Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[C:4]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=2[Cl:21])=[C:5]([C:9]([O:11]CC)=[O:10])[S:6][C:7]=1[I:8])#[N:2].O1CCCC1.O.[OH-].[Na+]>Cl>[C:1]([C:3]1[C:4]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=2[Cl:21])=[C:5]([C:9]([OH:11])=[O:10])[S:6][C:7]=1[I:8])#[N:2]
Reactant: CCOC(=O)c1sc(I)c(C#N)c1-c1ccc(Cl)cc1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: N#Cc1c(I)sc(C(=O)O)c1-c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 48 h
Yield: 98.9 %

Procedure:
To a solution of ethyl 4-cyano-3-(2,4-dichlorophenyl)-5-iodothiophene-2-carboxylate (1.26 g, 0.00279 mol) in Tetrahydrofuran (20 mL, 0.3 mol) was added water (9.2 mL, 0.51 mol) and 1M NaOH (19.5 mL, 0.0195 mol) and the solution was stirred at room temperature for 2 days. The mixture was acidified by 1M HCl (20 mL), extracted with EtOAc (3×100 mL). The organic extracts were combined, dried over Na2SO4, filtered and evaporated to afford the product (1.17 g, 99%). LCMS: (FA) ES+, 424, 426. 1H NMR (400 MHz, d1-chloroform) δ: 7.62-7.60 (m, 1H) 7.45-7.41 (m, 1H), 7.36-7.33 (m, 1H).
Reaction SMILES: [BH4-].[Na+].[CH2:3]([C:8]([C:10]1[CH:15]=[CH:14][C:13]([SH:16])=[CH:12][CH:11]=1)=O)[C:4]([CH3:7])([CH3:6])[CH3:5].O.S(=O)(=O)(O)O>COCCOCCOC>[CH2:8]([C:10]1[CH:11]=[CH:12][C:13]([SH:16])=[CH:14][CH:15]=1)[CH2:3][C:4]([CH3:7])([CH3:6])[CH3:5]
Reactant: CC(C)(C)CC(=O)c1ccc(S)cc1
Agent: O=S(=O)(O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: COCCOCCOC
Product: CC(C)(C)CCc1ccc(S)cc1
Yield: 59.2 %

Procedure:
7.5 g (0.2 mol) of sodium borohydride in 140 ml of diethylene glycol dimethyl ether are initially introduced, and a solution of 41.6 g (0.2 mol) of 4-(neopentylcarbonyl)-thiophenol in 60 ml of diethylene glycol dimethyl ether are added at 30°-40° C. The mixture is further reacted at 120° C. for 2 hours, 100 ml of water are added with ice-cooling, the mixture is acidified with 20% strength sulphuric acid, and another 200 ml of water are added. The reaction mixture is now extracted with 250 ml of methylenechloride, the organic phase is extracted with 250 ml of water, dried over magnesium sulphate and distilled through a split ring column to give 23 g (60% of theory) of 4-(neohexyl)-thiophenol of boiling point 98° C./0.4 mbar.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:9]([N:11]([CH3:13])[CH3:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH3:14]O.S(Cl)(Cl)=O>CCOCC>[OH:1][C:2]1[CH:10]=[C:9]([N:11]([CH3:13])[CH3:12])[CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH3:14])=[O:5]
Reactant: CN(C)c1ccc(C(=O)O)c(O)c1
Reactant: CO
Solvent: O=S(Cl)Cl
Solvent: CCOCC
Product: COC(=O)c1ccc(N(C)C)cc1O
Temperature: 25 °C
Yield: 73 %

