Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS(O[CH2:6][C:7]1[N:8]=[N:9][C:10]([O:16][CH2:17][CH3:18])=[C:11]([O:13][CH2:14][CH3:15])[CH:12]=1)(=O)=O.[NH3:19]>CO>[CH2:14]([O:13][C:11]1[CH:12]=[C:7]([CH2:6][NH2:19])[N:8]=[N:9][C:10]=1[O:16][CH2:17][CH3:18])[CH3:15]
Reactant: N
Reactant: CCOc1cc(COS(C)(=O)=O)nnc1OCC
Solvent: CO
Product: CCOc1cc(CN)nnc1OCC
Reaction time: 6 h

Procedure:
5,6-Diethoxypyridazin-3-ylmethyl methanesulfonate (620 mg) was dissolved in methanol (10 ml) and added dropwise while cooling with ice to an ammonia solution (16 ml; 7N in methanol). After being stirred for 6 h and left to stand overnight, the solvent was drawn off and the residue was purified by means of preparative HPLC. The product-containing fractions were combined, freed of the acetonitrile and freeze-dried. 305 mg of the desired product were obtained.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([OH:9])=O.C(N1C=CN=C1)(N1C=CN=C1)=O.[F:22][C:23]1[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:24]=1[NH2:25].C(=O)(O)[O-].[Na+]>CN(C)C=O>[F:22][C:23]1[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:24]=1[NH:25][C:7]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1)=[O:9]
Reactant: O=C(O)c1ccccn1
Reactant: Nc1ccc(F)cc1F
Agent: O=C([O-])O
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(F)cc1F)c1ccccn1
Reaction time: 24 h
Yield: 75.7 %

Procedure:
Picolinic acid (10.0 g, 81 mmol) was added to a solution of 1,1'-carbonyldiimidazole (13.13 g, 81 mmol) in dimethylformamide (80 mL) and the reaction mixture was stirred for 1 hour before introduction of 2,4-difluoroaniline (9.06 mL, 89 mmol). After 24 hours, the reaction mixture was poured into saturated sodium bicarbonate solution, extracted into ether, dried, concentrated, and recrystallized using a mixture of ether and petroleum ether to yield N-(2,4-difluorophenyl)-2-pyridine-carboxamide as a white solid (14.37 g, 76.0%) m.p. 90.5°-95° C.
Reaction SMILES: [NH2:1][C:2]1[CH:20]=[CH:19][C:5]([O:6][C@H:7]2[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8]2)=[CH:4][C:3]=1[C:21]([NH:23][C:24]1[CH:29]=[C:28]([C:30]([NH:32][CH:33]2[CH2:35][CH2:34]2)=[O:31])[CH:27]=[CH:26][C:25]=1[CH3:36])=[O:22].[CH2:37](OC(OCC)OCC)C>>[CH:33]1([NH:32][C:30]([C:28]2[CH:27]=[CH:26][C:25]([CH3:36])=[C:24]([N:23]3[C:21](=[O:22])[C:3]4[C:2](=[CH:20][CH:19]=[C:5]([O:6][C@H:7]5[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:16])([CH3:17])[CH3:18])=[O:13])[CH2:8]5)[CH:4]=4)[N:1]=[CH:37]3)[CH:29]=2)=[O:31])[CH2:34][CH2:35]1
Reactant: CCOC(OCC)OCC
Reactant: Cc1ccc(C(=O)NC2CC2)cc1NC(=O)c1cc(O[C@H]2CCN(C(=O)OC(C)(C)C)C2)ccc1N
Product: Cc1ccc(C(=O)NC2CC2)cc1-n1cnc2ccc(O[C@H]3CCN(C(=O)OC(C)(C)C)C3)cc2c1=O

Procedure:
Using an analogous procedure to that described paragraph (C) in the portion of Example 18 which is concerned with the preparation of starting material, tert-butyl (3S)-3-{4-amino-3-[({5-[(cyclopropylamino)carbonyl]-2-methylphenyl}amino)carbonyl]phenoxy}pyrrolidine-1-carboxylate was reacted with triethylorthoformate to give tert-butyl (3S)-3-[(3-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-4-oxo-3,4-dihydroquinazolin-6-yl)oxy]pyrrolidine-1-carboxylate; NMR Spectrum: (DMSOd6) 0.53 (m, 2H, 0.68 (m, 2H), 1.40 (s, 9H), 2.14 (m, 5H), 2.84 (m, 1H), 3.50 (m, 4H), 5.20 (s, 1H), 7.52 (m, 3H), 7.72 (d, 1H), 7.81 (s, 1H), 7.88 (m, 1H), 8.17 (s, 1H), 8.41 (s, 1H); Mass Spectrum: M+H+ 527.
