:1]([C:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[O:5][C:4]=1[CH:12]=[O:13])[CH3:2].O1CCCC1.[CH2:19]([Mg]Br)[CH:20]([CH3:22])[CH3:21].[Cl-].[NH4+]>O1CCCC1>[CH2:1]([C:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[O:5][C:4]=1[CH:12]([OH:13])[CH2:19][CH:20]([CH3:22])[CH3:21])[CH3:2]
Reactant: CCc1c(C=O)oc2ccccc12
Reactant: CC(C)C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCc1c(C(O)CC(C)C)oc2ccccc12
Reaction time: 1 h
Yield: 51 %

Procedure:
To a solution (50 mL) of 3-ethyl-1-benzofuran-2-carbaldehyde (2.27 g) synthesized above in tetrahydrofuran was added dropwise 1.0M isobutylmagnesium bromide tetrahydrofuran solution (19.5 mL) at 0° C., and the mixture was stirred for 1 hr. Saturated aqueous ammonium chloride solution was added to quench the reaction, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=3:17, volume ratio) to give the title object compound (1.55 g, 51%) as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[C:16]([C:17]([C:19]4[C:20]([F:33])=[C:21]([NH:26][S:27]([CH2:30][CH2:31][CH3:32])(=[O:29])=[O:28])[CH:22]=[CH:23][C:24]=4[F:25])=[O:18])=[CH:15][NH:14][C:11]3=[N:12][CH:13]=2)=[CH:4][CH:3]=1.[OH-].[K+].[C:36](=[O:44])([O:40][CH:41]([CH3:43])[CH3:42])[O:37][CH2:38]Cl>CN(C=O)C.CCOC(C)=O>[C:36](=[O:44])([O:40][CH:41]([CH3:43])[CH3:42])[O:37][CH2:38][N:14]1[C:11]2=[N:12][CH:13]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)[CH:9]=[C:10]2[C:16]([C:17](=[O:18])[C:19]2[C:24]([F:25])=[CH:23][CH:22]=[C:21]([NH:26][S:27]([CH2:30][CH2:31][CH3:32])(=[O:28])=[O:29])[C:20]=2[F:33])=[CH:15]1
Reactant: CC(C)OC(=O)OCCl
Reactant: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)c2c[nH]c3ncc(-c4ccc(Cl)cc4)cc23)c1F
Agent: [K+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)c2cn(COC(=O)OC(C)C)c3ncc(-c4ccc(Cl)cc4)cc23)c1F
Temperature: 10 °C
Reaction time: 3 h
Yield: 42.3 %

Procedure:
To a mixture of N-(3-(5-(4-chlorophenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluorophenyl)propane-1-sulfonamide (0.2 g, 0.41 mmol) and KOH (46 mg, 0.82 mmol) in DMF (1.5 mL) was added a solution of chloromethyl isopropyl carbonate (62 mg, 0.41 mmol) in DMF (0.5 mL) over 30 min. The reaction mixture was stirred at 10° C. for 3 h, then diluted with EtOAc (40 mL) and filtered. The filtrate was concentrated in vacuo and the residue was purified by a silica gel column chromatography (PE/EtOAc (v/v)=2/1) to afford the title compound as a white solid (105 mg, 43%). The title compound was characterized by LC-MS and 1H NMR as shown below:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C@@H:13]2[CH2:15][C@H:14]2[NH2:16])=[CH:9][CH:8]=1.[CH:20]1([CH2:26][CH:27]=O)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1.[BH4-].[Na+]>ClCCCl>[Br:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]([C@@H:13]2[CH2:15][C@H:14]2[NH:16][CH2:27][CH2:26][CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)=[CH:11][CH:12]=1
Reactant: O=CCC1CCCCC1
Reactant: N[C@@H]1C[C@H]1c1ccc(OCc2cccc(Br)c2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCCl
Product: Brc1cccc(COc2ccc([C@@H]3C[C@H]3NCCC3CCCCC3)cc2)c1
Temperature: 0 °C
Reaction time: 20 h
Yield: 18.8 %

