Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O)(C(F)(F)F)=O.C([O:12][C:13]([C:15]1[CH:16]=[C:17]([C:21]2[N:30]=[C:29]([NH:31][C:32]([C:34]3([C:37]4[CH:47]=[CH:46][C:40]5[O:41][C:42]([F:45])([F:44])[O:43][C:39]=5[CH:38]=4)[CH2:36][CH2:35]3)=[O:33])[CH:28]=[CH:27][C:22]=2[C:23]([O:25][CH3:26])=[O:24])[CH:18]=[CH:19][CH:20]=1)=[O:14])(C)(C)C>C(Cl)Cl.C([O-])(O)=O.[Na+]>[F:45][C:42]1([F:44])[O:41][C:40]2[CH:46]=[CH:47][C:37]([C:34]3([C:32]([NH:31][C:29]4[N:30]=[C:21]([C:17]5[CH:16]=[C:15]([CH:20]=[CH:19][CH:18]=5)[C:13]([OH:14])=[O:12])[C:22]([C:23]([O:25][CH3:26])=[O:24])=[CH:27][CH:28]=4)=[O:33])[CH2:36][CH2:35]3)=[CH:38][C:39]=2[O:43]1
Reactant: COC(=O)c1ccc(NC(=O)C2(c3ccc4c(c3)OC(F)(F)O4)CC2)nc1-c1cccc(C(=O)OC(C)(C)C)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)c1ccc(NC(=O)C2(c3ccc4c(c3)OC(F)(F)O4)CC2)nc1-c1cccc(C(=O)O)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.7 %

Procedure:
TFA (1 mL) was added to a solution of methyl 2-(3-(tert-butoxycarbonyl)-phenyl)-6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)nicotinate (290 mg, 0.50 mmol) in CH2Cl2 (2.5 mL). The reaction mixture was stirred at room temperature for 2 hours. The mixture was diluted with CH2Cl2 and neutralized with saturated aqueous NaHCO3. A white precipitate formed which was filtered, washed with H2O and air-dried to yield the product as a white solid (240 mg, 91%). ESI-MS m/z calc. 496.1, found 497.5 (M+1)+. Retention time 1.91 minutes. 1H NMR (400 MHz, DMSO-d6) δ 9.61 (s, 1H), 8.24 (d, J=8.7 Hz, 1H), 8.11 (d, J=8.7 Hz, 1H), 7.98-7.96 (m, 2H), 7.62 (d, J=7.8 Hz, 1H), 7.55-7.51 (m, 2H), 7.40-7.33 (m, 2H), 3.62 (s, 3H), 1.55-1.52 (m, 2H), 1.22-1.19 (m, 2H).
Reaction SMILES: [CH2:1]([C:3]1([CH2:10][O:11][C:12](=[O:16])[C:13]([CH3:15])=[CH2:14])[CH2:8][O:7][C:6](=[O:9])[O:5][CH2:4]1)[CH3:2].[CH3:17][OH:18].C1(C)C=CC(S(O)(=O)=O)=CC=1>ClCCCl>[CH2:1]([C:3]([CH2:10][O:11][C:12](=[O:16])[C:13]([CH3:15])=[CH2:14])([CH2:8][O:7][C:6]([O:5][CH3:4])=[O:9])[CH2:17][OH:18])[CH3:2]
Reactant: CO
Reactant: C=C(C)C(=O)OCC1(CC)COC(=O)OC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCCl
Product: C=C(C)C(=O)OCC(CC)(CO)COC(=O)OC
Temperature: 40 °C
Reaction time: 2 h

