Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]=[C:9]=[O:10].[NH2:11][C:12]1[N:17]=[N:16][C:15]([N:18]2[CH2:23][CH2:22][N:21]([C:24]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[C:32]([F:35])([F:34])[F:33])=[O:25])[CH2:20][CH2:19]2)=[CH:14][CH:13]=1>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]([NH:11][C:12]1[N:17]=[N:16][C:15]([N:18]2[CH2:19][CH2:20][N:21]([C:24](=[O:25])[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[C:32]([F:35])([F:34])[F:33])[CH2:22][CH2:23]2)=[CH:14][CH:13]=1)=[O:10]
Reactant: O=C=Nc1ccccc1F
Reactant: Nc1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nn1
Product: O=C(Nc1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nn1)Nc1ccccc1F

Procedure:
Following the procedure of Example 5, making variations only as required to use 2-flurophenylisocyanate in place of (2-isocyanatocyclopropyl)benzene to react with [4-(6-aminopyridazin-3-yl)piperazin-1-yl](2-trifluoromethylphenyl)-methanone, the title compound was obtained as a white solid (32% yield). 1H NMR (500 MHz, CDCl3) δ 7.90-8.30, 7.99, 7.75, 7.63, 7.57, 7.34, 7.10-7.17, 7.01-7.07, 3.94-4.01, 3.85-3.92, 3.56-3.66, 3.41-3.49, 3.24-3.29.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Br[C:8]1[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=1>O>[N:1]1([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: C1COCCN1
Reactant: N#Cc1ccc(Br)cc1
Solvent: O
Product: N#Cc1ccc(N2CCOCC2)cc1
Temperature: 120 °C
Yield: 59.6 %

Procedure:
A mixture of morpholine (3 g, 34 mmol) and 4-bromobenzonitrile (1.95 g, 10.7 mmol) is heated at 120° C. The conversion of the 4-bromobenzonitrile is complete after 24 hours. Water (10 ml) is then added into the reaction mixture. The precipitate is filtered off, washed with water and dried under vacuum (30° C.). Recrystallisation (50% aqueous ethanol) of the dried crude product gives 1.2 g of the title-compound. Yield: 65%, m.p. 82-83° C.; MS 188 (100, M+); H1 NMR (CDCl3): δ 7.46 (dd, 2H), 6.81 (dd, 2H), 3.79 (t, 4H), 3.22 (t, 4H); C13 NMR (CDCl3): δ 153.69, 133.71, 120.07, 114.26, 101.16, 66.65, 47.49.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=4[Cl:22])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:23]([CH2:27][CH3:28])[CH2:24][CH2:25][OH:26])=[CH:4][CH:3]=1.[H-].[Na+].I[CH3:32].O>CN(C)C=O>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=4[Cl:22])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:23]([CH2:27][CH3:28])[CH2:24][CH2:25][O:26][CH3:32])=[CH:4][CH:3]=1
Reactant: CCC(CCO)c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCC(CCOC)c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 52.6 %

Procedure:
To a solution of 3-[9-chloro-1-(2,4-dichlorophenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazol-6-yl]pentan-1-ol (148 mg, 0.34 mmol) in N,N-dimethylformamide (5.0 mL) was added sodium hydride (60% dispersion in mineral oil, 27 mg, 0.675 mmol) at 0° C. After the mixture was stirred at 0° C. for 0.5 hr, iodomethane (0.064 mL, 1.03 mmol) was added to the reaction mixture at 0° C. The mixture was stirred at room temperature for 4 hr. Water was added to the reaction mixture at room temperature and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with a 10-50% ethyl acetate/n-hexane gradient mixture and recrystallization from 2-propanol/n-hexane to give the title compound (81.1 mg, 0.179 mmol, 53%) as colorless crystals.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]([OH:24])([C@H:16]([N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1)[CH3:17])[CH2:10][N:11]1[CH:15]=[N:14][CH:13]=[N:12]1.[F:25][C:26]([F:37])([F:36])[C:27]1[CH:35]=[CH:34][C:30]([C:31](Cl)=[O:32])=[CH:29][CH:28]=1>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]([OH:24])([C@H:16]([N:18]1[CH2:19][CH2:20][N:21]([C:31](=[O:32])[C:30]2[CH:34]=[CH:35][C:27]([C:26]([F:25])([F:36])[F:37])=[CH:28][CH:29]=2)[CH2:22][CH2:23]1)[CH3:17])[CH2:10][N:11]1[CH:15]=[N:14][CH:13]=[N:12]1
Reactant: C[C@@H](N1CCNCC1)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1
Product: C[C@@H](N1CCN(C(=O)c2ccc(C(F)(F)F)cc2)CC1)[C@](O)(Cn1cncn1)c1ccc(F)cc1F

