Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][C:12]([C:14]([OH:16])=O)=[CH:13][C:8]=2[N:7]=[C:6]1[NH:17][C:18]1[S:19][C:20]2[CH:26]=[C:25]([O:27][C:28]([F:31])([F:30])[F:29])[CH:24]=[CH:23][C:21]=2[N:22]=1.[CH3:32][O:33][CH2:34][CH2:35][NH2:36].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:32][O:33][CH2:34][CH2:35][NH:36][C:14]([C:12]1[CH:11]=[CH:10][C:9]2[N:5]([CH2:4][CH2:3][O:2][CH3:1])[C:6]([NH:17][C:18]3[S:19][C:20]4[CH:26]=[C:25]([O:27][C:28]([F:31])([F:30])[F:29])[CH:24]=[CH:23][C:21]=4[N:22]=3)=[N:7][C:8]=2[CH:13]=1)=[O:16]
Reactant: COCCn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)O)ccc21
Reactant: COCCN
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COCCNC(=O)c1ccc2c(c1)nc(Nc1nc3ccc(OC(F)(F)F)cc3s1)n2CCOC
Yield: 37.3 %

Procedure:
1-(2-Methoxy-ethyl)-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid (2-methoxy-ethyl)-amide (42.0 mg) was prepared by following General Procedure F starting from 1-(2-methoxy-ethyl)-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid (100.0 mg), 2-methoxy-ethylamine (26.0 mg), HBTU (130.0 mg) and DIEA (0.1 mL) in DMF (1.0 mL). LCMS: m/z 511; and 1H NMR (DMSO-d6, 400 MHz): δ 8.47 (1H, br. s), 8.08 (1H, br. s), 7.93 (1H, br. s), 7.74-7.72 (1H, br. m), 7.51 (1H, m), 7.37-7.35 (1H, m), 4.35 (2H, br. s), 3.73-3.72 (2H, br. t), 3.53-3.43 (4H, m), 3.29 (3H, s), 3.24 (3H, s), 2 —NH proton signals were not observed.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:11]([C:12]([NH:14][CH3:15])=[O:13])=[C:10]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[O:9][C:5]2=[N:6][C:7]=1[Cl:8].B([C:26]1[CH:27]=[CH:28][C:29]([F:35])=[C:30]([CH:34]=1)[C:31]([OH:33])=[O:32])(O)O.C(=O)([O-])[O-].[Cs+].[Cs+]>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:8][C:7]1[N:6]=[C:5]2[O:9][C:10]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)=[C:11]([C:12](=[O:13])[NH:14][CH3:15])[C:4]2=[CH:3][C:2]=1[C:26]1[CH:27]=[CH:28][C:29]([F:35])=[C:30]([CH:34]=1)[C:31]([OH:33])=[O:32]
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2nc(Cl)c(Br)cc12
Reactant: O=C(O)c1cc(B(O)O)ccc1F
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: [Cs+]
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2nc(Cl)c(-c3ccc(F)c(C(=O)O)c3)cc12
Temperature: 65 °C
Reaction time: 16 h
Yield: 69.2 %