Procedure:
11.4 g of 5-ethyl-5-methacryloyloxymethyl-2-oxo-1,3-dioxane, 3.2 g of methanol and 0.285 g of p-toluenesulfonic acid were dissolved in 100 g of 1,2-dichloroethane. The solution was stirred for 2 hours at 40° C. and evaporated in vacuo to remove the solvent. After removing white precipitates by filtration, the residue was further concentrated whereupon the title compound was recovered as a colorless oil.
Reaction SMILES: [CH2:1]([O:8][C:9]([CH2:11][N:12]1[CH2:25][CH2:24][CH2:23][NH:22][CH2:21][CH2:20][N:19]([CH2:26][C:27]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[O:28])[CH2:18][CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:37]([C:40]1[CH:48]=[CH:47][C:43]([CH2:44][CH2:45]Br)=[CH:42][CH:41]=1)([O-:39])=[O:38].C([O-])([O-])=O.[K+].[K+]>C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]([CH2:11][N:12]1[CH2:25][CH2:24][CH2:23][NH:22][CH2:21][CH2:20][N:19]([CH2:26][C:27]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[O:28])[CH2:18][CH2:17][CH2:16][N:15]([CH2:45][CH2:44][C:43]2[CH:42]=[CH:41][C:40]([N+:37]([O-:39])=[O:38])=[CH:48][CH:47]=2)[CH2:14][CH2:13]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1ccc(CCBr)cc1
Reactant: O=C(CN1CCCNCCN(CC(=O)OCc2ccccc2)CCCNCC1)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: O=C(CN1CCCN(CCc2ccc([N+](=O)[O-])cc2)CCN(CC(=O)OCc2ccccc2)CCCNCC1)OCc1ccccc1
Yield: 70 %

Procedure:
A solution of compound (4) (1.19 g, 2.39 mmol), 4-nitrophenethyl bromide (1.09 g, 4.78 mmol), anhydrous K2CO3 (0.99 g, 7.17 mmol) and KI (1.19 g, 7.17 mmol) dissolved in dry toluene (150 ml) was stirred under reflux for 24 hours. The solvent was evaporated from the reaction mixture under reduced pressure, and CH2Cl2 (250 ml) was added thereto. The resultant brown slurry was filtered through a celite pad, and washed with CH2Cl2 (2×30 ml). The solvent was evaporated from the combined filtrate under reduced pressure. The residue thus obtained was purified via alumina (basic) column chromatography using EtOAc/methanol (10:2) as an eluent to provide compound (16) as a yellow oil (1.08 g, 70% yield). 1H NMR (500 MHz, CDCl3): δ 8.14-8.12 (dd, 2H), 7.49-7.47 (dd, 2H), 7.33-7.28 (m, 10H), 5.09 (s, 2H), 5.03 (s, 4H), 3.46 (s, 2H), 3.36 (s, 2H), 3.25 (s, 2H), 2.87 (brs, 2H), 2.76-2.72 (m, 4H), 2.65-2.63 (m, 6H), 2.59-2.57 (m, 2H), 2.44-2.42 (m, 2H), 1.69 (brs, 2H), 1.62-1.59 (m, 2H); 13C NMR (125 MHz, CDCl3): δ 171.3, 170.8, 148.1, 146.9, 135.7, 129.3, 128.5, 128.2, 128.1, 123.3, 66.0, 65.8, 58.1, 55.5, 53.6, 53.1, 52.5, 52.0, 51.2, 49.6, 47.9, 47.2, 25.7; HRMS (FAB) calculated for C36H48N5O6: 646.3605 [(M+H)+], measured value: 646.3602 [(M+H)+].
Reaction SMILES: O[C:2]1([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4][CH2:3]1.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[CH3:19][O:18][C:15]1[CH:14]=[CH:13][C:12]([C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH2:5][CH2:4][CH:3]=2)=[CH:17][CH:16]=1
Reactant: COc1ccc(C2(O)CCCc3ccccc32)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: COc1ccc(C2=CCCc3ccccc32)cc1
Temperature: 25 °C
Yield: 67 %