Procedure:
The example 13 was prepared form the reaction of piperazino derivative 2 and 4-(trifluoromethyl)benzoyl chloride by following the similar procedure described for the example 12.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8](=O)[CH2:9][CH2:10][C:11](=O)[CH3:12])[CH:5]=[CH:6][CH:7]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:24])=CC=1>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2[S:24][C:11]([CH3:12])=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)CCC(=O)c1cccc(Br)c1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: Cc1ccc(-c2cccc(Br)c2)s1
Temperature: 25 °C
Yield: 66.4 %

Procedure:
To a stirring solution of 1-(3-bromo-phenyl)-pentane-1,4-dione (18.32 mmol) in toluene (90 mL) was added Lawesson's Reagent (19.24 mmol, 1.05 eq.) and the mixture was heated to reflux for 20 min. The reaction mixture was then cooled to room temperature and diluted with 1:1 hexanes/ether (90 mL) resulting in a precipitate. The mixture was filtered through a small pad of celite and the filtrate was concentrated to a light yellow solid that was purified by recrystallization from hexanes to give the final product as a white solid (12.17 mmol, 66%). MS (ESI) m/z 254.3.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[CH:12][C:5](/[CH:6]=[CH:7]/[C:8]([O:10]C)=[O:9])=[C:4]([NH:14][C:15](OCC)=O)[CH:3]=1.Br.BrC[C:23]([C:25]1[CH:30]=[C:29]([CH3:31])[CH:28]=[CH:27][N:26]=1)=[O:24].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:5]([C:6]([CH2:7][C:8]([OH:10])=[O:9])=[C:15]([C:23]([C:25]3[CH:30]=[C:29]([CH3:31])[CH:28]=[CH:27][N:26]=3)=[O:24])[NH:14]2)=[CH:12][CH:13]=1
Reactant: Cc1ccnc(C(=O)CBr)c1
Reactant: CCOC(=O)Nc1cc(Cl)ccc1/C=C/C(=O)OC
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1ccnc(C(=O)c2[nH]c3cc(Cl)ccc3c2CC(=O)O)c1
Yield: 20 %

Procedure:
A mixture of methyl trans-4-chloro-2-(ethoxycarbonylamino)cinnamate (step 1, 1.5 g, 5.3 mmol), 2-bromoacetyl-4-methylpyridine hydrobromide*, potassium carbonate (7.3 g, 53 mmol) and acetonitrile (50 ml) was heated at reflux temperature for 17 h. The mixture was then cooled and concentrated. The residue was diluted in ethyl acetate (200 ml) and washed with water (200 ml) and brine (200 ml). After drying (MgSO4) and removal of solvent, the crude product was purified by flash column chromatography eluting with ethyl acetate/hexane (1:5) to afford 433 mg (20%) of the title compound.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:13]=[CH:12][O:11][CH:10]=2)O1.Br[C:16]1[CH:17]=[CH:18][C:19]([CH3:23])=[C:20]([CH:22]=1)[NH2:21]>>[O:11]1[CH:12]=[CH:13][C:9]([C:16]2[CH:17]=[CH:18][C:19]([CH3:23])=[C:20]([CH:22]=2)[NH2:21])=[CH:10]1
Reactant: Cc1ccc(Br)cc1N
Reactant: CC1(C)OB(c2ccoc2)OC1(C)C
Product: Cc1ccc(-c2ccoc2)cc1N
Yield: 98 %