Reaction SMILES: CO[C:3]([C:5]1[C:10]([C:11]([O:13][CH3:14])=[O:12])=[CH:9][CH:8]=[CH:7][N:6]=1)=[O:4].[F:15][C:16]1[CH:24]=[CH:23][C:19]([CH2:20][Mg]Cl)=[CH:18][CH:17]=1>O1CCCC1>[F:15][C:16]1[CH:24]=[CH:23][C:19]([CH2:20][C:3]([C:5]2[N:6]=[CH:7][CH:8]=[CH:9][C:10]=2[C:11]([O:13][CH3:14])=[O:12])=[O:4])=[CH:18][CH:17]=1
Reactant: COC(=O)c1cccnc1C(=O)OC
Reactant: Fc1ccc(C[Mg]Cl)cc1
Solvent: C1CCOC1
Product: COC(=O)c1cccnc1C(=O)Cc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of dimethylpyridine-2,3-dicarboxylate (1.0 g, 5.1 mmol) in tetrahydrofuran (50 ml) was added (4-fluorobenzyl)magnesium chloride (0.25 M in tetrahydrofuran, 20 ml, 5.1 mmol) through a syringe at −78° C. The reaction mixture was stirred at the same temperature for 30 minutes and was quenched with addition of water. After warming up to room temperature, the reaction mixture was partitioned between ethyl acetate and brine. The organic phase was washed with brine and concentrated. The residue was purified by flash chromatography (15% ethyl acetate in hexane) to give the title compound. MS (DCI/NH3) m/z 274 (M+H)+.
Reaction SMILES: [N:1]1([C:6]2[CH:23]=[CH:22][C:9]([O:10][CH2:11][CH2:12][C@@H:13]3[CH2:15][C@@H:14]3[CH:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)=[CH:8][CH:7]=2)[CH:5]=[N:4][N:3]=[N:2]1.[CH:24]1([CH2:30][C:31](O)=[O:32])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.C(N(C(C)C)CC)(C)C>CN(C)C=O>[CH:24]1([CH2:30][C:31]([N:19]2[CH2:20][CH2:21][CH:16]([C@H:14]3[CH2:15][C@H:13]3[CH2:12][CH2:11][O:10][C:9]3[CH:8]=[CH:7][C:6]([N:1]4[CH:5]=[N:4][N:3]=[N:2]4)=[CH:23][CH:22]=3)[CH2:17][CH2:18]2)=[O:32])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: c1cc(-n2cnnn2)ccc1OCC[C@@H]1C[C@@H]1C1CCNCC1
Reactant: O=C(O)CC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: O=C(CC1CCCCC1)N1CCC([C@H]2C[C@H]2CCOc2ccc(-n3cnnn3)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 23 mg (0.071 mmol) of 4-((1R,2S)-2-{2-[4-(1H-tetrazol-1-yl)phenoxy]ethyl}cyclopropyl)piperidine in 0.6 ml anhydrous N,N-dimethylformamide at ambient temperature was added 0.020 ml (0.14 mmol) cyclohexylacetic acid, followed by 27 mg (0.14 mmol) EDC, 9.6 mg (0.071 mmol) HOBt, and 0.062 ml (0.35 mmol) diisopropylethylamine. The solution was stirred overnight at ambient temperature. The crude in N,N-dimethylformamide was purified directly by reverse phase HPLC (TMC Pro-Pac C18; 30-100% acetonitrile/0.1% formic acid in water gradient). The pure fractions were lyophilized to yield the title compound as white solid.