Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:29])=[C:14]([C:24](OCC)=[O:25])[C:15](=[O:23])[N:16]3[CH2:19][CH2:20][CH2:21][OH:22])=[N:11][CH:10]=2)=[CH:4][CH:3]=1.[NH2:30][CH2:31][CH2:32][N:33]1[CH2:37][CH2:36][NH:35][C:34]1=[O:38]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:29])=[C:14]([C:24]([NH:30][CH2:31][CH2:32][N:33]4[CH2:37][CH2:36][NH:35][C:34]4=[O:38])=[O:25])[C:15](=[O:23])[N:16]3[CH2:19][CH2:20][CH2:21][OH:22])=[N:11][CH:10]=2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCCO)c1=O
Reactant: NCCN1CCNC1=O
Product: O=C(NCCN1CCNC1=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCCO)c1=O
Yield: 31 %

Procedure:
In a similar manner to that described in example 196, from ethyl 7-[(4-fluorophenyl)methyl]-4-hydroxy-1-(3-hydroxypropyl)-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate (60 mg, 0.15 mmol) and 1-(2-aminoethyl)-2-imidazolidinone (0.4 mL) was prepared 7-[(4-fluorophenyl)methyl]-4-hydroxy-1-(3-hydroxypropyl)-2-oxo-N-[2-(2-oxo-1-imidazolidinyl)ethyl]-1,2-dihydro-1,5-naphthyridine-3-carboxamide (22 mg, 31% yield) as a white solid after purification by reverse phase HPLC. 1H NMR (CDCl3) δ 10.25 (br s, 1 H), 8.55 (s, 1 H), 7.46 (s, 1 H), 7.16-7.12 (m, 2 H), 7.03-7.12 (m, 2 H), 4.73 (br s, 1 H), 4.29 (br s, 2 H), 4.11 (s, 2 H), 3.64-3.39 (m, 10 H), 1.79 (m, 2 H); HRMS m/z calcd for C24H27N5O5F: 484.1996. Found: 484.1997.
Reaction SMILES: CC(O[C:5]([CH3:7])=[O:6])=O.[CH3:8][C@H:9]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C@H:10]1[NH2:18].[OH-].[K+]>C1(C)C=CC=CC=1.O>[CH3:8][C@H:9]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C@H:10]1[NH:18][C:5](=[O:6])[CH3:7]
Reactant: CC(=O)OC(C)=O
Reactant: C[C@H]1Cc2ccccc2[C@H]1N
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Product: CC(=O)N[C@@H]1c2ccccc2C[C@@H]1C
Temperature: 90 °C
Reaction time: 2 h

