Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][O:12]1)[CH:5]=O.[N:17]1([CH2:22][CH2:23][O:24][C:25]2[CH:30]=[CH:29][C:28]([NH2:31])=[CH:27][CH:26]=2)[CH2:21][CH2:20][CH2:19][CH2:18]1.S([O-])([O-])(=O)=O.[Mg+2]>C(Cl)Cl>[CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][O:12]1)[CH2:5][NH:31][C:28]1[CH:29]=[CH:30][C:25]([O:24][CH2:23][CH2:22][N:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)=[CH:26][CH:27]=1
Reactant: Nc1ccc(OCCN2CCCC2)cc1
Reactant: Cc1cc(C=O)ccc1OC1CCCCO1
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: ClCCl
Product: Cc1cc(CNc2ccc(OCCN3CCCC3)cc2)ccc1OC1CCCCO1
Temperature: 25 °C
Reaction time: 8 h
Yield: 117.8 %

Procedure:
To a solution of 3-methyl-4-(tetrahydro-pyran-2-yloxy)-benzaldehyde (0.700 g, 3.18 mmol) and 4-(2-pyrrolidin-1-yl-ethoxy)-phenylamine (0.624 g, 3.02 mmol) in 20 mL methylene chloride was added magnesium sulfate (1.82 g, 15.12 mmol). The reaction mixture was stirred overnight at room temperature. The reaction mixture was filtered and concentrated. The residue was redissolved in 20 mL methylene chloride and was treated with magnesium sulfate (1.82 g, 15.12 mmol). The reaction was again stirred overnight at room temperature. The reaction was filtered and concentrated. The residue was again redissolved in 20 mL methylene chloride and was treated with magnesium sulfate (1.82 g, 15.12 mmol). The reaction was once again stirred overnight at room temperature. The reaction was filtered and concentrated. The resulting oil was dissolved in 12 mL ethanol and 6 mL methanol and was treated with sodium borohyride (0.560 g, 14.80 mmol) which was added in two portions over a period of 1 hr. The reaction was stirred at room temperature for 4 days at which time the solvent was removed in vacuo. To the residue was added water, and the mixture was extracted three times with methylene chloride. The combined organic layers were washed with saturated aqueous sodium chloride, dried (sodium sulfate), filtered, and concentrated to afford 1.46 g of the title compound. MS 411.4 (M+1)+
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[CH2:7][CH2:6][CH2:5][CH:4]([C:8]2([CH3:14])[CH:12]=[CH:11][CH:10]([CH3:13])[O:9]2)[CH2:3]1>[Pd]>[CH3:1][C:2]1([CH3:15])[CH2:7][CH2:6][CH2:5][CH:4]([C:8]2([CH3:14])[CH2:12][CH2:11][CH:10]([CH3:13])[O:9]2)[CH2:3]1
Reactant: CC1C=CC(C)(C2CCCC(C)(C)C2)O1
Agent: [Pd]
Product: CC1CCC(C)(C2CCCC(C)(C)C2)O1
Yield: 68.3 %

Procedure:
According to the procedure of example 2, by hydrogenation of 1.00 g (4.80 mmol) of 2-(3′,3′-dimethylcyclohexyl)-2,5-dimethyl-2,5-dihydrofuran in the presence of 100 mg (0.0940 mmol) of 10% palladium on activated charcoal. Kugelrohr distillation furnished at 65-70° C./0.1 mbar 690 mg (68%) of the title compound as a colorless odoriferous liquid.
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:9](Cl)=[N:8][CH:7]=[N:6][C:5]=2[N:4]([CH2:12][CH2:13][CH:14]([CH3:16])[CH3:15])[CH:3]=1.[OH-].[NH4+:18]>>[Br:1][C:2]1[C:10]2[C:9]([NH2:18])=[N:8][CH:7]=[N:6][C:5]=2[N:4]([CH2:12][CH2:13][CH:14]([CH3:16])[CH3:15])[CH:3]=1
Reactant: CC(C)CCn1cc(Br)c2c(Cl)ncnc21
Reactant: [NH4+]
Agent: [OH-]
Product: CC(C)CCn1cc(Br)c2c(N)ncnc21
Temperature: 25 °C
Yield: 97.3 %