Procedure:
To a solution of 2-hydroxy-4-(N,N-dimethylamino)benzoic acid (9.05 g, 50 mmol) and MeOH (100 mL) at 0° C. was added thionyl chloride (5.34 mL, 75 mmol) dropwise. The reaction was warmed to room temperature and refluxed for 14 hours. After cooling, ether was added to the mixture and the reaction was carefully quenched with satd NaHCO3. The mixture was diluted with ether (200 mL) and partitioned. The organic layer was dried over MgSO4 and the crude product was adsorbed onto silica gel. The crude product was chromatographed on silica gel (5% CH2Cl2/hexane to 25% CH2Cl2/hexane) and triturated with ether/hexane to give the desired product as a white solid (7.1 g, 73%).
Reaction SMILES: [C:1]([C:3]([C:6]1[CH:7]=[C:8]([CH:37]=[CH:38][CH:39]=1)[C:9]([NH:11][C:12]1[CH:13]=[CH:14][C:15]([CH3:36])=[C:16]([NH:18][C:19]([C:21]2[S:35][C:24]3=[N:25][CH:26]=[C:27]([C:29]4[CH:30]=[N:31][CH:32]=C[CH:34]=4)[N:28]=[C:23]3[CH:22]=2)=[O:20])[CH:17]=1)=[O:10])([CH3:5])[CH3:4])#[N:2].[N:40]1C=C(B(O)O)C=NC=1>>[C:1]([C:3]([C:6]1[CH:7]=[C:8]([CH:37]=[CH:38][CH:39]=1)[C:9]([NH:11][C:12]1[CH:13]=[CH:14][C:15]([CH3:36])=[C:16]([NH:18][C:19]([C:21]2[S:35][C:24]3=[N:25][CH:26]=[C:27]([C:29]4[CH:34]=[N:40][CH:32]=[N:31][CH:30]=4)[N:28]=[C:23]3[CH:22]=2)=[O:20])[CH:17]=1)=[O:10])([CH3:5])[CH3:4])#[N:2]
Reactant: Cc1ccc(NC(=O)c2cccc(C(C)(C)C#N)c2)cc1NC(=O)c1cc2nc(-c3cccnc3)cnc2s1
Reactant: OB(O)c1cncnc1
Product: Cc1ccc(NC(=O)c2cccc(C(C)(C)C#N)c2)cc1NC(=O)c1cc2nc(-c3cncnc3)cnc2s1
Yield: 7 %

Procedure:
Preparation analogous to the synthesis of 25h by using pyrimidine-5-boronic acid (1.5 eq). Purified by HPLC to give the title compound N-(5-(3-(2-cyanopropan-2-yl)benzamido)-2-methylphenyl)-2-(pyrimidin-5-yl)thieno[2,3-b]pyrazine-6-carboxamide 25j (2 mg, 7%). NMR (400 MHz, DMSO-d6) 1.76 (s, 6H), 2.28 (s, 3H), 7.33 (d, J=8.6 Hz, 1H), 7.58-7.67 (m, 2H), 7.76 (d, J=7.8 Hz, 1H), 7.9 (d, J=1.9 Hz, 1H), 7.95 (d, J=8.2 Hz, 1H), 8.06 (s, 1H), 8.63 (br s, 1H), 9.37 (s, 1H), 9.51 (s, 1H), 9.61 (s, 2H), 10.38 (br s, 1H). (m/z)=534 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[CH:13]=[C:12]([O:14][C:15]3[CH:20]=[CH:19][N:18]=[C:17]4[CH:21]=[CH:22][S:23][C:16]=34)[CH:11]=[CH:10][C:5]=2[C:6]=1[C:7]([OH:9])=O.[N:24]1([C:30]2[N:35]=[CH:34][C:33]([NH2:36])=[CH:32][CH:31]=2)[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.C([O-])(O)=O.[Na+]>CN(C=O)C>[N:24]1([C:30]2[N:35]=[CH:34][C:33]([NH:36][C:7]([C:6]3[C:5]4[CH:10]=[CH:11][C:12]([O:14][C:15]5[CH:20]=[CH:19][N:18]=[C:17]6[CH:21]=[CH:22][S:23][C:16]=56)=[CH:13][C:4]=4[O:3][C:2]=3[CH3:1])=[O:9])=[CH:32][CH:31]=2)[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1
Reactant: Nc1ccc(N2CCOCC2)nc1
Reactant: Cc1oc2cc(Oc3ccnc4ccsc34)ccc2c1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1oc2cc(Oc3ccnc4ccsc34)ccc2c1C(=O)Nc1ccc(N2CCOCC2)nc1