Procedure:
To a solution of Ac2O (1.45 g, 14.2 mmole) in toluene (12 ml), was added dropwise a solution of (rac), (cis)-2-methyl-1-aminoindan (Ex. 39, 1.85 g, 12.6 mmole). The mixture was heated at 90° C. for 15 min, cooled to 70° C., and a solution of 1.1 g KOH in 8.3 ml water was added. The reaction mixture was stirred at ambient temperature for 2 hrs; the solid was collected by filtration, washed with toluene (10 ml), dried and crystallized from hexane:EtOAc, to give 1.85 g (9.8 mmole, 78%), mp: 146°-7° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH3:29])[C:5]2[N:10]=[C:9]([C:11]3[N:15]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=4[Cl:22])[N:14]=[C:13]([C:23]([F:26])([F:25])[F:24])[CH:12]=3)[O:8][C:7](=[O:27])[C:6]=2[CH:28]=1.O.[NH2:31][NH2:32].O1CCCC1>O>[Cl:1][C:2]1[CH:3]=[C:4]([CH3:29])[C:5]([NH:10][C:9]([C:11]2[N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[Cl:22])[N:14]=[C:13]([C:23]([F:26])([F:24])[F:25])[CH:12]=2)=[O:8])=[C:6]([C:7]([NH:31][NH2:32])=[O:27])[CH:28]=1
Reactant: NN
Reactant: Cc1cc(Cl)cc2c(=O)oc(-c3cc(C(F)(F)F)nn3-c3ccccc3Cl)nc12
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(Cl)cc(C(=O)NN)c1NC(=O)c1cc(C(F)(F)F)nn1-c1ccccc1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 0.88 g of 6-chloro-2-[1-(2-chlorophenyl)-3-trifluoromethyl-1H-pyrazol-5-yl]-8-methyl-4H-3,1-benzoxazine-4-one, 0.19 ml of hydrazine monohydrate and 3 ml of tetrahydrofuran was stirred at room temperature for 2 hours. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate three times. The organic layers were combined, washed with an aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain 0.94 g of N-[4-chloro-2-(hydrazinocarbonyl)-6-methylphenyl]-1-(2-chlorophenyl)-3-trifluoromethyl-1H-pyrazole-5-carboxamide of the formula:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:10]([C:11]([C:13]2[CH:18]=[CH:17][C:16]3[O:19][CH2:20][O:21][C:15]=3[CH:14]=2)=[O:12])=[CH:9][CH:8]=[C:7]([CH2:22][OH:23])[N:6]=1)=[O:4].C(N(C(C)C)C(C)C)C.[CH3:33][Si:34]([CH3:41])([CH3:40])[CH2:35][CH2:36][O:37][CH2:38]Cl>ClCCl>[CH3:1][O:2][C:3]([C:5]1[C:10]([C:11]([C:13]2[CH:18]=[CH:17][C:16]3[O:19][CH2:20][O:21][C:15]=3[CH:14]=2)=[O:12])=[CH:9][CH:8]=[C:7]([CH2:22][O:23][CH2:38][O:37][CH2:36][CH2:35][Si:34]([CH3:41])([CH3:40])[CH3:33])[N:6]=1)=[O:4]
Reactant: C[Si](C)(C)CCOCCl
Reactant: COC(=O)c1nc(CO)ccc1C(=O)c1ccc2c(c1)OCO2
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1nc(COCOCC[Si](C)(C)C)ccc1C(=O)c1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 17 h

Procedure:
To a dichloromethane(9 ml) solution of 6-hydroxymethyl-3-(3,4-methylenedioxyphenylcarbonyl)pyridine-2-carboxylic acid methyl ester(1.71 g,4.50 mmol) were added ethyldiisopropylamine(3.9 ml) and 2-trimethylsilylethoxymethyl chloride(2.4 ml) at room temperature. The mixture was stirred at room temperature for 17 h, partitioned between AcOEt and water, The organic layer was washed with a saturated aqueous solution of NaHCO3 and brine, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by MPLC(E. Merck lobar column Kieselgel 60/hexane:AcOEt=3:1 to 1:1) to give 6-(2-trimethylsilylethoxymethoxymethyl)-3-(3,4-methylenedioxyphenylcarbonyl)pyridine-carboxylic acid methyl ester(1.44 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:16][CH3:17])=[C:6]([CH:8]2[CH2:13][C:12](=O)[CH2:11][C:10](=[O:15])[CH2:9]2)[CH:7]=1.C([O-])(=O)C.[NH4+:22]>C(O)C>[NH2:22][C:12]1[CH2:13][CH:8]([C:6]2[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=2[O:16][CH3:17])[CH2:9][C:10](=[O:15])[CH:11]=1
Reactant: COc1ccc(Cl)cc1C1CC(=O)CC(=O)C1
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: CCO
Product: COc1ccc(Cl)cc1C1CC(=O)C=C(N)C1