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:16]2[O:15][C:14]([CH3:18])([CH3:17])[O:13][C:12]=2[C:11]([C:19]([C:41]2[C:51]3[O:52][C:53]([CH3:56])([CH3:55])[O:54][C:50]=3[C:49]([C:57]([O:59]C)=[O:58])=[C:43]3[O:44][C:45]([CH3:48])([CH3:47])[O:46][C:42]=23)([C:21]2[C:31]3[O:32][C:33]([CH3:36])([CH3:35])[O:34][C:30]=3[C:29]([C:37]([O:39]C)=[O:38])=[C:23]3[O:24][C:25]([CH3:28])([CH3:27])[O:26][C:22]=23)[OH:20])=[C:10]2[C:6]=1[O:7][C:8]([CH3:62])([CH3:61])[O:9]2)=[O:4].[OH-].[Na+].O>CO.CO.O>[C:37]([C:29]1[C:23]2[O:24][C:25]([CH3:27])([CH3:28])[O:26][C:22]=2[C:21]([C:19]([C:11]2[C:12]3[O:13][C:14]([CH3:18])([CH3:17])[O:15][C:16]=3[C:5]([C:3]([OH:4])=[O:2])=[C:6]3[O:7][C:8]([CH3:61])([CH3:62])[O:9][C:10]=23)([C:41]2[C:51]3[O:52][C:53]([CH3:56])([CH3:55])[O:54][C:50]=3[C:49]([C:57]([OH:59])=[O:58])=[C:43]3[O:44][C:45]([CH3:47])([CH3:48])[O:46][C:42]=23)[OH:20])=[C:31]2[C:30]=1[O:34][C:33]([CH3:36])([CH3:35])[O:32]2)([OH:39])=[O:38]
Reactant: COC(=O)c1c2c(c(C(O)(c3c4c(c(C(=O)OC)c5c3OC(C)(C)O5)OC(C)(C)O4)c3c4c(c(C(=O)OC)c5c3OC(C)(C)O5)OC(C)(C)O4)c3c1OC(C)(C)O3)OC(C)(C)O2
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC1(C)Oc2c(c(C(O)(c3c4c(c(C(=O)O)c5c3OC(C)(C)O5)OC(C)(C)O4)c3c4c(c(C(=O)O)c5c3OC(C)(C)O5)OC(C)(C)O4)c3c(c2C(=O)O)OC(C)(C)O3)O1
Reaction time: 12 h

Procedure:
The ester of Example 15, tris(8-methoxycarbonyl-2,2,6,6-tetramethyl-benzo[1,2-d:4,5-d']bis(1,3)dioxole-4-yl)methanol (0.30 g, 0.34 mmol) was dissolved in MeOH (10 mL), and NaOH (0.041 g, 1.02 mmol) dissolved in MeOH/H2O (2.32M NaOH solution) was added until pH reached 7. In total 0.44 mL of the basic solution was used. The MeOH was evaporated in vacuum due to solubility problems and THF (3.5 mL) was added. The reaction mixture cleared with this treatment. After 12 h the reaction mixture was turbid and a precipitate had formed. This precipitate dissolved with the addition of water (10 mL). The THF was evaporated under reduced pressure and water (10 mL) was added and the aqueous phase was extracted with ether (10 mL). The organic phase was separated and the aqueous phase was acidified (pH 3.5) with 2M HCl. A yellow precipitate was formed and the aqueous phase was extracted with ether (3×20 mL) and CH2Cl2 (30 mL). The organic phases were collected, dried (Na2SO4) and the solvent was evaporated to yield the product tris(8-carboxy-2,2,6,6-tetramethyl-benzo[1,2-d:4,5-d']bis(1,3)dioxole-4-yl)methanol as a slightly tanned residue (0.25 g, 87%). The product contained a small impurity (appreciated to about 2% at the same extinction) according to HPLC (C18, ion pair (tetrabutyl-ammonium acetate) chromatography, CH3CN:H2O) with UV (254 nm) detection.