Procedure:
A solution of 1-hydroxy-1-(4-methoxyphenyl)tetralin (18 g., 0.071 mole) in toluene (250 ml.) was treated with para-toluenesulfonic acid (5 mg.) and the resulting solution stirred at reflux for 16 hours, with complete water removal accomplished by means of a Dean-Stark trap. The reaction mixture was then cooled to room temperature, washed sequentially with 10% aqueous sodium bicarbonate solution (100 ml.), water (100 ml.) and saturated aqueous sodium chloride solution (100 ml.), dried (MgSO4) and evaporated under vacuum to an oil, which was purified by silica gel chromatography (elution with a hexane-toluene gradient) to give 12 g. of the named compound (67% yield, oil).
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([CH:19]=[CH:20][C:21]=1[O:22][CH3:23])[O:7][C:8]1[C:13]([CH3:14])=[CH:12][C:11]([NH:15][C:16]#[N:17])=[CH:10][C:9]=1[CH3:18])([CH3:3])[CH3:2].[N-:24]=[N+:25]=[N-:26].[Na+].[Cl-].[NH4+]>>[CH:1]([C:4]1[CH:5]=[C:6]([CH:19]=[CH:20][C:21]=1[O:22][CH3:23])[O:7][C:8]1[C:13]([CH3:14])=[CH:12][C:11]([NH:15][C:16]2[NH:26][N:25]=[N:24][N:17]=2)=[CH:10][C:9]=1[CH3:18])([CH3:3])[CH3:2].[CH3:18][C:9]1[CH:10]=[C:11]([NH:15][C:16]2[NH:26][N:25]=[N:24][N:17]=2)[CH:12]=[C:13]([CH3:14])[C:8]=1[O:7][C:6]1[CH:19]=[CH:20][C:21]([OH:22])=[C:4]([CH:1]([CH3:3])[CH3:2])[CH:5]=1
Reactant: [N-]=[N+]=[N-]
Reactant: COc1ccc(Oc2c(C)cc(NC#N)cc2C)cc1C(C)C
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Product: COc1ccc(Oc2c(C)cc(Nc3nnn[nH]3)cc2C)cc1C(C)C
Product: Cc1cc(Nc2nnn[nH]2)cc(C)c1Oc1ccc(O)c(C(C)C)c1
Temperature: 165 °C

Procedure:
[4-(3-Isopropyl-4-methoxy-phenoxy)-3,5-dimethyl-phenyl]-(1H-tetrazol-5-yl)-amine was prepared from 4-(3-isopropyl-4-methoxy-phenoxy)-3,5-dimethyl-phenyl-cyanamide according to a procedure analogous to that described in EXAMPLE 1, Step C. Sodium azide (1.2 equiv) and ammonium chloride (10.0 equiv) were used, and the reaction was heated to 165° C. for 5 hours. After the reaction had been acidified, the mixture was extracted with ethyl acetate (3×10 ml). The combined organic extracts were washed with 1N HCl (3×50 ml) and brine (1×50 ml). The organic phase was dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by preparative TLC (methanol:water:dichloromethane 10:0.5:89.5) to afford the title product of Step C. MS (APCI+) Calc.: 353.4, Found: 354.1 (M+1).
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:5]=1[C:11]1[C:16]([C:17]2C=CN[N:18]=2)=[CH:15][N:14]=[C:13]([NH:22][CH2:23][CH2:24][NH:25][C:26]2[CH:31]=[CH:30][C:29]([N+:32]([O-:34])=[O:33])=[CH:28][N:27]=2)[N:12]=1.[Cl:35]C1C=C(Cl)C=CC=1[C:43](=O)[C:44](C1NC=C(C)N=1)=[CH:45][N:46](C)C>>[ClH:3].[ClH:35].[Cl:3][C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:5]=1[C:11]1[C:16]([C:17]2[NH:46][CH:45]=[C:44]([CH3:43])[N:18]=2)=[CH:15][N:14]=[C:13]([NH:22][CH2:23][CH2:24][NH:25][C:26]2[CH:31]=[CH:30][C:29]([N+:32]([O-:34])=[O:33])=[CH:28][N:27]=2)[N:12]=1
Reactant: Cc1c[nH]c(C(=CN(C)C)C(=O)c2ccc(Cl)cc2Cl)n1
Reactant: O=[N+]([O-])c1ccc(NCCNc2ncc(-c3cc[nH]n3)c(-c3ccc(Cl)cc3Cl)n2)nc1
Agent: Cl
Product: Cc1c[nH]c(-c2cnc(NCCNc3ccc([N+](=O)[O-])cn3)nc2-c2ccc(Cl)cc2Cl)n1