Procedure:
To 5-bromo-4-chloro-7-(3-methylbutyl)-7H-pyrrolo[2,3-d]pyrimidine (210 mg, 0.694 mmol) in a 5 mL sealable vial was added ammonium hydroxide (1.5 mL, 38.5 mmol). The mixture was then capped and heated at room temp overnight. The reaction was cooled and a precipitate formed. The solid was isolated by filtration and air dried to isolated 5-bromo-7-(3-methylbutyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (191 mg, 0.675 mmol, 97% yield) as a light brown solid. For 50-A1: LC/MS (ES) m/z=283.2, 285.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6) 8.10 (s, 1H), 7.48 (s, 1H), 6.70 (br. s., 2H), 4.12 (t, J=7.20 Hz, 2H), 1.64 (q, J=6.99 Hz, 2H), 1.44 (ddd, J=6.69, 6.82, 13.26 Hz, 1H), 0.90 (d, J=6.57 Hz, 6H).
Reaction SMILES: [NH2:1][C:2]1[C:7](Cl)=[N:6][CH:5]=[CH:4][N:3]=1.[CH:9]1([NH2:12])[CH2:11][CH2:10]1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].O1CCCC1>CC(C1C=C(C(C)C)C(C2C(P(C3CCCCC3)C3CCCCC3)=C(OC)C=CC=2OC)=C(C(C)C)C=1)C.C1C=[C-]C(CCN)=CC=1.Cl[Pd+].[NH4+].[Cl-]>[CH:9]1([NH:12][C:7]2[C:2]([NH2:1])=[N:3][CH:4]=[CH:5][N:6]=2)[CH2:11][CH2:10]1
Reactant: NC1CC1
Reactant: Nc1nccnc1Cl
Agent: Cl[Pd+]
Agent: COc1ccc(OC)c(P(C2CCCCC2)C2CCCCC2)c1-c1c(C(C)C)cc(C(C)C)cc1C(C)C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Solvent: C1CCOC1
Product: Nc1nccnc1NC1CC1
Temperature: 45 °C
Yield: 31 %

Procedure:
To a 250 mL round bottomed flask was added 2-amino-3-chloropyrazine (2.2204 g, 17.14 mmol, Synthetech, Inc.) and BrettPhos precatalyst (0.411 g, 0.514 mmol, Sigma-Aldrich Chemical Company, Inc.), and the reaction mixture were placed under vacuum. The round bottomed flask was flushed with argon. This process was repeated 3 times. Cyclopropylamine (1.803 ml, 25.7 mmol, Fluka Chemie GmbH) was added followed by a dropwise addition of lithium bis(trimethylsilyl)amide, 1.0 m solution in tetrahydrofuran (42.8 ml, 42.8 mmol, Sigma-Aldrich Chemical Company, Inc.). The reaction mixture was then heated to 45° C. for 2 h. The reaction mixture was then diluted with saturated NH4Cl and extracted with CH2Cl2. The organic extract was washed with water, saturated NaCl, dried over MgSO4, filtered and concentrated in vacuo. The crude product was adsorbed onto a plug of silica gel and chromatographed through a Biotage SNAP HP-silica gel column (50 g), eluting with a gradient of 10% to 60% Acetone in DCM, to provide the title compound (0.7993 g, 5.32 mmol, 31.1% yield). LCMS showed product peak at 0.629 min (m+1=151.1) with purity at 80-90%. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.31-0.38 (m, 2 H) 0.59-0.66 (m, 2 H) 2.64 (tq, J=6.85, 3.52 Hz, 1 H) 5.79 (s, 2 H) 6.25 (d, J=2.15 Hz, 1 H) 7.08 (d, J=3.13 Hz, 1 H) 7.20 (d, J=3.13 Hz, 1 H).
Reaction SMILES: [CH3:1][N:2]([C:11]1[CH:12]=[C:13]([C:17]2[CH:22]=[CH:21][C:20](/[CH:23]=[CH:24]/[C:25]([O:27][CH3:28])=[O:26])=[CH:19][C:18]=2[N+:29]([O-])=O)[CH:14]=[CH:15][CH:16]=1)[C:3]([NH:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])=[O:4]>CO.[Pd]>[NH2:29][C:18]1[CH:19]=[C:20]([CH2:23][CH2:24][C:25]([O:27][CH3:28])=[O:26])[CH:21]=[CH:22][C:17]=1[C:13]1[CH:14]=[CH:15][CH:16]=[C:11]([N:2]([CH3:1])[C:3]([NH:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])=[O:4])[CH:12]=1
Reactant: CCCCCNC(=O)N(C)c1cccc(-c2ccc(/C=C/C(=O)OC)cc2[N+](=O)[O-])c1
Agent: [Pd]
Solvent: CO
Product: CCCCCNC(=O)N(C)c1cccc(-c2ccc(CCC(=O)OC)cc2N)c1
Yield: 95 %