Reaction SMILES: O=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]3[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=3)[C:15]#[N:16])[CH:10]=2)[O:5][CH:4]([CH2:20][CH:21]2[CH2:25][CH2:24][CH2:23][O:22]2)[CH2:3]1.C[Si]([N:30]=[C:31]=[N:32][Si](C)(C)C)(C)C>C(Cl)Cl.Cl[Ti](Cl)(Cl)Cl>[C:15]([C:14]1[CH:13]=[C:12]([C:9]2[CH:10]=[C:11]3[C:6](=[CH:7][CH:8]=2)[O:5][CH:4]([CH2:20][CH:21]2[CH2:25][CH2:24][CH2:23][O:22]2)[CH2:3][C:2]3=[N:32][C:31]#[N:30])[CH:19]=[CH:18][CH:17]=1)#[N:16]
Reactant: N#Cc1cccc(-c2ccc3c(c2)C(=O)CC(CC2CCCO2)O3)c1
Reactant: C[Si](C)(C)N=C=N[Si](C)(C)C
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: N#CN=C1CC(CC2CCCO2)Oc2ccc(-c3cccc(C#N)c3)cc21
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 3-(4-oxo-2-((tetrahydrofuran-2-yl)methyl)chroman-6-yl)benzonitrile (233 mg, 0.70 mmol) in anhydrous DCM (18 mL) under N2 atmosphere was added 1 M TiCl4 (in DCM, 1.4 mL, 1.4 mmol) dropwise within 15 min at room temperature. It was stirred another 1 h after the addition. To this mixture was added Bis-trimethylsilylcarbodiimide (0.287 g, 0.35 mL, 1.54 mmol) dropwise. The resulting mixture was stirred overnight after the addition. The reaction mixture was poured into ice-water (25 g), and stirred for 30 min, then it was transferred to a separating funnel, the separated aqueous phase was extracted twice with DCM (2×30 mL). The combined organic phases were dried over anhydrous Na2SO4, and filtered, and concentrated to give N-(6-(3-cyanophenyl)-2-((tetrahydrofuran-2-yl)methyl)chroman-4-ylidene)cyanamide as light brown solid, which was used for next step without further purification. MS ESI+ve m/z 358 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:11]([CH:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)=[O:12])=[CH:8][C:9]=1[NH2:10])=[O:4].CO[CH:20]([N:23]([CH3:25])[CH3:24])OC>>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:11]([CH:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)=[O:12])=[CH:8][C:9]=1[N:10]=[CH:20][N:23]([CH3:25])[CH3:24])=[O:4]
Reactant: COC(=O)c1sc(C(=O)C2CCCC2)cc1N
Reactant: COC(OC)N(C)C
Product: COC(=O)c1sc(C(=O)C2CCCC2)cc1N=CN(C)C

Procedure:
3-Amino-5-cyclopentanecarbonylthiophene-2-carboxylic acid methyl ester and dimethoxymethyldimethylamine were reacted by method B. The product with the molecular weight of 308.40 (C15H20N2O3S) was obtained in this way; MS (ESI): 309 (14+H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][OH:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C(O[CH:17](OCC)[CH2:18][Cl:19])C.Cl>C(O)C>[Cl:19][CH2:18][CH:17]1[C:6]2[CH:7]=[C:8]([O:9][CH3:10])[C:3]([O:2][CH3:1])=[CH:4][C:5]=2[CH2:11][CH2:12][O:13]1
Reactant: COc1ccc(CCO)cc1OC
Reactant: CCOC(CCl)OCC
Agent: Cl
Solvent: CCO
Product: COc1cc2c(cc1OC)C(CCl)OCC2
Temperature: 25 °C
Reaction time: 24 h
Yield: 88 %

Procedure:
A mixture of 3,4-dimethoxybenzeneethanol and 62,8 g of chloroacetaldehyde diethylacetal in 1 l of absolute ethanol saturated with anhydrous hydrochloric acid, was stirred at ambient temperature for 24 h. The solvent was evaporated and 88,4 g (88,8%) of 1-chloromethyl-3,4-dihydro-6,7-dimethoxy-1H-2-benzopyran was obtained by distillation.