Procedure:
Made using the same procedure as for [4-(2,4-dichlorophenyl)-5-pyrazolylpyrimidin-2-yl]{2-[(5-nitro(2-pyridyl))amino]ethyl}amine dihydrochloride except that 1-(2,4-dichlorophenyl)-3-(dimethylamino)-2-(4-methylimidazolyl)prop-2-en-1-one (XI, 421 mg, 1.3 mmol) was used.
Reaction SMILES: [CH:1]1([NH2:4])[CH2:3][CH2:2]1.[F:5][C:6]([F:38])([F:37])[CH2:7][NH:8][C:9]([NH:11][C:12]1[CH:13]=[C:14]([C:18]2[N:22]3[N:23]=[CH:24][C:25]([C:27]4[CH:28]=[N:29][N:30]([CH:32]([CH3:36])[C:33](O)=[O:34])[CH:31]=4)=[CH:26][C:21]3=[N:20][CH:19]=2)[CH:15]=[CH:16][CH:17]=1)=[O:10].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C=O)C>[CH:1]1([NH:4][C:33](=[O:34])[CH:32]([N:30]2[CH:31]=[C:27]([C:25]3[CH:24]=[N:23][N:22]4[C:18]([C:14]5[CH:15]=[CH:16][CH:17]=[C:12]([NH:11][C:9]([NH:8][CH2:7][C:6]([F:38])([F:37])[F:5])=[O:10])[CH:13]=5)=[CH:19][N:20]=[C:21]4[CH:26]=3)[CH:28]=[N:29]2)[CH3:36])[CH2:3][CH2:2]1
Reactant: CC(C(=O)O)n1cc(-c2cnn3c(-c4cccc(NC(=O)NCC(F)(F)F)c4)cnc3c2)cn1
Reactant: NC1CC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C(=O)NC1CC1)n1cc(-c2cnn3c(-c4cccc(NC(=O)NCC(F)(F)F)c4)cnc3c2)cn1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Cyclopropylamine (17 μL, 0.24 mmol) was added to a mixture of 2-(4-{3-[3-({[(2,2,2-trifluoroethyl)amino]carbonyl}amino)phenyl]imidazo[1,2-b]pyridazin-7-yl}-1H-pyrazol-1-yl)propanoic acid (0.16 mmol) and benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (110 mg, 0.24 mmol) in DMF (2.0 mL), followed by triethylamine (45 μL, 0.32 mmol). The reaction mixture was stirred at r.t. for 30 min. The mixture was purified by RP-HPLC (pH=10) to afford the desired product. LCMS (M+H)+: m/z=513.2.
Reaction SMILES: Cl[C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[C:5]2=[N:12][N:13]=[N:14][N:4]2[N:3]=1.[NH:15]1[CH2:19][CH2:18][CH2:17][C:16]1=O>CO>[N:15]1([C:2]2[C:11]3[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=3[C:5]3=[N:12][N:13]=[N:14][N:4]3[N:3]=2)[CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: O=C1CCCN1
Reactant: Clc1nn2nnnc2c2c1CCCC2
Solvent: CO
Product: C1CCc2c(c(N3CCCC3)nn3nnnc23)C1

Procedure:
A mixture of 6 g of 6-chloro-7,8,9,10-tetrahydrotetrazolo[5,1-a]phthalazine, 150 ml of methanol and excess pyrrolidone was heated on a boiling-water steam bath for 10 minutes and cooled. The solid which formed was separated by filtration, washed with water and recrystallized from a mixture of dimethylsulfoxide and water to give 6-(1-pyrrolidinyl)-7,8,9,10-tetrahydrotetrazolo[5,1-a]phthalazine melting at about 272°-273° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[C:9]([CH2:11][CH:12]=O)[CH:8]=[CH:7][C:4]=1[C:5]#[N:6].[N:14]1([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1.C([BH3-])#N.[Na+].CC(O)=O>CO>[C:5]([C:4]1[CH:7]=[CH:8][C:9]([CH2:11][CH2:12][N:17]2[CH2:16][CH2:15][N:14]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:19][CH2:18]2)=[CH:10][C:3]=1[O:2][CH3:1])#[N:6]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: COc1cc(CC=O)ccc1C#N
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: COc1cc(CCN2CCN(C(=O)OC(C)(C)C)CC2)ccc1C#N
Reaction time: 0.17 h