Procedure:
A mixture of 5-bromo-6-chloro-2-(4-fluorophenyl)-N-methylfuro[2,3-b]pyridine-3-carboxamide (3.0 g, 7.8 mmol), 5-borono-2-fluorobenzoic acid (1.58 g, 8.60 mmol), Pd(Ph3P)4 (0.90 g, 0.78 mmol) and cesium carbonate (3.82 g, 11.7 mmol) was evacuated and charged with N2 (3×) and then diluted with water (0.95 ml)/DMF (9.5 ml). The mixture was again evacuated and charged with N2 (3×) and heated to 65° C. under N2 atmosphere. The reaction was allowed to stir at 65° C. for 16 h. LCMS showed peak with the expected M+H. The mixture was diluted with EtOAc (30 mL) and washed with 1M HCl, and sat aq NaCl. The organic phase was dried over Na2SO4, filtered and concentrated to give solid which was triturated with DCM to give the expected product 5-(6-chloro-2-(4-fluorophenyl)-3-(methylcarbamoyl)furo[2,3-b]pyridin-5-yl)-2-fluorobenzoic acid (2.4 g, 5.4 mmol, 69% yield) consistent by LCMS and NMR. LC-MS retention time: 2.64 min; m/z (MH+): 443. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna 3u C18 2.0×30 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 1 mL/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 2 min, a hold time of 2 min, and an analysis time of 4 min where solvent A was 5% MeOH/95% H2O/10 mM ammonium acetate and solvent B was 5% H2O/95% MeOH/10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode. 1H NMR (400 MHz, DMSO-d6) δ 13.46 (br. s, 1H), 8.55 (d, J=4.8 Hz, 1H), 8.21 (s, 1H), 8.10-8.04 (m, 2H), 8.00 (dd, J=7.0, 2.5 Hz, 1H), 7.82 (ddd, J=8.5, 4.5, 2.5 Hz, 1H), 7.52-7.39 (m, 3H), 2.82 (d, J=4.8 Hz, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[OH:13])[C:5]([O:7][CH2:8][CH3:9])=[O:6].[CH3:14][N:15]([CH3:19])[CH2:16][CH2:17]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C(Cl)Cl.C(OCC)(=O)C>[CH3:14][N:15]([CH3:19])[CH2:16][CH2:17][O:13][C:12]1[CH:11]=[CH:10][C:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])=[CH:3][C:2]=1[OH:1]
Reactant: CCOC(=O)c1ccc(O)c(O)c1
Reactant: CN(C)CCO
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCOC(=O)c1ccc(OCCN(C)C)c(O)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 35 %

Procedure:
To a solution of ethyl 3,4-dihydroxybenzoate (500 mg), N,N-dimethylethanol-amine (565 μL), and triphenylphosphine (1.51 g) in methylene chloride (20 mL) is added dropwise diisopropyl azodicarboxylate (1.37 mL) under argon gas atmosphere and ice-cooling. The mixture is stirred at room temperature for 1 day. The reaction mixture is diluted with ethyl acetate, washed with water and treated with 10% HCl to transfer basic materials in ethyl acetate layer to the aqueous layer. The aqueous layer is neutralized with saturated aqueous sodium hydrogencarbonate and extracted with chloroform/methanol/tetrahydrofuran (4:1:1, ×2). The extract is dried over anhydrous sodium sulfate and concentrated in vacuo. The residue is purified by flash column chromatography on NH-silica gel (Solvent; n-hexane:ethyl acetate=1:1→chloroform:methanol=19:1) to give ethyl 4-[2-(dimethylamino)ethoxy]-3-hydroxy-benzoate (240 mg, yield; 35%) as oil. MS (APCI) m/z; 254 [M+H]+
Reaction SMILES: [CH:1](=O)[CH3:2].C=O.[N:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>>[N:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:1]=1[CH3:2].[N:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: CC=O
Agent: C=O
Solvent: c1ccncc1
Product: Cc1ccccn1
Yield: 17 %

Procedure:
Specifically, Examples of the above-described U.S. Pat. No. 4,861,894 describe that the pyridine bases are synthesized using acetaldehyde and formaldehyde as starting materials to obtain pyridine yield of 47% and picoline yield of 17% (total yield of 61%). Furthermore, Japanese Patent Publication Kokoku No. 92368/1994 [Japanese Patent Publication Kokai No. 181256/1987] and Japanese Patent Publication Kokoku No. 92369/1994 [Japanese Patent Publication Kokai No. 139168/1988] describe processes in which there are employed zeolites in or on to which Tl, Co, and Pb compounds are carried.
Reaction SMILES: [C:1]([CH2:5][N:6]=[C:7]=[O:8])([O:3][CH3:4])=[O:2].[OH:9][C:10]1[CH:15]=[CH:14][NH:13][C:12](=[O:16])[CH:11]=1>O1CCOCC1>[C:1]([CH2:5][NH:6][C:7]([N:13]1[CH:14]=[CH:15][C:10]([OH:9])=[CH:11][C:12]1=[O:16])=[O:8])([O:3][CH3:4])=[O:2]
Reactant: O=c1cc(O)cc[nH]1
Reactant: COC(=O)CN=C=O
Solvent: C1COCCO1
Product: COC(=O)CNC(=O)n1ccc(O)cc1=O
Temperature: 90 °C
Reaction time: 0.5 h
Yield: 54 %