Procedure:
A solution of 5-(5-chloro-2-methoxyphenyl)cyclohexane-1,3-dione (5.0 g) and ammonium acetate (4.6 g) in ethanol (100 ml) was refluxed for 20 hours. Under reduced pressure, the solvent was evaporated, and the residue was dissolved in ethyl acetate. The solution was washed with water and saturated brine, and dried with magnesium sulfate. Under reduced pressure, the solvent was evaporated to give 1-amino-5-(5-chloro-2-methoxyphenyl)cyclohexen-3-one, which was dissolved in ethanol (120 ml) and toluene (210 ml). To the solution were added 3-oxobutylaldehydedimethylacetal (6.5 g) and powdery potassium hydroxide (0.92 g), and the mixture was refluxed. To the mixture was added powdery potassium hydroxide (0.19 g), 30 minutes later; were added powdery potassium hydroxide (0.19 g) and 3-oxobutylaldehydedimethylacetal (0.52 g), 1 hour later; and was added powdery potassium hydroxide (0.19 g), 1.5 hours later, and the mixture was stirred at the same temperature for 2 hours and cooled. Under reduced pressure, the solvent was evaporated, and to the residue was added ethyl acetate. The organic layer was washed with water and saturated brine, and dried with magnesium sulfate. Under reduced pressure, ethyl acetate was evaporated, and the residue was purified with silica gel column (ethyl acetate-hexane) to give 7-(5-chloro-2-methoxyphenyl)-4-methyl-5,6,7,8-tetrahydroquinolin-5-one (2.2 g) as colorless crystals.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:4]=[C:5]([CH:14]=[CH:15][CH:16]=1)[CH2:6][C:7]1[N:12]=[CH:11][NH:10][C:9](=O)[CH:8]=1.P(Cl)(Cl)([Cl:21])=O>>[F:1][C:2]([F:18])([F:17])[C:3]1[CH:4]=[C:5]([CH:14]=[CH:15][CH:16]=1)[CH2:6][C:7]1[N:12]=[CH:11][N:10]=[C:9]([Cl:21])[CH:8]=1
Reactant: O=c1cc(Cc2cccc(C(F)(F)F)c2)nc[nH]1
Reactant: O=P(Cl)(Cl)Cl
Product: FC(F)(F)c1cccc(Cc2cc(Cl)ncn2)c1

Procedure:
Under nitrogen atmosphere, 6-(3-trifluoromethylbenzyl)pyrimidin-4-one (7.0 g, 0.027 mol) is dissolved in phosphorus oxychloride (30 ml) and is refluxed for 1.5 hours. After cooling the solution is concentrated under reduced pressure. The solid is then dissolved in ethyl acetate, washed with water, saturated brine, dried and the crude product purified by flash column chromatography to give 6-(3-trifluoromethylbenzyl)-4-chloro-pyrimidine (6.3 g).
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][N:7]=[C:6]2[NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[CH:15]=1.[Na].[SH:22][C:23]1[N:24]([CH3:28])[CH:25]=[CH:26][N:27]=1.SC1N(C)C=CN=1.[O-]CC.[Na+]>C(O)C>[CH3:20][C:16]1[CH:15]=[C:14]([CH:19]=[CH:18][CH:17]=1)[NH:13][C:6]1[C:5]2[C:10](=[CH:11][CH:12]=[C:3]([CH2:2][S:22][C:23]3[N:24]([CH3:28])[CH:25]=[CH:26][N:27]=3)[CH:4]=2)[N:9]=[CH:8][N:7]=1
Reactant: Cc1cccc(Nc2ncnc3ccc(CBr)cc23)c1
Reactant: Cn1ccnc1S
Agent: CC[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CCO
Product: Cc1cccc(Nc2ncnc3ccc(CSc4nccn4C)cc23)c1
Yield: 65 %