Procedure:
Using the same method as in Example 5-(i), 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)furan was reacted with the 5-bromo-2-methylaniline to give 5-(furan-3-yl)-2-methylaniline (yield: 98%).
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[Cl:13])[C:3]=1[C:14]([OH:16])=O.Cl.C(N=C=NCCCN(C)C)C.[Cl:29][C:30]1[CH:31]=[C:32]([N:37]2[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]2)[CH:33]=[CH:34][C:35]=1[Cl:36]>ClCCl>[NH2:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[Cl:13])[C:3]=1[C:14]([N:40]1[CH2:39][CH2:38][N:37]([C:32]2[CH:33]=[CH:34][C:35]([Cl:36])=[C:30]([Cl:29])[CH:31]=2)[CH2:42][CH2:41]1)=[O:16]
Reactant: Nc1onc(-c2ccccc2Cl)c1C(=O)O
Reactant: Clc1ccc(N2CCNCC2)cc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: Nc1onc(-c2ccccc2Cl)c1C(=O)N1CCN(c2ccc(Cl)c(Cl)c2)CC1
Yield: 73.4 %

Procedure:
In a similar manner as described in Example 1, by using dichloromethane (30 mL), 5-amino-3-(2-chlorophenyl)isoxazol-4-carboxylic acid (440 mg, 1.84 mmol), 1-ethyl-3-(dimethylaminopropyl)carbodiimide hydrochloride (388 mg, 2.02 mmol) and 1-(3,4-dichlorophenyl)piperazine (425 mg, 1.84 mmol), a white solid required compound (577 mg, 1.35 mmol, 73%) was obtained.
Reaction SMILES: [C:1]1([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[CH:6]=[CH:5][C:4]([CH2:7][C:8]([N:31]2[C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=3[N:33]=[N:32]2)([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:9][C:10]2[CH:15]=[CH:14][C:13](B3OC(C)(C)C(C)(C)O3)=[CH:12][CH:11]=2)=[CH:3][CH:2]=1.[C:46]([N:50]1[C:54](=[O:55])[CH:53]=[C:52](Cl)[S:51]1(=[O:58])=[O:57])([CH3:49])([CH3:48])[CH3:47]>>[N:31]1([C:8]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)([CH2:7][C:4]2[CH:3]=[CH:2][C:1]([C:40]3[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=3)=[CH:6][CH:5]=2)[CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:52]3[S:51](=[O:58])(=[O:57])[N:50]([C:46]([CH3:49])([CH3:48])[CH3:47])[C:54](=[O:55])[CH:53]=3)=[CH:12][CH:11]=2)[C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=2[N:33]=[N:32]1
Reactant: CC1(C)OB(c2ccc(CC(Cc3ccc(-c4ccccc4)cc3)(c3ccccc3)n3nnc4ccccc43)cc2)OC1(C)C
Reactant: CC(C)(C)N1C(=O)C=C(Cl)S1(=O)=O
Product: CC(C)(C)N1C(=O)C=C(c2ccc(CC(Cc3ccc(-c4ccccc4)cc3)(c3ccccc3)n3nnc4ccccc43)cc2)S1(=O)=O

Procedure:
This compound was prepared according to the procedure of Example 1.1, Step 4, using 4.26-B of Example 2 and 9-A of Example 1.9 as the starting materials. LCMS found for C40H37N4O3S (M+H)+: m/z=653.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([S:20](=[O:23])(=[O:22])[NH2:21])[C:10]=1[NH:11][CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:5]([OH:7])=[O:6].[CH2:24](Br)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C(O)C>[CH2:24]([NH:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([S:20](=[O:23])(=[O:22])[NH2:21])[C:10]=1[NH:11][CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:5]([OH:7])=[O:6])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: BrCc1ccccc1
Reactant: Nc1cc(C(=O)O)cc(S(N)(=O)=O)c1NCCc1ccccc1
Solvent: CCO
Product: NS(=O)(=O)c1cc(C(=O)O)cc(NCc2ccccc2)c1NCCc1ccccc1