Procedure:
To a solution of (Trans)-2-(4-(3-bromobenzyloxy)phenyl)cyclopropanamine (2 g, 6.2 mmol) and 2-cyclohexylacetaldehyde (790 mg, 6.2 mmol) in DCE (20 mL) sodium triacetoxy borohydrate (2.3 g, 2 equiv) was added slowly at 0° C. and stirred for 20 h. After completion, the reaction mixture was evaporated. The residue was dissolved in Methanol (15 mL) and NaBH4 (627 mg, 3 equiv) was added slowly at 0° C. to the reaction mixture and stirred for 3 h. After completion, the reaction mixture was poured into ice water (50 mL) and extracted with EtOAc (2×50 mL). The combined organic layers were washed with brine (50 mL) and dried over anhydrous Na2SO4, filtered and evaporated. The crude residue was purified by flash column chromatography by using EtOAc: Pet ether to get (Trans)-2-(4-(3-bromobenzyloxy) phenyl)-N-(2-cyclohexylethyl)cyclopropane amine (500 mg, 21%) as a pale yellow liquid.
Reaction SMILES: C(O)=O.[NH2:4][CH2:5][CH2:6][C:7]1[CH:33]=[CH:32][C:10]([NH:11][CH:12]2[CH2:17][CH2:16][N:15]([C:18]([NH:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[C:23]=3[O:30][CH3:31])=[O:19])[CH2:14][CH2:13]2)=[CH:9][CH:8]=1.[C:34]([Si:38]([O:51][C:52]1[CH:57]=[CH:56][C:55]([O:58][CH2:59][CH:60]2[CH2:62][O:61]2)=[CH:54][CH:53]=1)([C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)([CH3:37])([CH3:36])[CH3:35]>C(Cl)(Cl)Cl.CO>[Si:38]([O:51][C:52]1[CH:57]=[CH:56][C:55]([O:58][CH2:59][C@@H:60]([OH:61])[CH2:62][NH:4][CH2:5][CH2:6][C:7]2[CH:8]=[CH:9][C:10]([NH:11][CH:12]3[CH2:17][CH2:16][N:15]([C:18]([NH:20][CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[C:23]=4[O:30][CH3:31])=[O:19])[CH2:14][CH2:13]3)=[CH:32][CH:33]=2)=[CH:54][CH:53]=1)([C:34]([CH3:35])([CH3:37])[CH3:36])([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[C:45]1[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=1
Reactant: COc1cccc(CNC(=O)N2CCC(Nc3ccc(CCN)cc3)CC2)c1OC
Reactant: CC(C)(C)[Si](Oc1ccc(OCC2CO2)cc1)(c1ccccc1)c1ccccc1
Solvent: O=CO
Solvent: ClC(Cl)Cl
Solvent: CO
Product: COc1cccc(CNC(=O)N2CCC(Nc3ccc(CCNC[C@H](O)COc4ccc(O[Si](c5ccccc5)(c5ccccc5)C(C)(C)C)cc4)cc3)CC2)c1OC
Yield: 34 %

Procedure:
4-[4-(2-Aminoethyl)anilino]-N-(2,3-dimethoxybenzyl)-1-piperidine-carboxamide formate (0.30 g, 0.64 mmol) was reacted with tert-butyl-(4-oxiranylmethoxy-phenoxy)-diphenyl-silane (0.238 g, 0.588 mmol) according to Procedure G (eluant: 20:1 chloroform-methanol) to give the title compound (0.163 g, 0.20 mmol).
Reaction SMILES: C([P:3]([CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[C:10]([O:17][CH3:18])[CH:9]=1)(=[O:5])[O-:4])C>Cl>[CH3:18][O:17][C:10]1[CH:9]=[C:8]([CH:13]=[CH:12][C:11]=1[N+:14]([O-:16])=[O:15])[CH2:7][CH2:6][PH:3](=[O:4])[OH:5]
Reactant: CCP(=O)([O-])CCc1ccc([N+](=O)[O-])c(OC)c1
Agent: Cl
Product: COc1cc(CC[PH](=O)O)ccc1[N+](=O)[O-]
Yield: 102 %