Procedure:
In a manner similar to that of Example (18e), by reaction of 300 mg (10% by mass) of 10% palladium-on-charcoal and 2.90 g (6.8 mmol, 1 eq) of methyl (E)-3-[3′-(1-methyl-3-pentylureido)-2-nitrobiphenyl-4-yl]acrylate in 50 ml of methanol, and after purification by chromatography on silica gel (50/50 heptane/ethyl acetate), 2.57 g of methyl 3-[2-amino-3′-(1-methyl-3-pentylureido)biphenyl-4-yl]propanoate are obtained in the form of a yellow oil. Yield=95%
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]3[CH:18]=[CH:17][C:13]([C:14](O)=[O:15])=[CH:12][CH:11]=3)=[CH:7][C:6]=2[CH:19]=1.Cl>C1COCC1>[OH:15][CH2:14][C:13]1[CH:12]=[CH:11][C:10]([C:8]2[O:9][C:5]3[CH:4]=[CH:3][C:2]([OH:1])=[CH:19][C:6]=3[CH:7]=2)=[CH:18][CH:17]=1
Reactant: O=C(O)c1ccc(-c2cc3cc(O)ccc3o2)cc1
Agent: Cl
Solvent: C1CCOC1
Product: OCc1ccc(-c2cc3cc(O)ccc3o2)cc1
Yield: 55.5 %

Procedure:
To a solution of 128 (0.15 g, 0.6 mmol), in THF (20 ml) was added BH3 (3 ml of 1.0M in THF) and the reaction was heated to reflux for 3 hr. The reaction was then cooled and poured into 2N HCl and extracted with EtOAc. The EtOAc was dried over MgSO4, filtered and concentrated and triturated with CH2Cl2 and filtered to give 129 as a solid (0.08 g, 57%); 1H NMR (DMSO-d6) δ 9.21 (br s, 1 H), 7.82 (d, 2 H, J=8.1 Hz), 7.43-7.38 (m, 3 H), 7.24 (s, 1 H), 6.92 (d, 1 H, J=2.1 Hz), 6.73 (dd, 1 H, J=8.5 Hz, 2.6 Hz), 5.28 (t, 1 H, J=5.7 Hz), 4.54 (d, 2 H, J=5.5 Hz); MS 239 (M−H)−.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[C:7]([O:9][CH3:10])[C:6]([O:11][CH3:12])=[CH:5][C:4]=1[CH:13]([CH2:18][CH2:19][C:20]([O:22][CH3:23])=[O:21])[C:14](OC)=[O:15])=O.C([O-])(=O)C.[NH4+:28]>C(O)(=O)C>[C:20]([CH2:19][CH2:18][C:13]1[C:4]2[C:3](=[CH:8][C:7]([O:9][CH3:10])=[C:6]([O:11][CH3:12])[CH:5]=2)[CH:1]=[N:28][C:14]=1[OH:15])([O:22][CH3:23])=[O:21]
Reactant: COC(=O)CCC(C(=O)OC)c1cc(OC)c(OC)cc1C=O
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: CC(=O)O
Product: COC(=O)CCc1c(O)ncc2cc(OC)c(OC)cc12
Temperature: 75 °C
Yield: 77.1 %