Procedure:
Using an analogous procedure to that described in Example 34, 6-bromomethyl-4-(3-methylanilino)quinazoline was reacted with 2-mercapto-1-methylimidazole sodium salt [prepared by the reaction of 2-mercapto-1-methylimidazole and sodium ethoxide in ethanol] to give 4-(3-methylanilino)-6-(N-methylimidazol-2-ylthiomethyl)quinazoline in 65% yield, m.p. 137-139° C.;
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]2[N:9]([S:26]([C:29]3[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=3)(=[O:28])=[O:27])[C:10]([C:12]3[C:16]4=[N:17][C:18]([O:23][CH3:24])=[C:19]([O:21][CH3:22])[CH:20]=[C:15]4[N:14]([CH3:25])[CH:13]=3)=[CH:11][C:4]=12.[NH2:36][CH2:37][CH:38]1[CH2:43][CH2:42][N:41]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[CH2:40][CH2:39]1>>[CH3:24][O:23][C:18]1[N:17]=[C:16]2[C:12]([C:10]3[N:9]([S:26]([C:29]4[CH:30]=[CH:31][C:32]([CH3:35])=[CH:33][CH:34]=4)(=[O:28])=[O:27])[C:5]4=[N:6][CH:7]=[CH:8][C:3]([CH2:2][NH:36][CH2:37][CH:38]5[CH2:43][CH2:42][N:41]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[CH2:40][CH2:39]5)=[C:4]4[CH:11]=3)=[CH:13][N:14]([CH3:25])[C:15]2=[CH:20][C:19]=1[O:21][CH3:22]
Reactant: COc1cc2c(nc1OC)c(-c1cc3c(CCl)ccnc3n1S(=O)(=O)c1ccc(C)cc1)cn2C
Reactant: CC(C)(C)OC(=O)N1CCC(CN)CC1
Product: COc1cc2c(nc1OC)c(-c1cc3c(CNCC4CCN(C(=O)OC(C)(C)C)CC4)ccnc3n1S(=O)(=O)c1ccc(C)cc1)cn2C
Yield: 48.7 %

Procedure:
The product is prepared by following the procedure described in example 52c, starting with 0.3 g of 3-[4-chloromethyl-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-2-yl]-5,6-dimethoxy-1-methyl-1H-pyrrolo[3,2-b]pyridine and 0.315 g of 4-(aminomethyl)-1-N-Boc-piperidine instead of the N-Boc-ethylenediamine used in example 52c. 0.197 g of tert-butyl 4-({[2-(5,6-dimethoxy-1-methyl-1H-pyrrolo[3,2-b]pyridin-3-yl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-ylmethyl]amino}methyl)piperidine-1-carboxylate is obtained with the following characteristics:
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[O:9][C:7](=[O:8])[CH2:6][C:4](=[O:5])[O:3]1.N1C=CC=CC=1.[CH3:17][O:18][CH2:19][C:20](Cl)=[O:21]>ClCCl>[CH3:17][O:18][CH2:19][C:20]([CH:6]1[C:7](=[O:8])[O:9][C:2]([CH3:10])([CH3:1])[O:3][C:4]1=[O:5])=[O:21]
Reactant: COCC(=O)Cl
Reactant: CC1(C)OC(=O)CC(=O)O1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COCC(=O)C1C(=O)OC(C)(C)OC1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 84.7 %

Procedure:
To a solution of Meldrum's acid (30 g, 0.208 mol) in dichloromethane (420 mL) was added pyridine (33.7 mL, 0.416 mol) over 3 minutes in an ice-methanol bath under nitrogen atmosphere (−9° C.). To this mixture was added dropwise a solution of methoxyacetyl chloride (24.8 g) in dichloromethane (180 mL) over 1 hour period at the temperature. After addition, the reaction mixture was stirred at the temperature for 1 hour and at ambient temperature for 2 hours. The mixture was quenched with 1N hydrochoric acid (600 mL). The organic layer was separated and the aqueous layer was extracted with dichloromethane. The combined organic layer was washed with brine, dried over magnesium sulfate, and evaporated in vacuo to give 5-(methoxyacetyl)-2,2-dimethyl-1,3-dioxane-4,6-dione as dark orange oil (38.1 g, 84.7%).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH:9]2[CH:14]3[CH2:15][CH2:16][N:11]([CH2:12][CH2:13]3)[CH2:10]2)=[CH:4][CH:3]=1.[NH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[N:11]12[CH2:16][CH2:15][CH:14]([CH2:13][CH2:12]1)[CH:9]([NH:8][C:5]1[CH:6]=[CH:7][C:2]([NH:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:3][CH:4]=1)[CH2:10]2
Reactant: Nc1ccccc1
Reactant: Ic1ccc(NC2CN3CCC2CC3)cc1
Product: c1ccc(Nc2ccc(NC3CN4CCC3CC4)cc2)cc1