Procedure:
2-(Methyloxy)-4-(2-oxoethyl)benzonitrile (200 mg, 1.142 mmol), tert-butyl piperazine-1-carboxylate (532 mg, 2.85 mmol), and SODIUM CYANOBOROHYDRIDE (717 mg, 11.4 mmol) were combined in a 50 mL Flask and dissolved in MeOH. The resulting mixture was then stirred for 10 minutes followed by addition of few drops of AcOH. The mixture was stirred for overnight. The reaction mixture was concentrated to dryness, re-dissolved in EtOAc and washed with saturated NaHCO3 solution, brine, and the organic layer was dried over Na2SO4, filtered and concentrated to dryness. The residue purified by MPLC to yield the title compound. LC-MS (IE, m/z): 346 [M+1]+;
Reaction SMILES: [NH:1]([C:3]1[N:8]([CH2:9][CH:10]([CH3:12])[CH3:11])[C:7](=[O:13])[N:6]([CH3:14])[C:5](=[O:15])[CH:4]=1)[NH2:2].[Cl:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][CH:21]=[C:20]2[CH:26]=O.[CH:28]([C:30]1[N:34]([CH3:35])[CH:33]=[C:32]([C:36]([OH:38])=[O:37])[CH:31]=1)=O>>[Cl:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][CH:21]=[C:20]2[CH2:26][N:2]1[C:28]([C:30]2[N:34]([CH3:35])[CH:33]=[C:32]([C:36]([OH:38])=[O:37])[CH:31]=2)=[C:4]2[C:3]([N:8]([CH2:9][CH:10]([CH3:11])[CH3:12])[C:7](=[O:13])[N:6]([CH3:14])[C:5]2=[O:15])=[N:1]1
Reactant: Cn1cc(C(=O)O)cc1C=O
Reactant: O=Cc1c[nH]c2ccc(Cl)cc12
Reactant: CC(C)Cn1c(NN)cc(=O)n(C)c1=O
Product: CC(C)Cn1c(=O)n(C)c(=O)c2c(-c3cc(C(=O)O)cn3C)n(Cc3c[nH]c4ccc(Cl)cc34)nc21

Procedure:
This compound was made following the procedure described above, starting with 6-hydrazino-1-isobutyl-3-methylpyrimidine-2,4(1H,3H)-dione, and condensing first with 5-chloro-1H-indole-3-carbaldehyde, followed by 5-formyl-1-methyl-1H-pyrrole-3-carboxylic acid. Mass: 509.18 (M+H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:18]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[C:10]([NH2:19])[C:9]=2[N:8]=[C:7]1[CH2:20][CH2:21][O:22][CH3:23].[C:24]1([C:34](O)=[O:35])[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=[CH:26][N:25]=1>>[NH2:19][C:10]1[C:9]2[N:8]=[C:7]([CH2:20][CH2:21][O:22][CH3:23])[N:6]([CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:34]([C:24]3[C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[CH:27]=[CH:26][N:25]=3)=[O:35])[C:18]=2[C:17]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:11]=1
Reactant: COCCc1nc2c(N)nc3ccccc3c2n1CCCCN
Reactant: O=C(O)c1nccc2ccccc12
Product: COCCc1nc2c(N)nc3ccccc3c2n1CCCCNC(=O)c1nccc2ccccc12