Procedure:
A mixture of 8.34 grams of dimethyl 2-(2-formyl-4,5-dimethoxyphenyl)glutarate (25.74 mmol) (which is the product of Example 8e(1)), 17.86 grams anhydrous ammonium acetate (232 mmol) and 15 ml glacial acetic acid was heated to 75° C. and was maintained at that temperature for 30 minutes. After cooling, the yellow precipitate was isolated by filtration, washed with water and dried to provide 5.78 grams of Compound Q (77% yield). Recrystallization from methanol and trituration with ether (to remove any trace amounts of methanol) provided 4.57 grams of pure Compound Q having a melting point of 178° to 180° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[CH2:18][C:17](=[O:19])[NH:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[F:8].[CH3:20][C:21]1[CH:25]=[C:24]([CH2:26][CH2:27][C:28]([N:30]2[CH2:35][CH2:34][N:33]([CH3:36])[CH2:32][CH2:31]2)=[O:29])[NH:23][C:22]=1[CH:37]=O>N1CCCCC1.C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[C:18](=[CH:37][C:22]4[NH:23][C:24]([CH2:26][CH2:27][C:28]([N:30]5[CH2:31][CH2:32][N:33]([CH3:36])[CH2:34][CH2:35]5)=[O:29])=[CH:25][C:21]=4[CH3:20])[C:17](=[O:19])[NH:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: Cc1cc(CCC(=O)N2CCN(C)CC2)[nH]c1C=O
Reactant: O=C1Cc2c(ncnc2Nc2ccc(F)c(Cl)c2)N1
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1cc(CCC(=O)N2CCN(C)CC2)[nH]c1C=C1C(=O)Nc2ncnc(Nc3ccc(F)c(Cl)c3)c21
Temperature: 65 °C
Reaction time: 2 h
Yield: 67.9 %

Procedure:
A mixture of 4-(3-chloro-4-fluoro-phenylamino)-5,7-dihydro-pyrrolo[2,3-d]pyrimidin-6-one (70 mg, 0.25 mmol), 3-methyl-5-[3-(4-methyl-piperazin-1-yl)-3-oxo-propyl]-1H-pyrrole-2-carbaldehyde (79 mg, 0.3 mmol) and piperidine (3 drops) in ethanol (2 mL) was stirred in an oil bath at 65° C. for 2 hours. The reaction was cooled at room temperature for overnight. The precipitate was collected by vacuum filtration, washed with ethanol (5×) and dried to give 88.9 mg (68%) of the title compound. 1H NMR (360 MHz, DMSO-d6) δ 13.15 (s, 1H, NH), 11.55 (br s, 1H, NH), 9.08 (s, 1H), 8.27 (s, 1H), 7.69 (dd, J=2.5 & 6.9 Hz, 1H), 7.30-7.40 (m, 3H), 6.08 (d, J=2.23 Hz, 1H), 3.43 (m, 4H, 2×CH2), 2.89 (t, J=7.4 Hz, 2H, CH2), 2.68 (t, J=7.4 Hz, 2H, CH2), 2.24 (m, 4H, 2×CH2), 2.16 (s, 6H, 2×CH3). MS 524 [M++1].
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:34]=[CH:33][C:12]2[N:13]([CH:16]([C:22]3[N:23]([CH2:27][C:28]([O:30]CC)=[O:29])[CH:24]=[CH:25][N:26]=3)[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH:14]=[N:15][C:11]=2[CH:10]=1)#[N:2].[OH-].[Na+]>C(O)C>[C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:34]=[CH:33][C:12]2[N:13]([CH:16]([C:22]3[N:23]([CH2:27][C:28]([OH:30])=[O:29])[CH:24]=[CH:25][N:26]=3)[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH:14]=[N:15][C:11]=2[CH:10]=1)#[N:2]
Reactant: CCCCCC(c1nccn1CC(=O)OCC)n1cnc2cc(-c3ccccc3C#N)ccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCCCC(c1nccn1CC(=O)O)n1cnc2cc(-c3ccccc3C#N)ccc21