Procedure:
A solution of 2-methyl-6-[thieno[3,2-b]pyridin-7-yloxy]benzofuran-3-carboxylic acid 100 (70 mg, 0.215 mmole), 6-Morpholin-4-yl-pyridin-3-ylamine (77 mg, 0.43 mmole), HATU (163 mg, 0.43 mmole), and diisopropylethylamine (75 μl, 0.43 mmole) were stirred in DMF (2 ml) at ambient temperature for 17 hr. The mixture was then added dropwise to a solution of cold aqueous NaHCO3 resulting in a precipitate which was collected by filtration. This material was purified on silica gel using a gradient of 0 to 5% methanol in a 1:1 mixture of ethyl acetate and dichloromethane as eluent to give 77 mg (74%) of a lavander solid. 1H NMR (CD3CN) δ 8.50 (1H, d, J=5.3 Hz), 8.37 (1H, d, J=2.5 Hz), 8.29 (1H, s), 7.92–7.88 (3H, m), 7.54 (1H, d, J=5.3 Hz), 7.45 (1H, d, J=2.0 Hz), 7.23 (1H, dd, J=8.6, 2.0 Hz), 6.78 (1H, d, J=9.1 Hz), 6.64 (1H, d, J=5.3 Hz), 3.76 (4H, t, J=4.9 Hz), 3.44 (4H, t, J=4.9 Hz), 2.72 (3H, s).
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:3].[Cl:11][C:12]1[CH:13]=[CH:14][C:15]([N:18]2[CH:26]([OH:27])[C:25]3[C:20](=[N:21][CH:22]=[CH:23][N:24]=3)[C:19]2=[O:28])=[N:16][CH:17]=1.O>N1C=CC=CC=1>[Cl:11][C:12]1[CH:13]=[CH:14][C:15]([N:18]2[CH:19]([O:28][C:2]([O:4][C:5]3[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=3)=[O:3])[C:20]3[C:25](=[N:24][CH:23]=[CH:22][N:21]=3)[C:26]2=[O:27])=[N:16][CH:17]=1
Reactant: O=C1c2nccnc2C(O)N1c1ccc(Cl)cn1
Reactant: O=C(Cl)Oc1ccccc1
Solvent: c1ccncc1
Solvent: O
Product: O=C(Oc1ccccc1)OC1c2nccnc2C(=O)N1c1ccc(Cl)cn1
Temperature: 60 °C
Reaction time: 1 h
Yield: 73.4 %

Procedure:
Phenyl chloroformate (141 g.) is added, with stirring and whilst keeping the temperature at about 5° C., to a suspension of 6-(5-chloropyrid-2-yl)-5-hydroxy-7-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazine (158 g.) in anhydrous pyridine (1,580 cc.). When the addition is complete, the reaction mixture is heated to a temperature of about 60° C. The heating is continued for one hour. Water (4,750 cc.) is added to the reaction mixture after it has been cooled to a temperature of about 20° C. The product which crystallises is filtered off and washed with water (2×250 cc.), acetonitrile (150 cc.) and diisopropyl ether (250 cc.). After drying, 6-(5-chloropyrid-2-yl)-7-oxo-5-phenoxycarbonyloxy-6,7-dihydro-5H-pyrrolo[3,4-b]-pyrazine (169 g.), which melts at 193° C., is obtained.
Reaction SMILES: Cl[C:2]1[C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:10]([Cl:18])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:19]([C:31]3[N:35]([CH3:36])[CH:34]=[N:33][CH:32]=3)([C:21]3[CH:22]=[N:23][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:25][CH:26]=3)[OH:20])[CH:8]=2)[N:3]=1.[F:37][C:38]([F:42])([F:41])[CH2:39][OH:40].C1(C)C=CC=CC=1.[H-].[Na+]>CCOC(C)=O>[Cl:18][C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:19]([C:31]3[N:35]([CH3:36])[CH:34]=[N:33][CH:32]=3)([C:21]3[CH:22]=[N:23][C:24]([C:27]([F:29])([F:30])[F:28])=[CH:25][CH:26]=3)[OH:20])[CH:8]=2)[N:3]=[C:2]([O:40][CH2:39][C:38]([F:42])([F:41])[F:37])[C:11]=1[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: Cn1cncc1C(O)(c1ccc(C(F)(F)F)nc1)c1ccc2nc(Cl)c(-c3ccccc3)c(Cl)c2c1
Reactant: OCC(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: Cn1cncc1C(O)(c1ccc(C(F)(F)F)nc1)c1ccc2nc(OCC(F)(F)F)c(-c3ccccc3)c(Cl)c2c1
Temperature: 25 °C