Procedure:
A solution of ethyl(3-methoxy-4-nitrobenzyl)methylphosphinate (Compound 216D, 0.500 g, 1.83 mmol) in 37% HCl (5.00 mL) was stirred at 100° C. for 6 hours. The reaction mixture was concentrated under reduced pressure to yield the desired product as a yellow foam, 457.2 mg (102% yield). This material was used in successive reactions without any further purification. 1H NMR (CDCl3, 400 MHz): δ=1.41 (d, J=13.89 Hz, 3H), 3.13 (d, J=16.42 Hz, 2H), 3.97 (s, 3H), 6.89 (d, J=8.08 Hz, 1H), 7.02 (s, 1H), 7.82 (d, J=8.34 Hz, 1H). MS (ES+): m/z 246.05 [MH+] (TOF, polar).
Reaction SMILES: [OH:1][CH:2]([C:30]1[CH:35]=[CH:34][C:33]([OH:36])=[CH:32][CH:31]=1)[CH2:3][NH:4][C:5]([NH:25][S:26]([CH3:29])(=[O:28])=[O:27])=[N:6][CH2:7][CH2:8][S:9][CH2:10][C:11]1[O:12][C:13]([CH2:16][N:17](C)[C:18](=O)C(Cl)(Cl)Cl)=[CH:14][CH:15]=1.Cl>C(O)C.[OH-].[Na+]>[OH:1][CH:2]([C:30]1[CH:31]=[CH:32][C:33]([OH:36])=[CH:34][CH:35]=1)[CH2:3][NH:4][C:5]([NH:25][S:26]([CH3:29])(=[O:28])=[O:27])=[N:6][CH2:7][CH2:8][S:9][CH2:10][C:11]1[O:12][C:13]([CH2:16][NH:17][CH3:18])=[CH:14][CH:15]=1
Reactant: CN(Cc1ccc(CSCCN=C(NCC(O)c2ccc(O)cc2)NS(C)(=O)=O)o1)C(=O)C(Cl)(Cl)Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CNCc1ccc(CSCCN=C(NCC(O)c2ccc(O)cc2)NS(C)(=O)=O)o1
Temperature: 25 °C
Reaction time: 2 h
Yield: 84.2 %

Procedure:
9.4 g of N-[2-hydroxy-2-(4-hydroxyphenyl)ethyl]-N'-methanesulfonyl-N"-[2-[[5-[N-methyl-N(trichloroacetyl)aminomethyl]-2-furyl]methylthio]ethyl]guanidine was dissolved in a mixture of 8 ml of ethanol and 47 ml of a 1N aqueous sodium hydroxide solution in a nitrogen atmosphere. The mixture was stirred at room temperature for 2 hours. Then, the mixture was adjusted to pH 9.7 with 6N hydrochloric acid with ice-cooling, a seed crystal was added thereto and the mixture was stirred for 4 hours at room temperature. The crystals deposited were collected by filtration to obtain 6.0 g (yield: 84%) of N-[2-hydroxy-2-(4hydroxyphenyl)ethyl]-N'-methanesulfonyl-N"-[2-[[5-(methylamino)methyl-2-furyl]methylthio]ethyl]guanidine.
Reaction SMILES: [C:1]1([C:7]2[N:12]3[N:13]=[CH:14][C:15]([C:16]#[N:17])=[C:11]3[N:10]=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-:18].[NH4+]>S(=O)(=O)(O)O>[C:1]1([C:7]2[N:12]3[N:13]=[CH:14][C:15]([C:16]([NH2:17])=[O:18])=[C:11]3[N:10]=[CH:9][CH:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: N#Cc1cnn2c(-c3ccccc3)ccnc12
Reactant: [OH-]
Agent: O=S(=O)(O)O
Agent: [NH4+]
Product: NC(=O)c1cnn2c(-c3ccccc3)ccnc12