Reaction SMILES: [NH2:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH:16]([O:20][CH2:21][CH3:22])[C:17]([OH:19])=[O:18])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.I.[C:26]1([NH:32][C:33](SC)=[N:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(N(CC)CC)C>CN(C)C=O.[Hg](Cl)Cl>[NH:34]([C:33]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH:16]([O:20][CH2:21][CH3:22])[C:17]([OH:19])=[O:18])=[CH:11][CH:10]=2)=[CH:23][CH:24]=1)=[N:32][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1
Reactant: CSC(=Nc1ccccc1)Nc1ccccc1
Reactant: CCOC(Cc1ccc(OCCc2ccc(N)cc2)cc1)C(=O)O
Agent: Cl[Hg]Cl
Agent: I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(Cc1ccc(OCCc2ccc(NC(=Nc3ccccc3)Nc3ccccc3)cc2)cc1)C(=O)O
Reaction time: 0.5 h
Yield: 50.1 %

Procedure:
3-{4-[(4-Aminophenethyl)oxy]phenyl}-2-ethoxypropanoic acid (20 mg, 0.061 mmol) and methyl N,N′-diphenylcarbamimidothioate hydroiodide (23.7 mg, 0.064 mmol) were mixed in 0.3 ml N,N-dimethylformamide. Triethylamine (34 ml, 0.244 mmol) was added. The mixture was then cooled in an ice-bath. Mercury (II)chloride (18 mg, 0.066 mmol) was added. After 30 minutes, the cooling bath was removed. The reaction mixture was stirred overnight. Water (1 ml) and ethyl acetate (0.5 ml) were added and then hydromatrix (ca. 0.5 g) was added. After a while, the mixture was filtered. The filtrate was evaporated to dryness. Chromatography of the residue on an ISOLUTE column (SI, 500 mg/3 ml) using ethyl acetate/heptane (10:90, then 25:75, and then 50:50) as eluant gave 16 mg, yield 50% of the desired product.
Reaction SMILES: [O:1]1[CH:6]([OH:7])[CH2:5][C@@H:4]([CH:8]([CH3:10])[CH3:9])[CH2:3][CH:2]1[C@H:11]([C@@H:13]1[C@:30]2([CH3:31])[C@H:16]([C@H:17]3[C@H:27]([CH2:28][CH2:29]2)[C@:25]2([CH3:26])[CH:20]([CH2:21][CH:22]([OH:32])[CH2:23][CH2:24]2)[CH2:19][CH2:18]3)[C:15](=[O:33])[CH2:14]1)[CH3:12].[OH-].[K+]>CO>[O:1]1[CH:6]([OH:7])[CH2:5][C@@H:4]([CH:8]([CH3:10])[CH3:9])[CH2:3][CH:2]1[C@H:11]([C@@H:13]1[C@:30]2([CH3:31])[C@@H:16]([C@H:17]3[C@H:27]([CH2:28][CH2:29]2)[C@:25]2([CH3:26])[CH:20]([CH2:21][CH:22]([OH:32])[CH2:23][CH2:24]2)[CH2:19][CH2:18]3)[C:15](=[O:33])[CH2:14]1)[CH3:12]
Reactant: CC(C)[C@@H]1CC(O)OC([C@@H](C)[C@H]2CC(=O)[C@H]3[C@@H]4CCC5CC(O)CC[C@]5(C)[C@H]4CC[C@]23C)C1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CC(C)[C@@H]1CC(O)OC([C@@H](C)[C@H]2CC(=O)[C@@H]3[C@@H]4CCC5CC(O)CC[C@]5(C)[C@H]4CC[C@]23C)C1

Procedure:
Epimerization of compound 248 at the C14 position using KOH in MeOH yields 22,29-epoxy-3,29-dihydroxy-14β-stigmastan-15-one (260). Compound 248 is dissolved in MeOH and a solution of KOH in MeOH (25 mg/ml) is added. The mixture is refluxed for 15 minutes then cooled to room temperature. Water is added and the aqueous slurry is extracted with chloroform and then dried over MgSO4. Filtration and concentration gives the crude product that contains an epimeric mixture of compounds 248 and 260. Separation of 248 and 260 is achieved using column chromatography.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:15]3[C:10](=[C:11]([NH2:16])[N:12]=[CH:13][CH:14]=3)[CH2:9][O:8][C:6]=2[CH:7]=1.[C:17](Cl)(=[O:19])[CH3:18]>N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:15]3[C:10](=[C:11]([NH:16][C:17](=[O:19])[CH3:18])[N:12]=[CH:13][CH:14]=3)[CH2:9][O:8][C:6]=2[CH:7]=1