Procedure:
(2,4-Dichloro-3-phenylquinolin-6-yl)(1-methyl-1H-imidazol-5-yl) [6-(trifluoromethyl) pyridin-3-yl]methanol (200 mg, 0.378 mmol, Example 66), 2,2,2-trifluoroethanol (14.0 μL, 0.19 mmol), toluene (2 mL), and sodium hydride (60% dispersion in mineral oil, 19 mg, 0.47 mmol) were combined in a round bottom flask under an N2 atmosphere. The reaction solution was heated to reflux and refluxed overnight. Analysis showed the reaction had only progressed a moderate amount, so additional reagents were added, 2,2,2-trifluoroethanol (14.0 μL, 0.19 mmol) and sodium hydride (60% dispersion in mineral oil, 6 mg, 0.19 mmol) and contents were heated at reflux for an additional 48 hours. The contents were cooled to room temperature then transferred to a separatory funnel with EtOAc dilution, and extracted with saturated, aqueous NH4Cl then saturated, aqueous NaHCO3 solutions. The organic phase was separated then dried over MgSO4, filtered and concentrated under reduced pressure. The crude material was purified via reverse phase chromatography using acetonitrile with 0.05% trifluoroacetic acid in water as eluent. The fractions from the purification containing the desired product were transferred to a separatory funnel with EtOAc and extracted with a saturated, aqueous NaHCO3 solution. The aqueous layer was separated, extracted with EtOAc, then the combined organic phases were dried over MgSO4, filtered and concentrated under reduced pressure to afford the title compound. MS (ESI): mass calcd. for C28H19ClF6N4O2, 592.1; m/z found, 593.2 [M+H]+; 1H NMR (600 MHz, CD3OD) δ ppm 8.80 (d, J=2.1 Hz, 1H), 8.28 (d, J=1.9 Hz, 1H), 8.17 (s, 1H), 8.05 (dd, J=8.2, 2.0 Hz, 1H), 7.97 (d, J=8.7 Hz, 1H), 7.86 (dd, J=8.3, 0.4 Hz, 1H), 7.75 (dd, J=8.8, 2.2 Hz, 1H), 7.51-7.42 (m, 3H), 7.37-7.34 (m, 2H), 6.60 (s, 1H), 5.00 (q, J=8.6 Hz, 2H), 3.56 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[B:11]([OH:13])[OH:12])[C:5]([OH:7])=[O:6].[CH3:14]N(C)C=O.C(OCC)C.C[Si](N=[N+]=[N-])(C)C.CCCCCC>C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]([O:7][CH3:14])=[O:6])[CH:8]=[CH:9][C:10]=1[B:11]([OH:13])[OH:12]
Reactant: CN(C)C=O
Reactant: O=C(O)c1ccc(B(O)O)c(Cl)c1
Agent: C[Si](C)(C)N=[N+]=[N-]
Solvent: CC(=O)O
Solvent: CCCCCC
Solvent: CCOCC
Product: COC(=O)c1ccc(B(O)O)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 42 %