Procedure:
A mixture of 3-amino-4-(β-phenylethylamino)-5-sulphamyl-benzoic acid (3.35 g), benzyl bromide (5.3 g), and anhydrous ethanol (30 ml) was refluxed for 48 hours. After cooling, the precipitated ethyl ester was collected by suction, recrystallized from ethanol and saponified by heating in 1N sodium hydroxide (30 ml) for 1 hour. The 3-benzylamino-4-(β-phenylethylamino)-5-sulphamyl-benzoic acid was precipitated at room temperature by addition of 4N hydrochloric acid until the pH was 2.5. After recrystallization from aqueous ethanol, the compound was obtained with a melting point of 203° C.
Reaction SMILES: [H-].[Na+].[CH:3]([OH:6])([CH3:5])[CH3:4].F[C:8]1[CH:9]=[CH:10][C:11]([N+:17]([O-:19])=[O:18])=[C:12]([CH:16]=1)[C:13]([OH:15])=[O:14].Cl>C1COCC1>[CH:3]([O:6][C:8]1[CH:9]=[CH:10][C:11]([N+:17]([O-:19])=[O:18])=[C:12]([CH:16]=1)[C:13]([OH:15])=[O:14])([CH3:5])[CH3:4]
Reactant: CC(C)O
Reactant: O=C(O)c1cc(F)ccc1[N+](=O)[O-]
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)Oc1ccc([N+](=O)[O-])c(C(=O)O)c1
Reaction time: 0.5 h

Procedure:
60% NaH in oil (950 mg, 23.8 mmol) was added to isopropyl alcohol (4.1 mL) in THF (20 mL) under a nitrogen atmosphere. After stirring for 30 min, 5-fluoro-2-nitrobenzoic acid (2.0 g, 10.8 mmol) was added, and the mixture was heated at reflux for 6 h. Following addition of 2N HCl to adjust the pH to 2, the mixture was extracted, washed with brine, dried (Na2SO4) and concentrated to dryness. Purification by chromatography gave 950 mg of 5-isopropoxy-2-nitro-benzoic acid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[NH:7][C@@H:8]1[CH2:12][CH2:11][N:10]([C:13](=[O:26])[CH2:14][NH:15]C(OCC2C=CC=CC=2)=O)[C@H:9]1[CH3:27])([CH3:4])([CH3:3])[CH3:2].[H][H]>C(O)C.[Pd]>[NH2:15][CH2:14][C:13]([N:10]1[CH2:11][CH2:12][C@@H:8]([NH:7][C:6](=[O:28])[O:5][C:1]([CH3:3])([CH3:2])[CH3:4])[C@@H:9]1[CH3:27])=[O:26]
Reactant: [H][H]
Reactant: C[C@H]1[C@H](NC(=O)OC(C)(C)C)CCN1C(=O)CNC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: C[C@H]1[C@H](NC(=O)OC(C)(C)C)CCN1C(=O)CN
Yield: 99.2 %

Procedure:
To [(2S,3R)-1-(2-benzyloxycarbonylamino-acetyl)-2-methyl-pyrrolidin-3-yl]-carbamic acid tert-butyl ester (example #14) (0.75 g, 1.916 mmol) in ethanol (101 mL) was added 10% palladium on carbon (0.020 g, 0.19 mmol). The flask was fitted with a hydrogen balloon and hydrogenated for about 16 h. The reaction mixture was filtered, washing with EtOH. The filtrate was concentrated under reduced pressure to afford tert-butyl (2S,3R)-1-(2-aminoacetyl)-2-methylpyrrolidin-3-ylcarbamate (0.50 g, 1.9 mmol). RP-HPLC (Table 1, Method d) Rt 3.05; m/z: (M+H)+ 258.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([CH:11]=O)[N:10]=2)[CH:7]=1.[CH:13]1([C:18]2([CH2:26][CH2:27][C:28]3[CH:33]=[C:32]([CH2:34][CH3:35])[C:31]([OH:36])=[C:30]([CH2:37][CH3:38])[CH:29]=3)[O:23][C:22](=[O:24])[CH2:21][C:20](=[O:25])[CH2:19]2)[CH2:17][CH2:16][CH2:15][CH2:14]1>>[Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([CH2:11][C:21]3[C:22](=[O:24])[O:23][C:18]([CH:13]4[CH2:14][CH2:15][CH2:16][CH2:17]4)([CH2:26][CH2:27][C:28]4[CH:33]=[C:32]([CH2:34][CH3:35])[C:31]([OH:36])=[C:30]([CH2:37][CH3:38])[CH:29]=4)[CH2:19][C:20]=3[OH:25])[N:10]=2)[CH:7]=1
Reactant: O=Cc1nc2ncc(Cl)cn2n1
Reactant: CCc1cc(CCC2(C3CCCC3)CC(=O)CC(=O)O2)cc(CC)c1O
Product: CCc1cc(CCC2(C3CCCC3)CC(O)=C(Cc3nc4ncc(Cl)cn4n3)C(=O)O2)cc(CC)c1O