Procedure:
A 2.49 g quantity of carbomethoxymethylisocyanate was added to a suspension of 2.00 g of 4-hydroxy-2(1H)-pyridone in 60 ml of dioxane, and the mixture was stirred at 90° C. for 30 minutes. The solvent was distilled off, and ether was added to the residue. The precipitate thus formed was filtered, giving 2.20 g of the title compound in a yield of 54%.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:11]2[S:15][C:14]([C:16]([OH:18])=O)=[CH:13][CH:12]=2)=[N:4][O:5][C:6]=1[C:7]([F:10])([F:9])[F:8].[CH3:19][N:20]1[CH2:26][CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1>>[CH3:19][N:20]1[CH2:26][CH2:25][CH2:24][N:23]([C:16]([C:14]2[S:15][C:11]([C:3]3[C:2]([CH3:1])=[C:6]([C:7]([F:8])([F:9])[F:10])[O:5][N:4]=3)=[CH:12][CH:13]=2)=[O:18])[CH2:22][CH2:21]1
Reactant: Cc1c(-c2ccc(C(=O)O)s2)noc1C(F)(F)F
Reactant: CN1CCCNCC1
Product: Cc1c(-c2ccc(C(=O)N3CCCN(C)CC3)s2)noc1C(F)(F)F

Procedure:
Prepared from 5-(4-Methyl-5-trifluoromethyl-isoxazol-3-yl)-thiophene-2-carboxylic acid and 1-methyl-[1,4]diazepane by the method described in Example 41. Yellow colored solid (49 mg, 37%). 1H NMR (CDCl3) 1.97-2.05 (m, 2 H), 2.36 (d, J=1.4, 3 H), 2.40 (s, 3 H), 2.62 (br s, 2 H), 2.74 (br s, 2 H), 3.80 (br s, 2 H), 7.37 (br s, 1 H), 7.45 (d, J=3.8, 1 H). 19F NMR −63.1. LC/MS 4.43 min, [M+1]+ 374.
Reaction SMILES: [OH:1][C:2]1[C:12]([I:13])=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][N:3]=1.I[CH:15]([CH3:17])[CH3:16].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[I:13][C:12]1[C:2]([O:1][CH:15]([CH3:17])[CH3:16])=[N:3][CH:4]=[C:5]([CH:11]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: CC(C)I
Reactant: CCOC(=O)c1cnc(O)c(I)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cnc(OC(C)C)c(I)c1
Temperature: 50 °C
Reaction time: 16 h
Yield: 36.6 %

Procedure:
To a solution of 500 mg (1.71 mmol) of ethyl 6-hydroxy-5-iodonicotinate (from Step A) in 10 mL of DMF were added 330 mg (1.96 mmol) of 2-iodopropane and 1.67 g (5.11 mmol) of cesium carbonate. After stirring at 50° C. for 16 h, the reaction mixture was partitioned between EtOAc (20 mL) and water (20 mL). The organic layer was washed with brine (3×20 mL), dried over MgSO4, and concentrated. Chromatography on a Biotage 25+M cartridge using 4:1 v/v hexanes/EtOAc as the eluant to afford 210 mg (37%) of a white solid as the title compound: 1H NMR (500 MHz, CDCl3) δ 1.40 (m, 9H), 4.37 (q, J=7.1, 2H), 5.37 (m, 1H), 8.59 (d, J=2.1, 1H), 8.74 (d, J=2.0, 1H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]([C:11]2([C:14]3[CH:24]=[CH:23][C:17]4[O:18][C:19]([F:22])([F:21])[O:20][C:16]=4[CH:15]=3)[CH2:13][CH2:12]2)=[O:10])[CH:5]=[CH:4][C:3]=1[CH3:25].B([C:29]1[CH:30]=[C:31]([CH:35]=[CH:36][CH:37]=1)[C:32]([OH:34])=[O:33])(O)O.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.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]>[F:21][C:19]1([F:22])[O:18][C:17]2[CH:23]=[CH:24][C:14]([C:11]3([C:9]([NH:8][C:6]4[N:7]=[C:2]([C:29]5[CH:30]=[C:31]([CH:35]=[CH:36][CH:37]=5)[C:32]([OH:34])=[O:33])[C:3]([CH3:25])=[CH:4][CH:5]=4)=[O:10])[CH2:13][CH2:12]3)=[CH:15][C:16]=2[O:20]1
Reactant: Cc1ccc(NC(=O)C2(c3ccc4c(c3)OC(F)(F)O4)CC2)nc1Cl
Reactant: O=C(O)c1cccc(B(O)O)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: Cc1ccc(NC(=O)C2(c3ccc4c(c3)OC(F)(F)O4)CC2)nc1-c1cccc(C(=O)O)c1
Temperature: 150 °C