Procedure:
To a mixture of 3-chloro-4-(dihydroxyboryl)benzoic acid (1.00 g, 5.10 mmol), N,N-dimethylformamide (10 mL) and diethyl ether (1 ml) was added dropwise a 0.6 M trimethylsilylazide-hexane solution (10.2 mL, 6.12 mmol), and the resulting mixture was stirred overnight at room temperature. Acetic acid was added to the reaction mixture, and the mixture was concentrated under reduced pressure. Water was added to the residue, and the precipitate was collected by filtration and recrystallized from water to give the title compound (0.46 g, yield 42%) as colorless crystals.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[N:13]=2)[CH:3]=1.[CH:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22](B(O)O)=[CH:21][N:20]=1.C(=O)([O-])[O-].[Na+].[Na+].O1CCOCC1>O>[CH:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22]([C:2]2[C:11]3[C:6](=[N:7][CH:8]=[CH:9][CH:10]=3)[N:5]=[C:4]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[N:13]=3)[CH:3]=2)=[CH:21][N:20]=1
Reactant: OB(O)c1cncc2ccccc12
Reactant: Cc1cccc(-c2cc(Cl)c3cccnc3n2)n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1cccc(-c2cc(-c3cncc4ccccc34)c3cccnc3n2)n1
Yield: 68 %

Procedure:
190 mg 4-chloro naphthyridine from example 3, 341 mg 4-isoquinoline boronic acid pinacole ester, 473 mg sodium carbonate were dissolved with 20 ml dioxan and 5 ml water, flushed with nitrogen, and 86 mg tetrakistriphenylphosphine palladium(0) were added. After 90 min reflux, workup as in example 20 yielded a grey-brownish oil, which was crystallized with ether to give 176 mg correct product as a brownish powder with correct LC_MS: M+H+ 349 and Rf˜1.76 min.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[CH:8]=[C:7]([CH2:9][CH2:10][NH:11]C(OC(C)(C)C)=O)[N:6]=[CH:5]1.C(N(CC)CC)C.C1C(=O)N([O:33][C:34]([CH2:36][CH2:37][C:38]2[CH:43]=[CH:42][C:41]([OH:44])=[CH:40][CH:39]=2)=O)C(=O)C1>C(Cl)Cl>[OH:44][C:41]1[CH:40]=[CH:39][C:38]([CH2:37][CH2:36][C:34]([NH:1][CH2:2][CH2:3][N:4]2[CH:8]=[C:7]([CH2:9][CH2:10][NH2:11])[N:6]=[CH:5]2)=[O:33])=[CH:43][CH:42]=1
Reactant: O=C(CCc1ccc(O)cc1)ON1C(=O)CCC1=O
Reactant: CC(C)(C)OC(=O)NCCc1cn(CCN)cn1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: NCCc1cn(CCNC(=O)CCc2ccc(O)cc2)cn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The following materials are introduced into a reaction vessel: 5 mg (0.02 mmol) of compound VII dissolved in 0.5 ml methylene chloride; 2.8 μl (0.02 mmol) of triethylamine; and last 5.3 mg (0.02 mmol) of N-succinimidyl-3-(4-hydroxyphenyl)propionate dissolved in 0.5 ml of methylene chloride. The solution is stirred for 2 hours at room temperature and then evaporated. The residue is dissolved in 0.5 ml of trifluoroacetic acid, and hydrolysis is allowed to proceed for 1 hour and 15 minutes at room temperature. The solution is evaporated, the residue then being separated on a reversed-phase column PepRPC (Pharmacia AB) with an 0.1% trifluoroacetic acid - acetonitrile gradient. At about 7% acetonitrile compound XIX is eluted. The structure has been confirmed by NMR analysis, the NMR data being the following: 2H-imidazole 8.3, 5H-imidazole 7.2, O-H-hydroxyphenyl 7.1, m-H-hydroxyphenyl 6.85, 1-CH2 -imidazole 4.15, --CH2NHCO 3.55, --CH2N + H3 3.25 t, 4-CH2 -imidazole 3.05 t, p-CH2 -hydroxyphenyl 2.75 t, --CH2CO 2.5 t.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]2[CH:7]=[N:8][NH:9][C:10]=2[CH:11]=[CH:12][C:13]=1[F:14])=[O:4].[Br:15]N1C(=O)CCC1=O>CN(C=O)C>[Br:15][C:7]1[C:6]2[C:5]([C:3]([O:2][CH3:1])=[O:4])=[C:13]([F:14])[CH:12]=[CH:11][C:10]=2[NH:9][N:8]=1
Reactant: COC(=O)c1c(F)ccc2[nH]ncc12
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Product: COC(=O)c1c(F)ccc2[nH]nc(Br)c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 68.6 %