Procedure:
According to the general method of Example 50, 1-(4-aminobutyl)-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin4-amine and isoquinoline-1-carboxylic acid were combined to provide N1-{4-[4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]butyl}-1-isoquinolinecarboxamide as a yellow crystalline solid, m.p. 61.0-63.0° C. 1H NMR (300 MHz, DMSO-d6) δ 8.94 (t, J=5.9 Hz, 1H), 8.87 (d, J=8.5 Hz, 1H), 8.51 (d, J=5.6 Hz, 1H), 8.05-7.96 (m, 3H), 7.84-7.96 (m, 1H), 7.70-7.65 (m, 1H), 7.61 (dd, J=8.3, 1.1 Hz, 1H), 7.37 (dt, J=7.7, 1.0 Hz, 11H), 7.19 (dt, J=7.6, 1.2 Hz, 11H), 6.53 (broad s, 2H), 4.60 (t, J=7.2 Hz, 2H), 3.81 (t, J=6.7 Hz, 2H), 3.41 (m, 2H), 3.28-3.12 (m, 5H), 1.92-1.76 (m, 4H); MS (EI) m/e 468.2261 (468.2274 calcd for C27H28N6O2).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[N:4]=[C:5](F)[C:6]([CH3:12])=[N:7]2.[CH:14]1([NH2:17])[CH2:16][CH2:15]1>>[Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[N:4]=[C:5]([NH:17][CH:14]1[CH2:16][CH2:15]1)[C:6]([CH3:12])=[N:7]2
Reactant: NC1CC1
Reactant: Cc1nc2cccc(Br)c2nc1F
Product: Cc1nc2cccc(Br)c2nc1NC1CC1
Yield: 82.8 %

Procedure:
This compound (1.06 g, 83% yield) as a light yellow crystalline solid was prepared similarly to that described in the preparation of Example 174a, using 5-bromo-3-fluoro-2-methylquinoxaline (Example 126f; 1.11 g, 4.60 mmol) and cyclopropanamine (Aldrich; 1.50 mL, 21.65 mmol) as starting materials. 1H NMR (400 MHz, CDCl3) δ ppm 7.84 (1H, dd, J=7.6, 1.2 Hz), 7.78 (1H, dd, J=8.2, 1.2 Hz), 7.19-7.26 (1H, m), 5.12 (1H, br. s.), 3.04-3.14 (1H, m), 2.47-2.55 (3H, m), 0.93-1.01 (2H, m), 0.60-0.68 (2H, m). m/z (ESI, +ve) 278/280 (M+H)+.
Reaction SMILES: [NH2:1][C@H:2]([C:6]([OH:8])=[O:7])[CH2:3][CH2:4][OH:5].[C:9]([Cl:12])(=[O:11])[CH3:10]>C(O)(=O)C>[ClH:12].[C:9]([O:5][CH2:4][CH2:3][C@@H:2]([C:6]([OH:8])=[O:7])[NH2:1])(=[O:11])[CH3:10]
Reactant: CC(=O)Cl
Reactant: N[C@@H](CCO)C(=O)O
Solvent: CC(=O)O
Product: CC(=O)OCC[C@H](N)C(=O)O
Product: Cl
Reaction time: 2 h
Yield: 75 %

Procedure:
72 g (0.60 mol) of L-homoserine are added in portions to a solution of 500 ml of acetic acid and 500 ml of acetyl chloride while cooling at <30° C. After 2 hours' stirring, no homoserine can be detected by TLC. The precipitate is filtered off with suction and washed with acetic acid. Drying in vacuo yields 90.1 g (75%) of O-acetyl-L-homo-serine hydrochloride.
Reaction SMILES: [C:1]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:6]=[CH:5][C:4]([C:7]2([C:10]([OH:12])=[O:11])[CH2:9][CH2:8]2)=[CH:3][CH:2]=1.S(Cl)(Cl)=O.S(=O)(=O)(O)O.[CH:28](O)([CH3:30])[CH3:29]>>[CH:28]([O:11][C:10]([C:7]1([C:4]2[CH:5]=[CH:6][C:1]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)=[CH:2][CH:3]=2)[CH2:9][CH2:8]1)=[O:12])([CH3:30])[CH3:29]
Reactant: O=C(O)C1(c2ccc(-c3ccccc3)cc2)CC1
Reactant: CC(C)O
Agent: O=S(=O)(O)O
Solvent: O=S(Cl)Cl
Product: CC(C)OC(=O)C1(c2ccc(-c3ccccc3)cc2)CC1
Temperature: 65 °C