Procedure:
N-(6-Chloro-5-methylpyridin-2-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide (37 mg, 0.10 mmol) was dissolved in 1 mL of DMF in a reaction tube. 3-Boronobenzoic acid (25 mg, 0.15 mmol), 0.2 mL of an aqueous 2 M potassium carbonate solution, and Pd(dppf)Cl2 (8 mg) were added and the reaction mixture was heated for 10 min at 150° C. in the microwave. The reaction mixture was filtered and purified by reverse-phase preparative liquid chromatography to yield 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid. ESI-MS m/z calc. 452.4, found 453.3 (M+1)+. Retention time 1.93 minutes.
Reaction SMILES: S([O-])([O-])(=O)=O.[Mg+2].[CH:7](=O)[CH2:8][CH2:9][CH2:10][CH3:11].O.C(O)(=O)C.[CH2:18]([NH:22][CH2:23][CH:24]([CH3:26])[CH3:25])[CH:19]([CH3:21])[CH3:20]>>[CH3:20][CH:19]([CH3:21])[CH2:18][N:22]([CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[CH2:23][CH:24]([CH3:26])[CH3:25]
Reactant: CC(C)CNCC(C)C
Reactant: CCCCC=O
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: CC(=O)O
Solvent: O
Product: CCCCCN(CC(C)C)CC(C)C
Temperature: 12.5 °C
Reaction time: 1 h
Yield: 90.1 %

Procedure:
To a suspension of magnesium sulfate (10.1 g) in diisobutylamine (72.0 g) was added dropwise valeraldehyde (24.6 g) at 0-5° C. under a nitrogen atmosphere, and it was stirred at 10-15° C. for 1 hour. After ice-cooling, water (60 ml) was added and it was stirred to dissolve the magnesium sulfate. After the removal of the aqueous layer, to the organic layer obtained was added a 9% (w/v) aqueous acetic acid solution (200 ml) at 0-5° C. and then stirred for 5 minutes. The aqueous layer was, then, removed again, a 0.5% (w/v) aqueous sodium hydroxide solution (60 ml) was added to the organic layer at 0-5° C., and stirred for 5 minutes. After stirring, the aqueous layer was removed to afford the title compound (51.3 g, yield: 80%, purity: 93.8%) as a colorless oil.
Reaction SMILES: [O:1]([CH2:8][C:9]1[N:13]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=2)[C:12]2[CH:26]=[CH:27][C:28]([C:30](O)=[O:31])=[CH:29][C:11]=2[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C)N=C=NC(C)C.[CH3:42][O:43][C:44]1[CH:45]=[C:46]([CH:50]=[CH:51][CH:52]=1)[CH2:47][CH2:48][NH2:49]>C1COCC1>[CH3:42][O:43][C:44]1[CH:45]=[C:46]([CH2:47][CH2:48][NH:49][C:30]([C:28]2[CH:27]=[CH:26][C:12]3[N:13]([CH2:14][C:15]4[CH:16]=[CH:17][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:19][CH:20]=4)[C:9]([CH2:8][O:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)=[N:10][C:11]=3[CH:29]=2)=[O:31])[CH:50]=[CH:51][CH:52]=1
Reactant: COc1cccc(CCN)c1
Reactant: O=C(O)c1ccc2c(c1)nc(COc1ccccc1)n2Cc1ccc(OC(F)(F)F)cc1
Agent: CC(C)N=C=NC(C)C
Solvent: C1CCOC1
Product: COc1cccc(CCNC(=O)c2ccc3c(c2)nc(COc2ccccc2)n3Cc2ccc(OC(F)(F)F)cc2)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
0.16 mmol of 2-phenoxymethyl-1-(4-trifluoromethoxy-benzyl)-1H-benzoimidazole-5-carboxylic acid were dissolved in 1 ml THF with 1 eq. DIC. After 15 min 1.5 eq of 3-methoxyphenethylamine were added and the reaction stirred at room temperature for 16 h. The crude material was purified via reversed phase preparative HPLC. MS(ISP): 576.3 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[C:14]2[C:13](=[O:15])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1.S(C1C=CC([N+]([O-])=O)=CC=1)(O[CH2:20][C@H:21]1[O:23][CH2:22]1)(=O)=O.C(=O)([O-])[O-].[K+].[K+]>>[O:23]1[CH2:22][C@H:21]1[CH2:20][O:1][C:2]1[C:14]2[C:13](=[O:15])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)OC[C@@H]2CO2)cc1
Reactant: O=C1c2ccccc2-c2cccc(O)c21
Agent: O=C([O-])[O-]
Agent: [K+]
Product: O=C1c2ccccc2-c2cccc(OC[C@@H]3CO3)c21
Yield: 20.3 %