Procedure:
To a solution of methyl-5-fluoro-1H-indazole-4-carboxylate (0.475 g, 2.45 mmol) in 25 mL of DMF was added N-bromosuccinimide (0.566 g, 3.18 mmol). This mixture was stirred at ambient temperature for one hour, then quenched with water. This mixture was extracted with EtOAc, and the combined organic extracts washed with brine, dried over sodium sulfate and concentrated under reduced pressure. Column chromatography (1:1 EtOAc/Hexane) afforded 0.459 g (69%) of the title compound.
Reaction SMILES: [C:1]([CH2:3][C:4]1[C:12]([O:13][CH3:14])=[CH:11][C:10]([CH3:15])=[C:9]2[C:5]=1[CH:6]=[CH:7][N:8]2[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])#[N:2].CI.[CH3:25][Si]([N-][Si](C)(C)C)(C)C.[Li+]>C1COCC1>[C:1]([CH:3]([C:4]1[C:12]([O:13][CH3:14])=[CH:11][C:10]([CH3:15])=[C:9]2[C:5]=1[CH:6]=[CH:7][N:8]2[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH3:25])#[N:2]
Reactant: COc1cc(C)c2c(ccn2C(=O)OC(C)(C)C)c1CC#N
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CI
Product: COc1cc(C)c2c(ccn2C(=O)OC(C)(C)C)c1C(C)C#N
Reaction time: 0.17 h

Procedure:
tert-Butyl 4-(cyanomethyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate (Example 155-B) (1.2 g, 4.00 mmol) was dissolved in THF (40.0 ml), MeI (0.300 ml, 4.79 mmol) was then added at −78° C. At this point, lithium bis(trimethylsilyl)amide (4.39 ml, 4.39 mmol) was added and the reaction stirred for 10 minutes. The reaction was then quenched at −78° C. with a saturated aq. solution of ammonium chloride, diluted with water and EtOAc and the layers were separated. The organic layer was dried over Na2SO4 and concentrated and purified via FCC (0-50% EtOAc:heptanes) to obtain the title compound. MS (ESI+) m/z 313.5 (M−H).
Reaction SMILES: [C:1]([N:8]1[CH:12]=[CH:11]N=C1)(N1C=CN=C1)=[S:2].NC1[C:18]([Cl:19])=[CH:17][S:16]C=1>C1COCC1>[Cl:19][C:18]1[C:12]([N:8]=[C:1]=[S:2])=[CH:11][S:16][CH:17]=1
Reactant: Nc1cscc1Cl
Reactant: S=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: S=C=Nc1cscc1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1.46 g of thiocarbonyldiimidazole are added to a solution of 1.1 g of 3-amino-4-chlorothiophene in 20 ml of anhydrous THF, and the mixture is stirred at room temperature for one hour. The solid is distilled off under reduced pressure, the residue is dissolved in ethyl acetate, the organic phase is treated twice with water in a separating funnel and then dried, and the solvent is again distilled off under reduced pressure. This gives 4-chloro-3-thienyl isothiocyanate as a dark oil which is then reacted further without further purification steps.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH:3]([CH2:7][CH2:8][C:9](OC)=[O:10])[CH2:2]1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>>[NH:1]1[CH2:6][CH2:5][O:4][CH:3]([CH2:7][CH2:8][CH2:9][OH:10])[CH2:2]1
Reactant: COC(=O)CCC1CNCCO1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: OCCCC1CNCCO1
Yield: 74 %