Procedure:
A mixture of 4.0 g of 7-phenylpyrazolo[1,5-a]pyrimidine-3-carbonitrile (prepared as described in Example 7 of U.S. Pat. No. 4,236,005) and 40 ml of concentrated sulfuric acid was stirred at room temperature for 16 hours. The solution was then carefully poured into ice with stirring and the mixture was carefully made just basic with concentrated ammonium hydroxide. The solid was collected by filtration and recrystallized from dichloromethane to give pale yellow needles m.p. 236°-238.5° C.
Reaction SMILES: C([O:3][C:4](=[O:27])[CH2:5][C:6]1[C:11]([C:12]#[N:13])=[CH:10][CH:9]=[C:8]([NH:14][CH2:15][C:16]([F:25])([F:24])[C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][N:18]=2)[C:7]=1[F:26])C.CO.[Li+].[OH-].Cl>O.C1COCC1>[C:12]([C:11]1[C:6]([CH2:5][C:4]([OH:27])=[O:3])=[C:7]([F:26])[C:8]([NH:14][CH2:15][C:16]([F:25])([F:24])[C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][N:18]=2)=[CH:9][CH:10]=1)#[N:13]
Reactant: CCOC(=O)Cc1c(C#N)ccc(NCC(F)(F)c2ccc(C)cn2)c1F
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(C(F)(F)CNc2ccc(C#N)c(CC(=O)O)c2F)nc1
Reaction time: 1.5 h

Procedure:
{6-Cyano-3-[2,2-difluoro-2-(5-methyl-pyridin-2-yl)-ethylamino]-2-fluoro-phenyl}-acetic acid ethyl ester (968 mg, 2.57 mmol), prepared as described in the previous step, was dissolved into MeOH:THF:H2O (51 mL, 1:2:1) and treated with LiOH (92 mg, 3.85 mmol, 1.5×). After 1.5 h, the reaction was neutralized with 428 μL, 12N HCl and concentrated in vacuo. The crude material was diluted with toluene and concentrated (3×25 mL) to afford the saponification product {6-cyano-3-[2,2-difluoro-2-(5-methyl-pyridin-2-yl)-ethylamino]-2-fluoro-phenyl}-acetic acid. {6-cyano-3-[2,2-difluoro-2-(5-methyl-pyridin-2-yl)-ethylamino]-2-fluoro-phenyl}-acetic acid, HCl salt of [N,N′-di(tert-butoxycarbonyl)]-2-aminoethoxyguanidine (1.8 g, 5.13 mmol, 2×) (prepared as described in Example 1d), and BOP (1.8 g, 4.16 mmol, 1.6×) were dissolved into CH3CN/CH2Cl2 (12 mL, 1:1) and cooled to 0° C. DIEA (2.7 mL, 15.6 mmol, 6×) was added dropwise and the reaction continued for 12 h, allowing the ice bath to warm to rt. The reaction was partitioned between EtOAc (50 mL) and H2O (50 mL), the organic phase dried over Na2SO4, and concentrated to afford the crude product as a white amorphous solid. Purification via flash chromatography (20% EtOAc/CH2Cl2) afforded the product as a white solid (832 mg, 1.28 mmol, 50% yield). 1H NMR (300 Hz, CDCl3) δ 9.14 (s, 1H), 8.49 (s, 1H), 7.61, m, 2H), 6.75 (t, J=8.2 Hz, 1H), 4.13 (m, 4H), 3.83 (s, 2H), 3.61 (m, 2H), 2.41 (s, 3H), 1.51 (s, 9H), 1.47 (s, 9H); LC/MS (m/z) [M+1]+ 650.3 (calculated for C30H39F3N7O6, 650.7).
Reaction SMILES: N[C:2]1[N:7]=[C:6]2[N:8]([CH2:20][CH3:21])[C:9]([C:11]([N:13]([CH:17]3[CH2:19][CH2:18]3)[CH:14]3[CH2:16][CH2:15]3)=[O:12])=[CH:10][C:5]2=[C:4]2[N:22]([CH3:25])[CH:23]=[N:24][C:3]=12.[Br:26]CBr.[N+]([O-])(OCCC(C)C)=O>C(OCC)(=O)C>[Br:26][C:2]1[N:7]=[C:6]2[N:8]([CH2:20][CH3:21])[C:9]([C:11]([N:13]([CH:17]3[CH2:19][CH2:18]3)[CH:14]3[CH2:16][CH2:15]3)=[O:12])=[CH:10][C:5]2=[C:4]2[N:22]([CH3:25])[CH:23]=[N:24][C:3]=12
Reactant: BrCBr
Reactant: CCn1c(C(=O)N(C2CC2)C2CC2)cc2c3c(ncn3C)c(N)nc21
Agent: CC(C)CCO[N+](=O)[O-]
Solvent: CCOC(C)=O
Product: CCn1c(C(=O)N(C2CC2)C2CC2)cc2c3c(ncn3C)c(Br)nc21
Temperature: 60 °C
Yield: 98 %