Reactant: Nc1nccc2c1COc1cc(Cl)ccc1-2
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Product: CC(=O)Nc1nccc2c1COc1cc(Cl)ccc1-2
Reaction time: 2 h

Procedure:
To a stirred solution of 8-chloro-5H-chromeno[3,4-c]pyridin-4-amine (0.08 g, 0.344 mmol) in pyridine (5 mL) at 0° C. was added acetyl chloride (0.024 mL, 0.344 mmol) and the solution was stirred for 2 h. The volatile organics were removed under reduced pressure and the residue was diluted with water (5 mL). The reaction mixture was extracted with CH2Cl2 (2×15 mL). The combined organic extracts were washed with brine (1×10 mL), dried over sodium sulfate and concentrated under reduced pressure. The crude residue was taken to the next step without purification. LCMS (ESI) m/e 273 [(M)−, calcd for C14H10ClN2O2 273.1]; LC/MS retention time (Method C): tR=1.89 min.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH2:32][CH2:33][CH:34]([CH3:36])[CH3:35])[CH:9]2[CH2:14][CH2:13][N:12]([C:15]([C@@H:17]([NH:22][C:23]([N:25]3[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)=[O:24])[CH2:18][CH:19]([CH3:21])[CH3:20])=[O:16])[CH2:11][CH2:10]2)=[CH:4][CH:3]=1.[CH:37](=O)[CH2:38][CH:39]([CH3:41])[CH3:40].[BH-](OC(C)=O)(OC(C)=O)O[C:45](C)=O.[Na+]>C(Cl)Cl.CCOC(C)=O>[CH3:40][C:39]([CH3:41])([CH3:45])[CH2:38][CH2:37][NH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH2:32][CH2:33][CH:34]([CH3:36])[CH3:35])[CH:9]2[CH2:14][CH2:13][N:12]([C:15]([C@@H:17]([NH:22][C:23]([N:25]3[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)=[O:24])[CH2:18][CH:19]([CH3:21])[CH3:20])=[O:16])[CH2:11][CH2:10]2)=[CH:4][CH:3]=1
Reactant: CC(C)CCN(c1ccc(N)cc1)C1CCN(C(=O)[C@H](CC(C)C)NC(=O)N2CCCCCC2)CC1
Reactant: CC(C)CC=O
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)CCN(c1ccc(NCCC(C)(C)C)cc1)C1CCN(C(=O)[C@H](CC(C)C)NC(=O)N2CCCCCC2)CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
(S)-Azepane-1-carboxylic acid (1-{4-[(4-amino-phenyl)-(3-methyl-butyl)-amino]-piperidine-1-carbonyl}-3-methyl-butyl)-amide (Example 35, 0.25 g, 0.50 mmol) was dissolved in CH2Cl2 (4 mL), treated with isovaleraldehyde (63 μL, 0.50 mmol), and stirred for 30 minutes. The reaction was cooled to 0° C., treated with NaBH(OAc)3 (0.16 g, 0.75 mmol), and allowed to warm to room temperature and stir overnight. The reaction was diluted with EtOAc (100 mL), washed with saturated bicarbonate solution and brine, dried over Na2SO4, and concentrated. The residue was chromatographed on silica gel eluting with 4% to 5% MeOH/CH2Cl2 to give the desired product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:14]3[CH:15]=[CH:16][N:17]([CH3:18])[C:13]=3[C:12]([C:19]([N:21]3[CH2:26][CH2:25][S:24][CH2:23][CH2:22]3)=[O:20])=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.ClC1C=C(C=CC=1)C(OO)=[O:32]>C(Cl)Cl>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:14]3[CH:15]=[CH:16][N:17]([CH3:18])[C:13]=3[C:12]([C:19]([N:21]3[CH2:22][CH2:23][S:24](=[O:32])[CH2:25][CH2:26]3)=[O:20])=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cn1ccc2c(Nc3cccc(Cl)c3)ncc(C(=O)N3CCSCC3)c21