Procedure:
The product of Example 35A (200 mg, 0.61 mmol) was treated with aniline (Aldrich, 93 mg, 1 mmol) according to the procedure of Example 17A. The title product was purified by chromatography (SiO2, CH2Cl2:MeOH:NH3.H2O, 90:10:2, Rf. 0.20) as an oil (120 mg, yield, 68%). 1H NMR (MeOH-d4, 300 MHz) δ 1.45–1.57 (m, 1H), 1.72–1.84 (m, 2H), 1.93–2.06 (m, 2H), 2.63 (ddd, J=12.9, 5.1, 2.7 Hz, 1H), 2.82–2.99 (m, 4H), 3.30–3.40 (m, 1H), 3.56–3.64 (m, 1H), 6.56–7.13 (m, 9H) ppm. MS (DCl/NH3) m/z 294 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[N:11][N:10]([CH3:13])[C:9]=2[CH2:14][O:15][C:16]2[CH:20]=[C:19]([C:21]([OH:23])=O)[O:18][N:17]=2)=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:55][CH:56]1[CH2:61][CH2:60][O:59][CH2:58][CH2:57]1>CN(C=O)C>[O:59]1[CH2:60][CH2:61][CH:56]([NH:55][C:21]([C:19]2[O:18][N:17]=[C:16]([O:15][CH2:14][C:9]3[N:10]([CH3:13])[N:11]=[N:12][C:8]=3[C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[CH:20]=2)=[O:23])[CH2:57][CH2:58]1
Reactant: NC1CCOCC1
Reactant: Cn1nnc(-c2ccc(F)cc2)c1COc1cc(C(=O)O)on1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cn1nnc(-c2ccc(F)cc2)c1COc1cc(C(=O)NC2CCOCC2)on1
Temperature: 25 °C
Reaction time: 1 h
Yield: 67.1 %

Procedure:
To a solution of 3-[5-(4-fluoro-phenyl)-3-methyl-3H-[1,2,3]triazol-4-ylmethoxy]-isoxazole-5-carboxylic acid (40 mg, 0.13 mmol) and TBTU (64.6 mg, 0.20 mmol) in DMF (2.0 mL) was added DIPEA (106.9 μL, 0.63 mmol). Then 4-aminotetrahydropyran (14 mg, 0.14 mmol) was added and the mixture was stirred at room temperature under Ar for 1 h. The mixture was then evaporated and purification by chromatography (silica, 50 to 100% ethyl acetate in heptane) afforded the title compound (35 mg, 70%) as a white solid. MS: m/e=402.2 [M+H]+.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:11][C:10]([CH3:13])([CH3:12])[CH:9]3[O:14][CH:8]3[C:7]=2[CH:15]=1)#[N:2].[C:16]([NH:24][NH2:25])(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CCCCCC.C(O)C>[C:16]([NH:24][NH:25][C@@H:8]1[C:7]2[CH:15]=[C:3]([C:1]#[N:2])[CH:4]=[CH:5][C:6]=2[O:11][C:10]([CH3:13])([CH3:12])[C@H:9]1[OH:14])(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CC1(C)Oc2ccc(C#N)cc2C2OC21
Reactant: NNC(=O)c1ccccc1
Solvent: CCCCCC
Solvent: CCO
Product: CC1(C)Oc2ccc(C#N)cc2[C@@H](NNC(=O)c2ccccc2)[C@@H]1O
Yield: 54.1 %

Procedure:
The procedure of Reference Example 2 was repeated except that 1.3 g of 6-cyano-3,4-epoxy-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran and 1.0 g of benzoylhydrazine was used, and 1.18 g of trans-4-(2-benzoylhydrazino)-6-cyano-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-3-ol was obtained as white crystals, m.p. 197°-199° C. (recrystallized from hexane-ethanol).
Reaction SMILES: [CH2:1]([C:13]1[NH:14][C:15]2[C:20]([CH:21]=1)=[CH:19][CH:18]=[C:17]([C:22]([OH:24])=[O:23])[CH:16]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].Cl.[CH2:26](O)[CH3:27]>>[CH2:1]([C:13]1[NH:14][C:15]2[C:20]([CH:21]=1)=[CH:19][CH:18]=[C:17]([C:22]([O:24][CH2:26][CH3:27])=[O:23])[CH:16]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCO
Reactant: CCCCCCCCCCCCc1cc2ccc(C(=O)O)cc2[nH]1
Agent: Cl
Product: CCCCCCCCCCCCc1cc2ccc(C(=O)OCC)cc2[nH]1