Procedure:
The ester was dissolved in 20 ml ethanol and 40 ml of 2N NaOH and stirred at room temperature overnight. The solution was concentrated. The residue was dissolved in water and washed with ether. The pH was adjusted to 3.5 using 2N HCl. The precipitate was dissolved in ethyl acetate, washed with water, dried over sodium sulfate and concentrated to yield 770 mg of 2-[1-[5-(2-cyanophenyl)-1H-benzimidazol-1-yl]hexyl]-1H-imidazole-1-acetic acid. (MS)
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][NH:11][CH:10]([CH2:14][OH:15])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:24][C:25](Cl)=[O:26]>O1CCCC1>[CH2:1]([N:8]1[CH2:13][CH2:12][N:11]2[CH:10]([CH2:14][O:15][CH2:24][C:25]2=[O:26])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cl)CCl
Reactant: OCC1CN(Cc2ccccc2)CCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: O=C1COCC2CN(Cc3ccccc3)CCN12
Temperature: 25 °C
Reaction time: 12 h
Yield: 35.2 %

Procedure:
To a mixture of (4-benzylpiperazin-2-yl)methanol (6.4 g, 30 mmol) prepared according to J. Med. Chem. 1993, 36, 2075-2083, water (100 ml) and tetrahydrofuran (100 ml) were successively added potassium carbonate (8.3 g, 60 mmol) with chloroacetyl chloride (3.6 mL, 45 mmol), and the mixture was stirred at room temperature for 12 hr. The reaction mixture was concentrated under reduced pressure, and the residue was partitioned between ethyl acetate and water. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was dissolved in ethanol (100 ml), potassium hydroxide (2 g) was added, and the mixture was stirred at 50° C. for 3 hr. The reaction mixture was concentrated under reduced pressure, and the residue was partitioned between ethyl acetate and water. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the title compound (2.6 g, yield 35%) as a yellow oil. MS 247 (M+1).
Reaction SMILES: [CH:1](=[N:8]/[C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[C:11]([F:16])[CH:10]=1)\[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].[C:19](O)(=[O:21])[CH3:20]>>[CH2:1]([N:8]([C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[C:11]([F:16])[CH:10]=1)[C:19](=[O:21])[CH3:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Oc1ccc(/N=C/c2ccccc2)cc1F
Reactant: CC(=O)O
Agent: [Na+]
Agent: [OH-]
Product: CC(=O)N(Cc1ccccc1)c1ccc(O)c(F)c1
Temperature: 25 °C
Yield: 39 %

Procedure:
To a stirred solution of (E)-4-(benzylideneamino)-2-fluorophenol (430 mg, 2 mmol) in 1 mL glacial acetic acid at 0° C. under nitrogen was added a solution of trimethylamine/borane complex (160 mg, 2.2 mmol) in 1 mL glacial acetic acid dropwise by syringe. After complete addition, the reaction was allowed to warm to room temperature and was then heated to reflux overnight. 6N NaOH was then added until pH was neutral. The aqueous solution was extracted with ether, and the combined ether extracts were dried (MgSO4), filtered and concentrated. The material was loaded onto a Biotage 40S column with dichloromethane and eluted with 4/1 hexanes/EtOAc to afford the product as a white solid (200 mg, 39% yield).
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15](=[O:32])[C:16]2[CH:21]=[C:20]([OH:22])[CH:19]=[C:18]([O:23][C:24]3[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[CH:26][CH:25]=3)[CH:17]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[CH2:34]([O:36][C:37](=[O:45])[C:38]1[CH:43]=[CH:42][C:41](F)=[CH:40][CH:39]=1)[CH3:35]>>[CH2:34]([O:36][C:37](=[O:45])[C:38]1[CH:43]=[CH:42][C:41]([O:22][C:20]2[CH:19]=[C:18]([O:23][C:24]3[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[CH:26][CH:25]=3)[CH:17]=[C:16]([C:15](=[O:32])[NH:14][CH:11]3[CH2:12][CH2:13][CH:8]([NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:33])[CH2:9][CH2:10]3)[CH:21]=2)=[CH:40][CH:39]=1)[CH3:35]
Reactant: CC(C)(C)OC(=O)NC1CCC(NC(=O)c2cc(O)cc(Oc3ccc(C#N)cc3)c2)CC1
Reactant: CCOC(=O)c1ccc(F)cc1
Product: CCOC(=O)c1ccc(Oc2cc(Oc3ccc(C#N)cc3)cc(C(=O)NC3CCC(NC(=O)OC(C)(C)C)CC3)c2)cc1
Yield: 68.2 %