Procedure:
Methyl 3-(morpholin-2-yl)propanoate (0.69 g, 4 mmol) was reacted with LiAlH4 (0.23 g, 6 mmol) according to the procedure as described in Example 68, Step A to give the title compound as colorless oil (0.43 g, 75%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: CC1C=CC(S([CH:11]2[CH:15]([C:16]3[CH:21]=[C:20]([C:22]([NH2:24])=[O:23])[CH:19]=[CH:18][N:17]=3)O[CH:13]=[N:12]2)(=O)=O)=CC=1.[NH3:25]>CO>[NH:12]1[CH:11]=[C:15]([C:16]2[CH:21]=[C:20]([C:22]([NH2:24])=[O:23])[CH:19]=[CH:18][N:17]=2)[N:25]=[CH:13]1
Reactant: Cc1ccc(S(=O)(=O)C2N=COC2c2cc(C(N)=O)ccn2)cc1
Reactant: N
Solvent: CO
Product: NC(=O)c1ccnc(-c2c[nH]cn2)c1
Temperature: 125 °C
Reaction time: 8 h
Yield: 36.8 %

Procedure:
2-[4-(4-methylphenyl)sulfonyl-4,5-dihydro-1,3-oxazol-5-yl]pyridine-4-carboxamide (23 g, 63.98 mmol) was added to a solution of NH3 in MeOH (5 g/120 mL) and stirred overnight at 125° C., concentrated and purified by flash column chromatography to give the title compound (5 g, 36.8%). [M+H] Calc'd for C9H8N4O, 189. Found, 189.
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@H:6]1[CH2:11][CH2:10][C@H:9]([NH:12][C:13]([C:15]2([CH2:20][CH:21]([CH:25]3[CH2:30][CH2:29][CH2:28][CH:27]=[CH:26]3)[C:22]([OH:24])=[O:23])[CH2:19][CH2:18][CH2:17][CH2:16]2)=[O:14])[CH2:8][CH2:7]1)=[O:5])[CH3:2]>C(O)C.[Pd]>[CH2:1]([O:3][C:4]([C@@H:6]1[CH2:7][CH2:8][C@H:9]([NH:12][C:13]([C:15]2([CH2:20][CH:21]([CH:25]3[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)[C:22]([OH:24])=[O:23])[CH2:16][CH2:17][CH2:18][CH2:19]2)=[O:14])[CH2:10][CH2:11]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)[C@H]1CC[C@@H](NC(=O)C2(CC(C(=O)O)C3C=CCCC3)CCCC2)CC1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)[C@H]1CC[C@@H](NC(=O)C2(CC(C(=O)O)C3CCCCC3)CCCC2)CC1

Procedure:
3-{1-[(cis-4-Ethoxycarbonyl-cyclohexyl)carbamoyl]-cyclopentyl}-2-(cyclohex-2-enyl)propanoic acid (185 mg, 0.441 mmol) was dissolved in absolute ethanol (50 ml) and hydrogenated at 50 p.s.i. (3.45 bar) over 5% palladium on charcoal (10 mg) as catalyst. The solution was filtered and the solvent evaporated to give the title compound as a colourless gum (180 mg, 97%). Found: C,65.56; H,9.05; N,3.31. C24H39NO5.H2O requires C,65.57; H,9.39; N,3.18%.
Reaction SMILES: C([O:3][C:4](=[O:27])[C:5]([S:16]([C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=1)(=[O:18])=[O:17])([CH3:15])[CH2:6][CH:7]=[CH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)C>CO.[OH-].[Na+]>[CH3:26][O:25][C:22]1[CH:21]=[CH:20][C:19]([S:16]([C:5]([CH3:15])([CH2:6][CH:7]=[CH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:4]([OH:27])=[O:3])(=[O:18])=[O:17])=[CH:24][CH:23]=1
Reactant: CCOC(=O)C(C)(CC=Cc1ccccc1)S(=O)(=O)c1ccc(OC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(S(=O)(=O)C(C)(CC=Cc2ccccc2)C(=O)O)cc1