Procedure:
The title compound was prepared analogously to Example A(224) where 6-chloro-[1,2,4]triazolo[1,5-a]pyrimidine-2-carbaldehyde was used in place of 6-methyl-[1,2,4]triazolo[1,5-a]pyrimidine-2-carbaldehyde and 6-cyclopentyl-6-[2-(3,5-diethyl-4-hydroxyphenyl)ethyl]dihydro-2H-pyran-2,4(3H)-dione (Example A(235)) was used in place of 6-cyclopentyl-6-{2-[4-hydroxy-3-(2,2,2-trifluoroethyl)phenyl]ethyl}dihydro-2H-pyran-2,4(3H)-dione in that example. 1H NMR (DMSO): δ 1.15 (t, J=3.89 Hz, 6H), 1.30–1.80 (brm, 8H), 2.00–2.20 (brm, 5H), 2.43 (q, J=20.06 Hz 4H), 2.85 (m, 4H), 3.55 (m, 3H), 6.70 (s, 2H), 8.76 (s, 1H), 8.82 (s, 1H). Anal. Calcd. For C28H33O4N4Cl, C, 64.05; H, 6.34; N, 10.67. Found: C, 64.35; H, 6.50; N, 10.75.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:14]=[CH:13][C:8]([O:9][CH2:10][CH2:11][OH:12])=[CH:7][CH:6]=1)(=O)=O.ClCCO.CSC1C=CC(O)=CC=1.C(=O)([O-])[O-].[K+].[K+]>>[CH3:1][S:2][C:5]1[CH:14]=[CH:13][C:8]([O:9][CH2:10][CH2:11][OH:12])=[CH:7][CH:6]=1
Reactant: CS(=O)(=O)c1ccc(OCCO)cc1
Agent: CSc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: OCCCl
Product: CSc1ccc(OCCO)cc1

Procedure:
To a solution of 20.5 g (0.095 mole) of 2-[4-(methylsulfonyl)phenoxy]ethanol (m.p. 96°-98° C.) [prepared by reacting 2-chloroethanol with 4-(methylthio)phenol and potassium carbonate, isolating the 2-[4-(methylthio)phenoxy]ethanol, m.p. 55°-56.5° C. and oxidizing with metachloroperoxybenzoic acid] and 12.25 g (0.12 mole) of triethylamine in a mixture of 200 ml of benzene and 500 ml of methylene chloride was slowly added a solution of 14.31 g (0.125 mole) of mesyl chloride in methylene chloride and the solution was stirred at room temperature for about 2 hr. The solvent was removed in vacuo, and the residue was partitioned between methylene chloride and dilute sodium hydroxide. The methylene chloride layer was dried over magnesium sulfate and the solvent was removed in vacuo to give a residue. The residue was dissolved in a mixture of 100 ml of acetonitrile and 300 ml of isopropylamine and the solution stirred at room temperature for about 60 hr. The solvent was removed in vacuo and the residue was partitioned between methylene chloride and dilute sodium hydroxide. The methylene chloride phase was extracted with dilute sulfuric acid. The acidic extract was made basic with 50% sodium hydroxide and the resulting solution was extracted with methylene chloride. The methylene chloride solution was dried over magnesium sulfate and the solvent removed in vacuo to give 17.45 g (62.7%) of the free base of the title compound as a solid. Part of the free base was converted to the hydrochloride salt and the salt was recrystallized from methanol-diethyl ether to give white crystals, m.p. 182°-184° C.
Reaction SMILES: Br[C:2]1[C:18]([F:19])=[CH:17][C:5]2[O:6][CH2:7][CH2:8][C:9]3[S:13][C:12]([C:14]([NH2:16])=[O:15])=[N:11][C:10]=3[C:4]=2[CH:3]=1.[F:20][CH2:21][C:22]([CH3:26])([OH:25])[C:23]#[CH:24]>>[F:19][C:18]1[C:2]([C:24]#[C:23][C:22]([OH:25])([CH3:26])[CH2:21][F:20])=[CH:3][C:4]2[C:10]3[N:11]=[C:12]([C:14]([NH2:16])=[O:15])[S:13][C:9]=3[CH2:8][CH2:7][O:6][C:5]=2[CH:17]=1
Reactant: C#CC(C)(O)CF
Reactant: NC(=O)c1nc2c(s1)CCOc1cc(F)c(Br)cc1-2
Product: CC(O)(C#Cc1cc2c(cc1F)OCCc1sc(C(N)=O)nc1-2)CF
Yield: 28 %