Procedure:
Using 2.0 g (4.4 mmol) of {4-[3-(4-cyano-phenoxy)-5-hydroxy-benzoylamino]-cyclohexyl}-carbamic acid tert-butyl ester and 4-fluoro-benzoic acid ethyl ester (1.2 g, 6.6 mmol) and following the procedure of Example 42(b) afforded 1.8 g of the required product. 1H NMR (DMSO-d6): δ 1.35 (4H, m), 1.4 (9H, s), 1.8 (4H, m), 3.2 (1H, m), 3.68 (1H, m), 4.30 (2H, q), 6.75 (1H, d), 7.20 (5H, m), 7.48 (2H, d), 7.88 (2H, d), 8.00 (2H, d), 8.36 (1H, d).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:32]=[CH:33][C:34]=1[O:35][CH3:36])[CH2:6][CH:7]1[C:13]2[CH:14]=[C:15]([O:20][CH3:21])[C:16]([O:18][CH3:19])=[CH:17][C:12]=2[CH2:11][CH2:10][CH2:9][N:8]1[CH:22]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:23](O)=[O:24].Cl.[CH2:38]([S:40][CH2:41][CH2:42][NH2:43])[CH3:39]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:32]=[CH:33][C:34]=1[O:35][CH3:36])[CH2:6][CH:7]1[C:13]2[CH:14]=[C:15]([O:20][CH3:21])[C:16]([O:18][CH3:19])=[CH:17][C:12]=2[CH2:11][CH2:10][CH2:9][N:8]1[CH:22]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:23]([NH:43][CH2:42][CH2:41][S:40][CH2:38][CH3:39])=[O:24]
Reactant: CCSCCN
Reactant: COc1ccc(CC2c3cc(OC)c(OC)cc3CCCN2C(C(=O)O)c2ccccc2)cc1OC
Agent: Cl
Product: CCSCCNC(=O)C(c1ccccc1)N1CCCc2cc(OC)c(OC)cc2C1Cc1ccc(OC)c(OC)c1

Procedure:
prepared by reaction of [1-(3,4-dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-phenyl-acetic acid with 2-(ethylthio)ethylamine hydrochloride.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([CH2:13][N:14]([CH3:24])[C:15](=[O:23])[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@@H:10]([CH2:25][N:26]([CH:43]([CH3:45])[CH3:44])[C:27](=[O:42])[C:28]2[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[C:30]([O:36][CH2:37][CH2:38][CH2:39][O:40][CH3:41])[CH:29]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(O)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([CH2:13][N:14]([CH3:24])[C:15](=[O:23])[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@H:10]([CH2:25][N:26]([CH:43]([CH3:45])[CH3:44])[C:27](=[O:42])[C:28]2[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[C:30]([O:36][CH2:37][CH2:38][CH2:39][O:40][CH3:41])[CH:29]=2)[CH2:9]1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: COCCCOc1cc(C(=O)N(C[C@H]2CN(C(=O)OC(C)(C)C)C[C@@H]2CN(C)C(=O)Cc2ccccc2)C(C)C)ccc1OC
Solvent: CCO
Product: COCCCOc1cc(C(=O)N(C[C@@H]2CN(C(=O)OC(C)(C)C)C[C@H]2CN(C)C(=O)Cc2ccccc2)C(C)C)ccc1OC