Procedure:
1-(Biphenyl-4-yl)cyclopropanecarboxylic acid (10 g, 42 mmol), isopropanol (100 mL), thionyl chloride (6.8 mL, 92 mmol) were heated to 65° C. for 4 hours. Sulfuric acid (20 mL) was added and heated at 65° C. overnight. The product is extracted with CH2Cl2 and water (2×) dried and evaporated to yield 10.8 g of the title compound.
Reaction SMILES: [CH3:1][C:2]([CH2:6][OH:7])([CH2:4][OH:5])[CH3:3].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:20]([O:27][C:28]1[CH:35]=[CH:34][C:31]([CH:32]=O)=[CH:30][C:29]=1[O:36][CH2:37][CH2:38][CH3:39])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C1(C)C=CC=CC=1>[CH2:20]([O:27][C:28]1[CH:35]=[CH:34][C:31]([CH:32]2[O:7][CH2:6][C:2]([CH3:3])([CH3:1])[CH2:4][O:5]2)=[CH:30][C:29]=1[O:36][CH2:37][CH2:38][CH3:39])[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: CC(C)(CO)CO
Reactant: CCCOc1cc(C=O)ccc1OCc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CCCOc1cc(C2OCC(C)(C)CO2)ccc1OCc1ccccc1
Temperature: 25 °C
Yield: 64.8 %

Procedure:
1.45 g (13.9 mmol) of neopentylglycol and 88 mg (0.46 mmol) of p-toluenesulfonic acid monohydrate were added to a solution of 1.25 g (4.63 mmol) of 4-benzyloxy-3-propoxybenzaldehyde in 50 ml of toluene and then refluxed for 1 hour under a water separator. Thereafter, the reaction mixture was cooled to room temperature and partitioned between toluene and a saturated sodium bicarbonate solution, and the organic phase was washed several times with water, dried over magnesium sulfate, filtered and evaporated down. Crystallization of the residue from 10 ml of diethyl ether gave 1.07 g of 2-(4-benzyloxy-3-propoxyphenyl)-5,5-dimethyl-1,3-dioxane.
Reaction SMILES: F[C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8]CC)=[O:7])=[CH:4][CH:3]=1.[C:13]([S:17][Na])([CH3:16])([CH3:15])[CH3:14]>CN(C=O)C>[C:13]([S:17][C:2]1[CH:3]=[CH:4][C:5]([C:6]([OH:8])=[O:7])=[CH:11][CH:12]=1)([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)S[Na]
Reactant: CCOC(=O)c1ccc(F)cc1
Solvent: CN(C)C=O
Product: CC(C)(C)Sc1ccc(C(=O)O)cc1
Temperature: 80 °C
Reaction time: 20 h

Procedure:
Ethyl 4-fluorobenzoate (1.5 g, 8.9 mmol) and tert-butylsulfanylsodium (2.00 g, 17.8 mmol) were combined in DMF (10 mL). The reaction mixture was heated at 80° C. for 2 hours. A large amount of precipitate formed and an additional 15 mL of DMF was added and the reaction mixture was stirred for an additional 20 hours at 80° C. The reaction mixture was partitioned between ethyl acetate (100 mL) and water (100 mL). The organic layer was discarded, and the water layer was made acidic with 4M hydrochloric acid. The water layer was extracted two times with ethyl acetate. The combined extracts were dried over sodium sulfate, filtered, and evaporated to dryness to yield 4-(tert-butylthio)benzoic acid as a colorless oil. ESI-MS m/z calc. 210.3, found 211.1 (M+1)+. Retention time: 1.74 minutes (3 min run).
Reaction SMILES: Br[C:2]1[CH:6]=[CH:5][N:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=2)[CH:3]=1.[Cl:13][C:14]1[CH:15]=[C:16](B(O)O)[CH:17]=[CH:18][CH:19]=1.C(=O)([O-])[O-].[K+].[K+].CCOC(C)=O>COCCOC.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:13][C:14]1[CH:19]=[C:18]([C:2]2[CH:6]=[CH:5][N:4]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=3)[CH:3]=2)[CH:17]=[CH:16][CH:15]=1
Reactant: OB(O)c1cccc(Cl)c1
Reactant: Brc1ccn(-c2ccccn2)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: O
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: Clc1cccc(-c2ccn(-c3ccccn3)c2)c1
Temperature: 84 °C