Procedure:
Similar to as described in General Procedure G, 9-bromo-8-fluoro-4,5-dihydrobenzo[2,3]oxepino[4,5-d]thiazole-2-carboxamide was reacted with 1-fluoro-2-methylbut-3-yn-2-ol to give the titled compound as an off-white solid (6 mg, 28%).
Reaction SMILES: I[C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[Cl:9][C:10]1[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:11]=1B(O)O.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:9][C:10]1[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:11]=1[C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1
Reactant: Nc1ccc(I)cc1
Reactant: OB(O)c1ccc(Cl)cc1Cl
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: Nc1ccc(-c2ccc(Cl)cc2Cl)cc1
Temperature: 70 °C

Procedure:
4-Iodoaniline (6.9 g, 31.7 mmol), (2,4-dichlorophenyl)boronic acid (7.3 g, 38.0 mmol), Pd(dppf)Cl2 (1.3 g, 1.6 mmol), and 2M aqueous K2CO3 (31.7, 63.4 mmol) were dissolved in 1,4-dioxane (127 mL) and the resulting mixture was heated to 70° C. After 2.5 d the resulting mixture was cooled to room temperature, concentrated, diluted with EtOAc and 4M aqueous NaCl, and the layers were separated. The aqueous layer was extracted with EtOAc and the combined organics were dried (Na2SO4), concentrated, and purified via column chromatography to yield the title compound.
Reaction SMILES: Cl.Cl.[C:3]1([N:12]2[CH2:16][CH2:15][C@H:14]([NH2:17])[CH2:13]2)[C:4]2[N:5]([CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:7][N:8]=1.Cl.[CH3:19][C:20]1[CH:21]=[C:22]2[C:27](=[CH:28][CH:29]=1)[N:26]=[C:25]([C:30](O)=[O:31])[N:24]=[CH:23]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.[C:66]([OH:72])([C:68]([F:71])([F:70])[F:69])=[O:67]>CN1C(=O)CCC1.CS(C)=O.C(#N)C.O>[CH3:19][C:20]1[CH:21]=[C:22]2[C:27](=[CH:28][CH:29]=1)[N:26]=[C:25]([C:30]([NH:17][C@H:14]1[CH2:15][CH2:16][N:12]([C:3]3[C:4]4[N:5]([CH:9]=[CH:10][CH:11]=4)[CH:6]=[CH:7][N:8]=3)[CH2:13]1)=[O:31])[N:24]=[CH:23]2.[C:66]([OH:72])([C:68]([F:71])([F:70])[F:69])=[O:67]
Reactant: N[C@H]1CCN(c2nccn3cccc23)C1
Reactant: Cc1ccc2nc(C(=O)O)ncc2c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCCC1=O
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc2nc(C(=O)N[C@H]3CCN(c4nccn5cccc45)C3)ncc2c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
43 mg (0.156 mmol) of (3S)-1-pyrrolo[1,2-a]pyrazin-1-ylpyrrolidin-3-amine dihydrochloride and 33 mg (0.156 mmol) of 6-methylquinazoline-2-carboxylic acid hydrochloride were dissolved in 0.4 mL of NMP. To this mixture was added 85 mg (0.224 mmol) of HATU and 155 μL (0.892 mmol) of N,N-diisopropylethylamine. The mixture was stirred at rt for 30 minutes, then diluted with 3 mL of DMSO and injected directly onto a reverse-phase semi-preparative HPLC system (5-40% acetonitrile/water, 0.1% TFA). Pure fractions were concentrated in vacuo to give 39 mg of the desired product as a TFA salt (51% yield). 1H NMR (400 MHz, CD3OD) δ 9.49 (s, 1 H), 8.04 (d, J=9.1 Hz, 1 H), 7.93 (d, J=6.9 Hz, 2 H), 7.75 (d, J=1.5 Hz, 1 H), 7.70 (d, J=5.9 Hz, 1 H), 7.55 (s, 1 H), 6.92 (s, 1 H), 6.85 (d, J=5.5 Hz, 1 H), 5.00-3.70 (m, 5 H), 3.30 (s, 3 H), 2.60-2.30 (m, 2 H); MS: (ES) m/z calculated for C21H20N6O [M+H]+ 373.2, found 373.
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[CH:21]=[CH:20][C:7]([O:8][CH2:9][CH2:10][NH:11][C:12]2[C:17]([Cl:18])=[C:16]([CH3:19])[N:15]=[CH:14][N:13]=2)=[C:6]([CH3:22])[CH:5]=1.[NH:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1>C(O)C>[Cl:18][C:17]1[C:12]([NH:11][CH2:10][CH2:9][O:8][C:7]2[CH:20]=[CH:21][C:4]([CH2:3][CH2:2][N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)=[CH:5][C:6]=2[CH3:22])=[N:13][CH:14]=[N:15][C:16]=1[CH3:19]
Reactant: Cc1cc(CCBr)ccc1OCCNc1ncnc(C)c1Cl
Reactant: C1COCCN1
Solvent: CCO
Product: Cc1cc(CCN2CCOCC2)ccc1OCCNc1ncnc(C)c1Cl
Yield: 85.3 %