Procedure:
A round bottom flask charged with 4-amino-N,N-dicyclopropyl-6-ethyl-1-methyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-7-carboxamide (134.4 mg, 0.397 mmol) under an atmosphere of nitrogen was treated with dibromomethane (397 μL). Isoamyl nitrate (107 μL, 0.794 mmol) was added and the reaction mixture was heated at 60° C. 3.5 h and cooled to rt. The reaction mixture was diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate. The organics were dired over anhydrous sodium sulfate, filtered and concentrated in vacuo. 4-Bromo-N,N-dicyclopropyl-6-ethyl-1-methyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-7-carboxamide (0.156 g, 0.388 mmol, 98% yield) was isolated as a brown glassy solid. The product was used immediately in the next reaction.
Reaction SMILES: [C:1]([CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13](=[O:18])[CH2:12][CH2:11]2)([OH:3])=O.C(N(CC)CC)C.ClC(OCC(C)C)=O.[CH:34]1([CH2:40][NH2:41])[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1>O.CN(C)C=O>[CH:34]1([CH2:40][NH:41][C:1]([CH2:4][CH2:5][CH2:6][O:7][C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[NH:14][C:13](=[O:18])[CH2:12][CH2:11]3)=[O:3])[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1
Reactant: O=C(O)CCCOc1ccc2c(c1)CCC(=O)N2
Reactant: NCC1CCCCC1
Agent: CC(C)COC(=O)Cl
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(CCCOc1ccc2c(c1)CCC(=O)N2)NCC1CCCCC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2.5 Grams of 6-(3-carboxy)propoxy-3,4-dihydrocarbostyril and 1.6 ml of triethylamine are added to 150 ml of dimethylformamide, and the mixture is further added dropwise with 1.3 ml of isobutyl chloroformate under external ice cooling and agitation while maintaining the internal temperature at 10° to 20° C. After this dropwise addition, the mixture is agitated at room temperature for 30 minutes, added with 1.3 ml of cyclohexylmethylamine and further agitated for 1 hour. After the reaction, the reaction solution is poured into about 1 liter of water and the precipitated crystals are filtered out and washed with water. The obtained crystals are dried and recrystallized from chloroform-petroleum ether to obtain 3.0 g of 6-{3-[N-(cyclohexylmethyl)aminocarbonyl]propoxy}-3,4-dihydrocarbostyril in the form of colorless needle-like crystals with m.p. of 170°-172° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:13])=[C:4]([C:9]([Br:12])=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[N:14]([O-])=O.[Na+]>C(O)(=O)C.O>[Br:12][C:9]1[CH:10]=[CH:11][C:2]2[NH:1][N:14]=[CH:13][C:3]=2[C:4]=1[C:5]([O:7][CH3:8])=[O:6]
Reactant: O=N[O-]
Reactant: COC(=O)c1c(Br)ccc(N)c1C
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: COC(=O)c1c(Br)ccc2[nH]ncc12
Reaction time: 20 h
Yield: 85.4 %

Procedure:
To a solution of methyl 3-amino-6-bromo-2-methylbenzoate (5.44 g, 22.3 mmol) in acetic acid (110 mL) was added a solution of sodium nitrite (1.69 g, 24.5 mmol) in water (11 mL) at room temperature and, after stirring for 20 hr, the organic solvent was evaporated under reduced pressure. The residual aqueous solution was diluted with saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane=10/90→30/70) to give the title compound (4.86 g, yield 86%).