Procedure:
Prepared from 1-hydroxy-9-fluorenone (3.0 g, 15.2 mmol), (S)-glycidyl nosylate (3.06 g, 15.2 mmol) and potassium carbonate (2.1 g, 15.2 mmol) according to the procedure used for Intermediate 1 to give 0.78 g product as a yellow solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[CH:15]=[CH:14][CH:13]=[C:12]([C:17]([O:19]CC3C=CC=CC=3)=[O:18])[C:11]=2[CH:10]=[C:9]1[C:27]([O:29][CH2:30][CH3:31])=[O:28])=[O:7])([CH3:4])([CH3:3])[CH3:2]>[Pd].C(O)=O.CO>[C:1]([O:5][C:6]([N:8]1[C:16]2[CH:15]=[CH:14][CH:13]=[C:12]([C:17]([OH:19])=[O:18])[C:11]=2[CH:10]=[C:9]1[C:27]([O:29][CH2:30][CH3:31])=[O:28])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)c1cc2c(C(=O)OCc3ccccc3)cccc2n1C(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CO
Solvent: O=CO
Product: CCOC(=O)c1cc2c(C(=O)O)cccc2n1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 85 %

Procedure:
To a mixture of 10% palladium on charcoal (130 mg) in 5.0% formic acid-methanol (5.0 ml) was added a solution of benzyl 1-tert-butoxycarbonyl-2-ethoxycarbonylindole-4-carboxylate (130 mg) in 5.0% formic acid-methanol (5.0 ml). The mixture was stirred under nitrogen atmosphere at ambient temperature for 30 minutes. The resulting mixture was filtered through a bed of celite and the filtrate was evaporated in vacuo to give 1-tert-butoxycarbonyl-2-ethoxycarbonylindole-4-carboxylic acid (87 mg) as a white crystal.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([Br:12])[CH:8]=[CH:9][C:10]=1[OH:11])([CH3:4])([CH3:3])[CH3:2].I[CH2:14][CH2:15][CH3:16]>>[C:1]([C:5]1[CH:6]=[C:7]([Br:12])[CH:8]=[CH:9][C:10]=1[O:11][CH2:14][CH2:15][CH3:16])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cc(Br)ccc1O
Reactant: CCCI
Product: CCCOc1ccc(Br)cc1C(C)(C)C
Yield: 86.7 %

Procedure:
Following the basic procedure of Example 46(a), by reacting 4.58 g (0.02 mol) of 3-tert-butyl-4-hydroxybromobenzene with 2.2 ml (0.022 mol) of 1-iodopropane, 4.7 g (87%) of 3-tert-butyl-4-propyloxybromobenzene were obtained in form of a colorless oil.
Reaction SMILES: C[O:2][C:3]([C@H:5]1[CH2:10][CH2:9][C@H:8]2[C@H:11]3[C@H:21]([C:22](=[O:24])[CH2:23][C@:6]12[CH3:7])[C@:19]1([CH3:20])[C@H:14]([CH2:15][CH:16]=[CH:17][CH2:18]1)[CH2:13][CH2:12]3)=[O:4]>[OH-].[K+]>[CH3:7][C@:6]12[CH2:23][C:22](=[O:24])[C@H:21]3[C@@H:11]([CH2:12][CH2:13][C@@H:14]4[C@:19]3([CH3:20])[CH2:18][CH:17]=[CH:16][CH2:15]4)[C@@H:8]1[CH2:9][CH2:10][C@@H:5]2[C:3]([OH:4])=[O:2]
Reactant: COC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4CC=CC[C@]4(C)[C@H]3C(=O)C[C@]12C
Agent: [K+]
Agent: [OH-]
Product: C[C@]12CC=CC[C@@H]1CC[C@H]1[C@@H]3CC[C@H](C(=O)O)[C@@]3(C)CC(=O)[C@@H]12
Yield: 57.4 %