Solvent: ClCCl
Product: Cl
Product: Cn1ccc2c(Nc3cccc(Cl)c3)ncc(C(=O)N3CCS(=O)CC3)c21
Reaction time: 0.5 h
Yield: 147.9 %

Procedure:
A solution of N-(3-chlorophenyl)-1-methyl-7-(4-thiomorpholinylcarbonyl)-1H-pyrrolo[3,2-c]pyridin-4-amine (100 mg) in DCM (3 ml) was cooled to −78 C and meta-chloroperoxybenzoic acid (58 mg) was added and the reaction stirred under argon for 30 minutes. The reaction was partitioned between dichloromethane and water and the organic layer separated. The organic layer was then washed three times with water, aqueous sodium sulfite solution, dried (Na2SO4) and evaporated. The residue was purified by MDAP to afford the free base as a white solid (84 mg). This was dissolved in methanol and a solution of 11.0M hydrochloric acid in diethyl ether (0.5 ml) and after evaporation afforded the title compound as a white solid (85 mg).
Reaction SMILES: [Cl-].[Li+].C(OP([CH:11]([CH2:17][C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][CH:19]=1)[C:12]([O:14][CH2:15][CH3:16])=[O:13])(OCC)=O)C.[CH2:28]1CCN2C(=NCCC2)CC1.C=O>C1COCC1>[C:18]1([CH2:17][C:11](=[CH2:28])[C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][CH:19]=1
Reactant: CCOC(=O)C(Cc1cccc2ccccc12)P(=O)(OCC)OCC
Reactant: C1CCC2=NCCCN2CC1
Agent: C=O
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: C=C(Cc1cccc2ccccc12)C(=O)OCC
Temperature: 25 °C
Reaction time: 3 h

Procedure:
1.92 g of lithium chloride was suspended-in 50 ml of dry THF, and 15 g of ethyl 2-diethylphosphono-3-(1-naphthyl)propionate was dropwise added thereto. Then, 16 ml of a 50% dry THF solution of DBU was dropwise added thereto, and 2.01 g of paraformaldehyde suspended in dry THF was added thereto. The mixture was stirred at room temperature for 3 hours, and the insolubles were removed by filtration and washed with a small amount of diethyl ether. The washing solution and and the filtrate were put together, and the solvent was distilled off. The resulting syrup was dissolved in 180 ml of diethyl ether. The diethyl ether layer was washed sequentially with a 10% citric acid aqueous solution, with water and with a saturated sodium chloride aqueous solution and dried over anhydride sodium sulfate. The solvent was distilled off, and the syrup thereby obtained was purified by silica gel column chromatography (n-hexane/diethyl ether=20/1) to obtain 6.48 g of ethyl 2-(1-naphthyl)methyl-2-propenoate as colorless oily substance.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:49])[NH:4][C@H:5]([C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[C:16]1[NH:17][CH:18]=[C:19]([C:21]2[CH:26]=[CH:25][C:24]([C:27]3[CH:32]=[CH:31][C:30]([NH:33][C:34]([C:36]4[CH:37]=[N:38][C:39]([N:42]5[CH2:47][CH2:46][NH:45][CH2:44][C@H:43]5[CH3:48])=[CH:40][CH:41]=4)=[O:35])=[CH:29][CH:28]=3)=[CH:23][CH:22]=2)[N:20]=1)=[O:10])[CH:6]([CH3:8])[CH3:7].