Procedure:
2-(4-Methoxy-benzenesulfonyl)-2-methyl-5-phenyl-pent-4-enoic acid was prepared starting from 2-(4-methoxy-benzenesulfonyl)-2-methyl-5-phenyl-pent-4-enoic acid ethyl ester (3.0 g, 11 mmol) dissolved in methanol (50 ml) and 10 N NaOH (30 ml). The resulting reaction mixture was worked up as outlined in Example 9. Yield 1.9 g, 68%; yellowish oil; MS: 361 (M+H)+.
Reaction SMILES: [ClH:1].[CH2:2]([O:5][C:6]1[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=1[C:8]([NH2:10])=[NH:9])CC.Cl.COC1C=CC=CC=1C(N)=O>>[ClH:1].[CH3:2][O:5][C:6]1[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=1[C:8]([NH2:10])=[NH:9]
Reactant: CCCOc1ccccc1C(=N)N
Agent: COc1ccccc1C(N)=O
Agent: Cl
Product: COc1ccccc1C(=N)N

Procedure:
In a manner similar to that described for the preparation of 2-n-propoxybenzamidine hydrochloride in Preparation 7, 2-methoxybenzamindine hydrochloride, m.p. 150°-152° was prepared from 2-methoxybenzamide.
Reaction SMILES: C(C1C=C2C(=CC=1)N(C)C=C2C1CCC(=O)CC1)#N.O1[C:24]2([CH2:29][CH2:28][CH:27]([C:30]3[C:38]4[C:33](=[CH:34][CH:35]=[C:36]([C:39]#[N:40])[CH:37]=4)[N:32]([CH2:41][CH3:42])[CH:31]=3)[CH2:26][CH2:25]2)[O:23]CC1>>[C:39]([C:36]1[CH:37]=[C:38]2[C:33](=[CH:34][CH:35]=1)[N:32]([CH2:41][CH3:42])[CH:31]=[C:30]2[CH:27]1[CH2:28][CH2:29][C:24](=[O:23])[CH2:25][CH2:26]1)#[N:40]
Reactant: CCn1cc(C2CCC3(CC2)OCCO3)c2cc(C#N)ccc21
Agent: Cn1cc(C2CCC(=O)CC2)c2cc(C#N)ccc21
Product: CCn1cc(C2CCC(=O)CC2)c2cc(C#N)ccc21
Yield: 73.9 %

Procedure:
This compound was prepared in the manner described above for intermediate 6a by replacing 3-(1,4-dioxa-spiro[4,5]dec-8-yl)-5-cyano-1-methyl-indole with 3-(1,4-dioxa-spiro[4,5]-dec-8-yl)-5-cyano-1-ethyl-indole (6.77 g, 22 mmol) to afford 4.33 g (75%) of the title compound as a white solid: mp 124° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([C:20]1([OH:24])[CH2:23][CH2:22][CH2:21]1)[C:10]([O:12]CC1C=CC=CC=1)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]>[Pd].C(O)C>[C:1]([O:5][C:6]([NH:8][CH:9]([C:20]1([OH:24])[CH2:21][CH2:22][CH2:23]1)[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC(C(=O)OCc1ccccc1)C1(O)CCC1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)NC(C(=O)O)C1(O)CCC1
Yield: 87.5 %

Procedure:
N-(t-Butoxycarbonyl)-α-(1-hydroxycyclobutyl)glycine, benzyl ester (7.8 g, 23.3 mmoles) was hydrogenated at 1 atmosphere over 1.0 g of 10% palladium on charcoal in 150 ml of absolute ethanol for 4 hours at 25° C. The catalyst was filtered and the solvent evaporated in vacuo. Benzene was added and evaporated twice, to give 5.0 g of product as a hard foam.