Procedure:
A solution of 17β-methoxycarbonyl-5α-androst-2-en-11-one (4.6g.,) in 3% ethanolic potassium hydroxide (50 ml.) was refluxed under N2 for 36 hr. and then concentrated to small volume prior to pouring into water. After acidification the solid product was filtered, dried and recrystallised from chloroform/benzene to give the title compound (2.53 g.), m.p. 201°-214°; [α]D + 129°
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([CH2:31][CH3:32])[C:12]([NH:17][C@H:18]2[C@@H:22]([O:23][CH2:24][CH3:25])[CH2:21][N:20]([C:26]3S[CH:28]=[CH:29][N:30]=3)[CH2:19]2)=[N:13][C:14]=1[CH2:15][CH3:16].Br[C:34]1N=CC=C[N:35]=1>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([CH2:31][CH3:32])[C:12]([NH:17][C@H:18]2[C@@H:22]([O:23][CH2:24][CH3:25])[CH2:21][N:20]([C:26]3[N:35]=[CH:34][CH:28]=[CH:29][N:30]=3)[CH2:19]2)=[N:13][C:14]=1[CH2:15][CH3:16]
Reactant: Brc1ncccn1
Reactant: CCO[C@H]1CN(c2nccs2)C[C@H]1Nc1nc(CC)c(-c2ccc(Cl)cc2Cl)nc1CC
Product: CCO[C@H]1CN(c2ncccn2)C[C@H]1Nc1nc(CC)c(-c2ccc(Cl)cc2Cl)nc1CC

Procedure:
Following the procedure for the preparation of 5-(2,4-dichlorophenyl)-N-[(3R,4S)-4-ethoxy-1-(1,3-thiazol-2-yl)pyrrolidin-3-yl]-3,6-diethylpyrazin-2-amine but substituting 2-bromo pyrimidine provided the title compound as an amporphous solid: 1H NMR (400 MHz, CDCl3) δ) 8.38, 7.50, 7.32, 7.26, 6.56, 5.30, 4.91, 4.25, 3.94, 3.76, 3.55, 2.73, 2.47, 1.33–1.26, 1.16; HRMS (ESI) calcd for C24H28N6OCl2+H1 487.1780. found 487.1770.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:8][NH:9][CH2:10][CH2:11][OH:12].O>O1CCCC1>[CH3:8][N:9]([CH2:10][CH2:11][OH:12])[C:2]1[N:7]=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: Clc1ncccn1
Reactant: CNCCO
Solvent: O
Solvent: C1CCOC1
Product: CN(CCO)c1ncccn1

Procedure:
A mixture of 2-chloropyrimidine (10 g) and 2-methylaminoethanol in dry tetrahydrofuran (100 ml) was boiled under reflux for 3 hours. The solution was cooled, water (200 ml) was added, the mixture extracted with dichloromethane, the organic extracts were dried (MgSO4), filtered and evaporated to dryness. The residual oil was used in Preparation 5 without further purification.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[Cl:6][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:15]=1[N:14]([CH2:16][CH:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1)[CH:13]=[C:12]2[C:23]([NH2:25])=O>CN(C)C=O>[Cl:6][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:15]=1[N:14]([CH2:16][CH:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1)[CH:13]=[C:12]2[C:23]#[N:25]
Reactant: NC(=O)c1cn(CC2CCOCC2)c2c(Cl)cccc12
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: N#Cc1cn(CC2CCOCC2)c2c(Cl)cccc12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 68.7 %