[CH3:50][C:51]1([CH3:57])[CH2:53][C@@H:52]1[C:54](O)=[O:55].CN(C)C=O.C(N(CC)C(C)C)(C)C>>[CH3:1][O:2][C:3](=[O:49])[NH:4][C@H:5]([C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[C:16]1[NH:17][CH:18]=[C:19]([C:21]2[CH:26]=[CH:25][C:24]([C:27]3[CH:32]=[CH:31][C:30]([NH:33][C:34]([C:36]4[CH:37]=[N:38][C:39]([N:42]5[CH2:47][CH2:46][N:45]([C:54]([C@H:52]6[CH2:53][C:51]6([CH3:57])[CH3:50])=[O:55])[CH2:44][C@H:43]5[CH3:48])=[CH:40][CH:41]=4)=[O:35])=[CH:29][CH:28]=3)=[CH:23][CH:22]=2)[N:20]=1)=[O:10])[CH:6]([CH3:8])[CH3:7]
Reactant: CC1(C)C[C@@H]1C(=O)O
Reactant: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1nc(-c2ccc(-c3ccc(NC(=O)c4ccc(N5CCNC[C@H]5C)nc4)cc3)cc2)c[nH]1)C(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1nc(-c2ccc(-c3ccc(NC(=O)c4ccc(N5CCN(C(=O)[C@H]6CC6(C)C)C[C@H]5C)nc4)cc3)cc2)c[nH]1)C(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 57.8 %

Procedure:
To a mixture of the hydrochloride salt of ((S)-2-methyl-1-{(S)-2-[4-(4′-{[6-((R)-2-methyl-piperazin-1-yl)-pyridine-3-carbonyl]-amino}-biphenyl-4-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-propyl)-carbamic acid methyl ester (60.0 mg, 0.0775 mmol) and (S)-(+)-2,2-dimethylcyclopropane carboxylic acid (10.6 mg, 0.093 mmol) in N,N-dimethylformamide (1.5 mL, 19 mmol) at RT was added N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yOuronium hexafluorophosphate (35.4 mg, 0.093 mmol) and N,N-diisopropylethylamine (54.0 uL, 0.310 mmol). The reaction mixture was stirred at RT overnight, and then concentrated. The residue was redissolved in 1:1 acetic acid:water (6 mL), filtered and purified by reverse phase preparative HPLC. Desired fractions were combined and freeze dried to give a white solid 34.1 mg). (m/z): [M+H]+ calcd for C43H52N8O5 761.42 found 761.7. 1H NMR (CD3OD, 400 MHz) δ (ppm): 8.76 (s, 1H), 8.18-8.20 (m, 1H), 7.76-7.86 (m, 7H), 7.68-7.7 (m, 2H), 6.95-6.99 (m, 1H), 5.22-5.26 (t, 1H, J=16), 4.59-4.73 (m, 1H), 4.03-4.38 (m, 5H), 3.82-3.89 (m, 1H), 3.69-3.74 (m, 1H), 3.65 (s, 3H), 3.12-3.2 & 3.3-3.5 (m, total 2H), 2.53-2.6 (m, 1H), 2.0-2.3 (m, 4H), 1.75-1.78 & 1.82-1.85 (m, total 1H), 1.25 (s, 3H), 1.12 (s, 3H), 1.07-1.1 & 1.14-1.17 (m, total 1H), 0.96 (s, 3H), 0.88-0.96 & 1.21-1.27 (m, total 6H), 0.76-0.8 (m, 1H).
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[Cl:14])=[CH:6][CH:7]=1.[CH:15]([NH:17][NH2:18])=O>C(O)CCC>[Cl:14][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[C:5]1[CH:6]=[CH:7][C:2]2[N:3]([CH:15]=[N:17][N:18]=2)[N:4]=1
Reactant: NNC=O
Reactant: Clc1ccc(-c2ccccc2Cl)nn1
Solvent: CCCCO
Product: Clc1ccccc1-c1ccc2nncn2n1

Procedure:
A mixture of 5.67 g. of 3-chloro-6-(o-chlorophenyl)pyridazine, 3.03 g. of formylhydrazine in 50 ml. of butanol is refluxed 48 hrs. to give 2.3 g. of product as pale yellow crystals, m.p. 156°-158° C.