Procedure:
Racemic (3R*,4R*)-3-({isopropyl-[4-methoxy-3-(3-methoxy-propoxy)-benzoyl]-amino}-methyl)-4-[(methyl-phenylacetyl-amino)-methyl]-pyrrolidine-1-carboxylic acid tert-butyl ester is separated into the single enantiomers by preparative chiral HPLC on a Chiralpak AD-H column (4.6×250 mm, 5 μM particle size; flow rate 1 mL/min, UV=210 nM, injection=1.7 g in 5 mL ethanol and using ethanol as the eluent to give the enantiomerically pure title compound: tR (HPLC, Chiralpak AD-H, HPLC 250×4.6 mm, ethanol, flow: 0.5 ml/min): 26.46 min; and (3S,4S)-3-({isopropyl-[4-methoxy-3-(3-methoxy-propoxy)-benzoyl]-amino}-methyl)-4-[(methyl-phenylacetyl-amino)-methyl]-pyrrolidine-1-carboxylic acid tert-butyl ester: tR (HPLC, Chiralpak AD-H, HPLC 250×4.6 mm, ethanol, flow: 0.5 ml/min): 13.53 min.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[N:10][C:9]=2[C:19]2[C:20]([F:32])=[C:21]([NH:25]C(=O)OCC=C)[CH:22]=[CH:23][CH:24]=2)[CH:5]=[CH:4][N:3]=1.CC(O)=O.C([SnH](CCCC)CCCC)CCC>C(Cl)Cl.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([N:13]3[CH2:14][CH2:15][O:16][CH2:17][CH2:18]3)=[N:10][C:9]=2[C:19]2[C:20]([F:32])=[C:21]([CH:22]=[CH:23][CH:24]=2)[NH2:25])[CH:5]=[CH:4][N:3]=1
Reactant: C=CCOC(=O)Nc1cccc(-c2nc(N3CCOCC3)sc2-c2ccnc(Cl)n2)c1F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCCC[SnH](CCCC)CCCC
Solvent: CC(=O)O
Solvent: ClCCl
Product: Nc1cccc(-c2nc(N3CCOCC3)sc2-c2ccnc(Cl)n2)c1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 91.4 %

Procedure:
To a solution of 2-propen-1-yl {3-[5-(2-chloro-4-pyrimidinyl)-2-(4-morpholinyl)-1,3-thiazol-4-yl]-2-fluorophenyl}carbamate (57 g, 120 mmol) (prepared by a process analogous to that described for Intermediate 26) in DCM (500 mL), HOAc (17.3 g, 288 mmol), Pd(PPh3)2Cl2 (1.68 g, 2.4 mmol) were added. Then tri-n-butyltin hydride (38.4 g, 132 mmol) was added dropwise to the mixture at 0° C. The mixture was stirred at rt for 30 min. The reaction was quenched by adding saturated NaHCO3 (300 mL) slowly. The two layers were separated. The aqueous layer was extracted with DCM (1 L×2). The combined organic layers were washed with water and brine successively, dried over Na2SO4, filtered and concentrated under reduced pressure to give the crude product, which was washed with petroleum ether (500 mL) to afford the title compound (43 g, 91.6% yield). 1H NMR (400 MHz, CDCl3) δ ppm 8.15 (d, J=5.5 Hz, 1H), 6.95-7.07 (m, 1H), 6.83-6.92 (m, 1H), 6.74-6.80 (m, 1H), 6.70 (d, J=5.5 Hz, 1H), 3.57-3.63 (m, 4H), 3.75-3.88 (m, 4H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([I:15])=[CH:11][C:10]=2[F:16])=[C:4]([C:17]([OH:19])=O)[CH:3]=1.[CH3:20][C:21]1([CH3:29])[O:25][CH:24]([CH2:26][O:27][NH2:28])[CH2:23][O:22]1.C(N(C(C)C)CC)(C)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>ClCCl>[CH3:20][C:21]1([CH3:29])[O:25][CH:24]([CH2:26][O:27][NH:28][C:17]([C:4]2[CH:3]=[C:2]([Cl:1])[N:7]=[N:6][C:5]=2[NH:8][C:9]2[CH:14]=[CH:13][C:12]([I:15])=[CH:11][C:10]=2[F:16])=[O:19])[CH2:23][O:22]1
Reactant: CC1(C)OCC(CON)O1
Reactant: O=C(O)c1cc(Cl)nnc1Nc1ccc(I)cc1F
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC1(C)OCC(CONC(=O)c2cc(Cl)nnc2Nc2ccc(I)cc2F)O1
Reaction time: 5 h