Procedure:
Phosphorus oxychloride (9.6 ml, 103 mmol) was added dropwise, via a pressure equalising funnel, to a cooled (5-10° C.) solution of 7-chloro-1-(tetrahydropyran-4-yl)methyl-1H-indole-3-carboxylic acid amide (20.0 g, 68.3 mmol) in dimethylformamide (200 ml). Following complete addition of phosphorus oxychloride the reaction was left to stir for 10 mins before warming to room temperature and allowing to stir for a further 30 mins. The reaction mixture was then poured carefully into ice cold water (2000 ml), the resulting precipitate filtered off and washed with water. The filter cake was then dissolved in dichloromethane, washed with water and brine, dried over sodium sulfate and the solvent removed in vacuo. The resulting solid was crystallised from diethyl ether to yield 7-chloro-1-(tetrahydro-pyran-4-yl)methyl-1H-indole-3-carbonitrile (12.9 g, 46.9 mmol) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([C:7]2[O:8][CH:9]=[CH:10][CH:11]=2)[NH:4][C:3]=1[C:12]([O:14]CC)=O.C(O)(=O)C.[CH:21](N)=[NH:22]>C(O)C>[O:8]1[CH:9]=[CH:10][CH:11]=[C:7]1[C:5]1[NH:4][C:3]2[C:12](=[O:14])[NH:22][CH:21]=[N:1][C:2]=2[CH:6]=1
Reactant: CCOC(=O)c1[nH]c(-c2ccco2)cc1N
Reactant: N=CN
Solvent: CCO
Solvent: CC(=O)O
Product: O=c1[nH]cnc2cc(-c3ccco3)[nH]c12
Temperature: 25 °C
Yield: 95.9 %

Procedure:
To a solution of ethyl 3-amino-5-(2-furyl)-1H-pyrrole-2-carboxylate (2.58 g) in ethanol (35 mL) was added formamidine acetate (1.83 g), and the mixture was heated under reflux for 18 hrs. After cooling to room temperature, the precipitated solid was collected by filtration, washed with ethanol, and dried under reduced pressure at 60° C. to give the title compound (2.26 g).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:11]=[CH:10][C:7]([CH2:8][Cl:9])=[CH:6][CH:5]=1)[CH3:2].S(Cl)(Cl)=O.[CH2:16](OC1C=CC(CO)=CC=1)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]CC>C(Cl)Cl>[CH2:1]([O:3][C:4]1[CH:11]=[CH:10][C:7]([CH2:8][Cl:9])=[CH:6][CH:5]=1)[CH2:2][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: CCCCCCCCOc1ccc(CO)cc1
Reactant: CCOc1ccc(CCl)cc1
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: CCCCCCCCOc1ccc(CCl)cc1

Procedure:
This compound was synthesized following the same general procedure as that for the preparation of 4-ethoxybenzyl chloride; thionyl chloride (6.36 g, 53.4 mmol), 4-octyloxybenzyl alcohol (12.4 g, 52.5 mmol), CH2Cl2 (150 mL).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH:9]2[CH2:26][CH2:25][C:12]3([CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]3)[CH2:11][CH2:10]2)[C:5]([Cl:27])=[CH:4][N:3]=1.[CH:28]1([CH2:31][N:32]2[CH:36]=[C:35]([NH2:37])[CH:34]=[N:33]2)[CH2:30][CH2:29]1.FC(F)(F)C(O)=O>O1CCOCC1>[Cl:27][C:5]1[C:6]([NH:8][CH:9]2[CH2:10][CH2:11][C:12]3([CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:22])([CH3:24])[CH3:23])=[O:19])[CH2:14][CH2:13]3)[CH2:25][CH2:26]2)=[N:7][C:2]([NH:37][C:35]2[CH:34]=[N:33][N:32]([CH2:31][CH:28]3[CH2:30][CH2:29]3)[CH:36]=2)=[N:3][CH:4]=1
Reactant: Nc1cnn(CC2CC2)c1
Reactant: CC(C)(C)OC(=O)N1CCC2(CCC(Nc3nc(Cl)ncc3Cl)CC2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCC2(CCC(Nc3nc(Nc4cnn(CC5CC5)c4)ncc3Cl)CC2)CC1
Temperature: 100 °C
Reaction time: 8 h
Yield: 88.1 %

Procedure:
To a solution of tert-butyl 9-[(2,5-dichloropyrimidin-4-yl)amino]-3-azaspiro[5.5]undecane-3-carboxylate (500.5 mg, 1.21 mmol) and 1-(cyclopropylmethyl)-1H-pyrazol-4-amine (330.5 mg, 2.41 mmol) in 1,4-dioxane (50 mL) was added trifluoroacetic acid (686.5 mg, 6.02 mmol). The mixture was stirred at 100° C. overnight and concentrated in vacuo. The residue was purified with a silica gel column chromatography (PE/EtOAc (v/v)=1/1 to DCM/MeOH (v/v)=7/1) to give the product as a light yellow solid (550 mg, 88.45%).