Procedure:
2-(3-Bromo-1H-pyrrol-1-yl)pyridine (1.34 g, 2 mmol), 3-chlorophenylboronic acid (0.62 g, 4 mmol), Pd(PPh3)4 (116 mg, 0.1 mmol) and potassium carbonate (560 mg, 4 mmol) were dissolved in a mixture of DME (18 mL) and H2O (2 mL) and degassed for 15 min with Ar (g). The reaction mixture was then heated at 84° C. for 18 h. At this time, a further 0.25 eq. of 3-chlorophenylboronic acid (0.16 g, 1 mmol) was added and heating was continued. After a total of 42 h, the reaction mixture was cooled to rt, H2O (40 mL) and EtOAc (40 mL) were added and the reaction mixture shaken, the EtOAc layer was separated and the aqueous layer shaken with EtOAc (2×30 mL). The combined organic layers were dried over Na2SO4 and concentrated to a yellow oil. This was purified by liquid chromatography on silica gel eluting with EtOAc:hexane (3:7) to afford a white solid that was further purified by preparative HPLC to afford 2-[3-(3-chlorophenyl)-1H-pyrrol-1-yl]pyridine as a white solid. 1H NMR (CD3Cl, 300 MHz) δ 8.52-8.54 (1H, m), 7.61 (1H, ddd), 7.35-7.37 (1H, m), 7.28 (1H, s), 7.15-7.24 (3H, m), 6.99 (1H, ddd), 6.86 (1H, d), 6.47-6.48 (1H, m), 6.41 (1H, dd).). MS (ESI) 255 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][C:5](/[CH:6]=[N:7]/[C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH2:10][O:11][C:12]3=[O:17])=[CH:4][CH:3]=1.[CH3:20][N:21]1[C:25]([CH3:26])=[C:24]([CH3:27])[N:23]=[C:22]1[CH:28]=O.[O-:30][CH2:31][CH3:32].[Na+].C(O)C>C(OCC)(=O)CC>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:6]2[CH:28]([C:22]3[N:21]([CH3:20])[C:25]([CH3:26])=[C:24]([CH3:27])[N:23]=3)[C:31](=[O:30])[C:32]3[C:13]([C:12]([O:11][CH2:10][CH3:9])=[O:17])=[CH:14][CH:15]=[CH:16][C:8]=3[NH:7]2)=[CH:18][CH:19]=1
Reactant: CC[O-]
Reactant: O=C1OCc2c(/N=C/c3ccc(F)cc3)cccc21
Reactant: Cc1nc(C=O)n(C)c1C
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(=O)CC
Product: CCOC(=O)c1cccc2c1C(=O)C(c1nc(C)c(C)n1C)C(c1ccc(F)cc1)N2
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 18 %

Procedure:
A mixture of compound (E)-4-(4-fluorobenzylideneamino)isobenzofuran-1(3H)-one (510 mg, 2.0 mmol) and 1,4,5-trimethyl-1H-imidazole-2-carbaldehyde (304 mg, 2.2 mmol) in ethyl propionate (20 mL) was cooled to 0° C. Then a solution of sodium ethoxide in ethanol (sodium (184 mg, 8.0 mmol) in ethanol (10 mL)) was added dropwise. After the addition, the mixture was stirred at room temperature for 2.5 hr. The mixture was quenched with water (20 mL) and solvent was removed under reduced pressure. The residue was dissolved in water and extracted with ethyl acetate (100 mL×3), then the extraction was washed with water, brine and evaporated, the crude product was purified by chromatography to obtain a yellow solid (150 mg, yield: 18%). LC-MS (ESI) m/z: 421 (M+1)+.