Procedure:
A solution of 2-(n-dodecyl)indole-6-carboxylic acid (14.0 g) in ethanol (70 ml) containing a solution of hydrogen chloride gas in ethanol (100 ml, of strength 35% w/v) was refluxed for 5 hours. The solid, which crystallised on cooling, was collected, washed with light petroleum ether (b.p. 40°-60° C.) and was recrystallised from ethanol to give ethyl 2-(n-dodecyl)-indole-6-carboxylate (9.1 g), in the form of a pale pink solid, m.p. 83°-86° C.
Reaction SMILES: [O:1]=[C:2]1[N:6]([CH:7]([CH3:18])[C:8]([O:10]CC2C=CC=CC=2)=[O:9])[CH2:5][CH2:4][O:3]1.[H][H]>[Pd].C(O)C>[O:1]=[C:2]1[N:6]([CH:7]([CH3:18])[C:8]([OH:10])=[O:9])[CH2:5][CH2:4][O:3]1
Reactant: CC(C(=O)OCc1ccccc1)N1CCOC1=O
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CC(C(=O)O)N1CCOC1=O
Reaction time: 3 h
Yield: 100.5 %

Procedure:
A 25 mL round bottom flask under an atmosphere of nitrogen was charged with 0.030 g (0.028 mmol) of 10 weight percent palladium on activated carbon and wet with 2 mL of ethanol. Next, a solution of 0.37 g (1.5 mmol) of benzyl 2-(2-oxo-1,3-oxazolidin-3-yl)propanoate from step B above in 10 mL of ethanol was added and the mixture placed under 1 atmosphere of hydrogen. The reaction was stirred for 3 h then filtered through a pad of Celite®. The pad was washed with 20 mL of ethanol and the filtrate was evaporated in vacuo to afford the title compound as a colorless solid (0.24 g, quantitative yield). 1H-NMR (500 MHz, CD3OD) δ: 4.60-4.30 (m, 3H), 3.80-3.60 (m, 2H), 1.45 (d, J=3.5, 3H). LC-MS: m/z (ES) 160 (MH)+.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[N:20]3[N:21]=[CH:22][C:23]([OH:25])=[CH:24][C:19]3=[C:18]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:17]=2[CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([F:39])[C:34]=2[CH3:40])=[O:15])[CH2:10][CH2:9]1)=O)(C)(C)C.Cl.O1CCOCC1>C(Cl)Cl>[F:39][C:35]1[C:34]([CH3:40])=[C:33]([CH:38]=[CH:37][CH:36]=1)[CH2:32][C:17]1[C:18]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[C:19]2[CH:24]=[C:23]([OH:25])[CH:22]=[N:21][N:20]2[C:16]=1[C:14]([N:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1)=[O:15]
Reactant: Cc1c(F)cccc1Cc1c(-c2ccccc2)c2cc(O)cnn2c1C(=O)N1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: Cc1c(F)cccc1Cc1c(-c2ccccc2)c2cc(O)cnn2c1C(=O)N1CCNCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.1 %