Procedure:
To a mixture of 6-chloro-3-(2-fluoro-4-iodo-phenylamino)-pyridazine-4-carboxylic acid (46 mg, 0.12 mmol), O-(2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-hydroxylamine (18.9 mg, 0.13 mmol) and diisopropyl ethylamine (27.2 mg, 0.21 mmol) in dichloromethane, was added PyBop (36.4 mg, 0.06 mmol). The reaction was carried out at room temperature for 5 hours. The mixture was concentrated and purified by flash chromatography to afford the desired adduct. LC/MS [9.50 min; 523 (M+1)].
Reaction SMILES: [Cl:1][C:2]1[C:3](F)=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.[Cl:10][C:11]1[CH:12]=[C:13]([CH:19]=[CH:20][C:21]=1[S:22](=[O:36])(=[O:35])[NH:23][CH2:24][C:25]1[CH:26]=[C:27]2[C:31](=[CH:32][CH:33]=1)[N:30]([CH3:34])[CH:29]=[CH:28]2)[C:14]([O:16][CH2:17][CH3:18])=[O:15]>>[Cl:10][C:11]1[CH:12]=[C:13]([CH:19]=[CH:20][C:21]=1[S:22](=[O:36])(=[O:35])[N:23]([C:3]1[C:2]([Cl:1])=[CH:7][C:6]([Cl:8])=[CH:5][N:4]=1)[CH2:24][C:25]1[CH:26]=[C:27]2[C:31](=[CH:32][CH:33]=1)[N:30]([CH3:34])[CH:29]=[CH:28]2)[C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: CCOC(=O)c1ccc(S(=O)(=O)NCc2ccc3c(ccn3C)c2)c(Cl)c1
Reactant: Fc1ncc(Cl)cc1Cl
Product: CCOC(=O)c1ccc(S(=O)(=O)N(Cc2ccc3c(ccn3C)c2)c2ncc(Cl)cc2Cl)c(Cl)c1

Procedure:
The titled compound was prepared according to the procedure described in step-2 of Example 1 from 3,5-dichloro-2-fluoropyridine and ethyl 3-chloro-4-(N-((1-methyl-1H-indol-5-yl)methyl)sulfamoyl)benzoate (step-1 of Example 8).
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([N+:11]([O-])=O)[C:6]=1[C:14]#[C:15][C@H:16]([OH:18])[CH3:17].[H][H]>[Pd].CO>[NH2:11][C:7]1[CH:8]=[CH:9][CH:10]=[C:5]([O:4][CH2:3][O:2][CH3:1])[C:6]=1[CH2:14][CH2:15][C@H:16]([OH:18])[CH3:17]
Reactant: COCOc1cccc([N+](=O)[O-])c1C#C[C@@H](C)O
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: COCOc1cccc(N)c1CC[C@@H](C)O
Reaction time: 0.25 h
Yield: 100 %

Procedure:
A 400-mL Parr bottle charged with (R)-4-(2-(methoxymethoxy)-6-nitrophenyl)but-3-yn-2-ol (2.9 g, 11.54 mmol), methanol (58 mL), and 10% palladium on carbon (50% water, 1.228 g, 0.577 mmol) was pressurized to 39 psig with hydrogen and then shaken. Hydrogen was quickly consumed, and within 15 min, the pressure had dropped to 0 psig. The bottle was re-pressurized to 39 psig and shaking was continued. The pressure dropped to ca. 20 psig over the next 15 min and stabilized. The bottle was re-pressurized to 34 psig and held there with continued shaking for 2 h. The mixture was flushed with nitrogen, and then filtered through a pad of Celite. The bottle and catalyst were rinsed with methanol, and the filtrate concentrated under reduced pressure. Toluene was added and the mixture was concentrated to afford (R)-4-(2-amino-6-(methoxymethoxy)phenyl)butan-2-ol (2.60 g, 100%) as a dark yellow syrup which was used without further purification. MS (ESI, pos. ion) m/z 248 [M+23]+.