Procedure:
The compound of step 3 (0.109 g, 0.20 mmol) was dissolved in 3 ml of anhydrous DCM and a 4 M solution of hydrogen chloride in dioxane (1.0 ml, 4.0 mmol) was added. After stirring at room temperature overnight, the mixture was evaporated to dryness under reduced pressure. The obtained solid was triturated several times with diethyl ether and dried in vacuo at 55° C. to give 0.073 g of the title compound in the form of [6-(3-fluoro-2-methyl-benzyl)-3-hydroxy-5-phenyl-pyrrolo[1,2-b]pyridazin-7-yl]-piperazin-1-yl-methanone hydrochloride as a greenish-yellow solid with the following characteristics:
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][CH:8]=[C:7]([I:11])[C:3]=1[C:4]([OH:6])=O.[F:12][C:13]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:14]=1[NH2:15].C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:1][C:2]1[N:10]=[CH:9][CH:8]=[C:7]([I:11])[C:3]=1[C:4]([NH:15][C:14]1[CH:16]=[CH:17][C:18]([F:20])=[CH:19][C:13]=1[F:12])=[O:6]
Reactant: Nc1ccc(F)cc1F
Reactant: O=C(O)c1c(I)ccnc1Cl
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccc(F)cc1F)c1c(I)ccnc1Cl
Reaction time: 63 h
Yield: 54.5 %

Procedure:
To a homogeneous mixture of 2-chloro-4-iodonicotinic acid (CB Research & Development, Inc., 0.58 g, 2.0 mmol) and 2,4-difluoroaniline (Aldrich, 0.21 mL, 2.0 mmol) in anhydrous DMF (7 mL) was added PyBroP (Novabiochem, 1.4 g, 3.1 mmol) followed by DIPEA (1.1 mL, 6.6 mmol). The mixture was stirred for 63 hours, and then partitioned between chloroform and 10% LiCl (aq). After the aqueous layer was extracted with chloroform, the combined organic layers were washed twice with 10% LiCl (aq), dried over anhydrous MgSO4, and then concentrated in vacuo. Purification of the residue by flash column chromatography (SiO2, eluting with 1:1 hexane/EtOAc) afforded the desired compound (0.43 g, 53%). MS(ESI+) m/z 395 (M+H)+.
Reaction SMILES: [CH3:1][NH:2][CH3:3].C(N(CC)C(C)C)(C)C.Br[CH2:14][C:15]1[CH:20]=[C:19]([C:21]([CH3:24])([CH3:23])[CH3:22])[CH:18]=[C:17]([Cl:25])[N:16]=1.C(=O)(O)[O-].[Na+]>O1CCCC1>[C:21]([C:19]1[CH:18]=[C:17]([Cl:25])[N:16]=[C:15]([CH2:14][N:2]([CH3:3])[CH3:1])[CH:20]=1)([CH3:24])([CH3:23])[CH3:22]
Reactant: CC(C)(C)c1cc(Cl)nc(CBr)c1
Reactant: CNC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)Cc1cc(C(C)(C)C)cc(Cl)n1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 100 %

Procedure:
Stir a solution of 2N dimethylamine (9.00 mL, 18.08 mmol) in tetrahydrofuran, N,N-diisopropylethylamine (2.80 g, 3.80 mL, 21.69 mmol) while adding a solution of 2-bromomethyl-4-tert-butyl-6-chloro-pyridine (1.90 g, 7.23 mmol) in tetrahydrofuran (20 mL). Stir for 2.5 hours at ambient temperature, dilute the reaction with aqueous sodium bicarbonate (80 mL) and extract the aqueous layer with ethyl acetate (3×75 mL). Pool, desiccate, filter and concentrate the organics to yield the title compound (99%) (1.64 g, 7.23 mmol). MS(ES), m/z 227 (M+1).
Reaction SMILES: C([O:5][C@@H:6]1[C@@H:10]([CH2:11][O:12][C:13](=[O:32])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[C:20]([O:22][C:23]2[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=2)=[O:21])[O:9][C@@:8]([SiH](C)C)([N:33]2[CH:41]=[C:39]([CH3:40])[C:37](=[O:38])[NH:36][C:34]2=[O:35])[CH2:7]1)(C)(C)C.F.N1C=CC=CC=1>ClCCl>[N+:29]([C:26]1[CH:27]=[CH:28][C:23]([O:22][C:20]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[C:13]([O:12][CH2:11][C@H:10]2[O:9][C@@H:8]([N:33]3[CH:41]=[C:39]([CH3:40])[C:37](=[O:38])[NH:36][C:34]3=[O:35])[CH2:7][C@@H:6]2[OH:5])=[O:32])=[O:21])=[CH:24][CH:25]=1)([O-:31])=[O:30]
Reactant: Cc1cn([C@@]2([SiH](C)C)C[C@H](OC(C)(C)C)[C@@H](COC(=O)c3ccccc3C(=O)Oc3ccc([N+](=O)[O-])cc3)O2)c(=O)[nH]c1=O
Agent: F
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1cn([C@H]2C[C@H](O)[C@@H](COC(=O)c3ccccc3C(=O)Oc3ccc([N+](=O)[O-])cc3)O2)c(=O)[nH]c1=O
Temperature: 25 °C
Reaction time: 5 h

Procedure:
O3′-tert.-butyldimethylsilyl-O5′-(2-(4-nitrophenoxycarbonyl)benzoyl)thymidine, PSNp-dT-Si (6f) (24.4 g, 39 mmol) was dissolved in dichloromethane (300 ml). Hydrogen fluoride in pyridine (65% HF, 12.6 ml, 450 mmol) was added and the mixture was stirred at ambient temperature for 5 hours. The reaction was quenched by the addition of solid calcium carbonate (25.9 g) and stirred for 1 hour. After removal of the solid material by filtration the organic phase was extracted with 5% sodium hydrogencarbonate solution (2 times 500 ml) and water (2 times 500 ml). The organic phase was dried over sodium sulfate and concentrated to a foam by evaporation. The foam was dissolved in dichloromethane (120 ml) and added dropwise to a mixture of hexanes and diethylether (8:2, v/v, 1500 ml). The precipitate was filtered off and washed with a small volume of hexanes. Further purification by column chromatography on silica gel (ethyl acetate/hexanes, gradient elution) afforded the product in 99.8% purity by RP-HPLC (18.4 g, 92%). ESI-MS (pos. mode) m/z 512 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[NH2:21])[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10][N:9]=1)=[O:6].[CH3:22][O:23][C:24](=[O:37])[CH2:25][CH2:26][C:27]1[CH:32]=[C:31]([CH3:33])[C:30]([CH:34]=O)=[C:29]([CH3:36])[CH:28]=1.OOS([O-])=O.[K+].O>CN(C=O)C>[CH3:22][O:23][C:24](=[O:37])[CH2:25][CH2:26][C:27]1[CH:32]=[C:31]([CH3:33])[C:30]([C:34]2[NH:1][C:2]3[CH:3]=[C:4]([C:5](=[O:6])[NH:7][C:8]4[C:17]5[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=5)[CH:11]=[CH:10][N:9]=4)[CH:18]=[CH:19][C:20]=3[N:21]=2)=[C:29]([CH3:36])[CH:28]=1
Reactant: Nc1ccc(C(=O)Nc2nccc3ccccc23)cc1N
Reactant: COC(=O)CCc1cc(C)c(C=O)c(C)c1
Agent: O=S([O-])OO
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)CCc1cc(C)c(-c2nc3ccc(C(=O)Nc4nccc5ccccc45)cc3[nH]2)c(C)c1
Reaction time: 1 h

Procedure:
A solution of 3,4-diamino-N-isoquinolin-1-yl-benzamide (200 mg) and 3-(4-formyl-3,5-dimethylphenyl)-propionic acid methyl ester (189 mg) (from Example 6-17) in 5 mL DMF/0.5 mL water was stirred at ambient temperature for 15 min then oxone (292 mg) was added and stirring was continued for 1 h. Water was added and the mixture was extracted with EtOAc. The organic phase was dried over sodium sulfate and the solvent was removed under reduced pressure. The residue was purified by flash chromatography using 5% MeOH/methylene chloride as eluent to give 3-{4-[6-(Isoquinolin-1-ylcarbamoyl)-1H-benzoimidazol-2-yl]-3,5-dimethylphenyl}-propionic acid methyl ester. MS (ESI)m/z 479.1 (M+H), retention time=1.33 min, Method 10.