Procedure:
3.0 g of 4-{2-[4-(2-bromoethyl)-2-methylphenoxy]ethylamino}-5-chloro-6-methylpyrimidine and 1.4 g of morpholine were dissolved in 40 ml of ethanol, and the mixture was charged into an autoclave. Then, the mixture was allowed to react at 120° to 130° C. for 8 hours. At the end of this time, the ethanol was removed by distillation and water was added to the residue. The oily substance which separated was then extracted with ethyl acetate. The extract was washed with water and dried over anhydrous sodium sulfate, after which the ethyl acetate was removed by distillation under reduced pressure to obtain an oily substance. The substance obtained was subjected to column chromatography (Wakogel C-200, eluted with ethanol), to obtain 2.6 g of the title compound as a pale yellow oily liquid, n25.7 =1.5643.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:22]=[CH:21][C:20]2[C@@H:19]3[C@H:10]([C@H:11]4[C@@:15]([CH2:17][CH2:18]3)([CH3:16])[C:14](=[O:23])[CH2:13][CH2:12]4)[C@H:9]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][O:35][C:36](=[O:38])[CH3:37])[CH2:8][C:7]=2[CH:6]=1)(=[O:3])[CH3:2].[CH2:39](O)[CH2:40][OH:41].C(OC)(OC)OC.C1(C)C=CC(S(O)(=O)=O)=CC=1>ClCCl>[C:1]([O:4][C:5]1[CH:22]=[CH:21][C:20]2[C@@H:19]3[C@H:10]([C@H:11]4[C@@:15]([CH2:17][CH2:18]3)([CH3:16])[C:14]3([O:41][CH2:40][CH2:39][O:23]3)[CH2:13][CH2:12]4)[C@H:9]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][O:35][C:36](=[O:38])[CH3:37])[CH2:8][C:7]=2[CH:6]=1)(=[O:3])[CH3:2]
Reactant: OCCO
Reactant: CC(=O)OCCCCCCCCCCC[C@@H]1Cc2cc(OC(C)=O)ccc2[C@H]2CC[C@]3(C)C(=O)CC[C@H]3[C@H]12
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: COC(OC)OC
Solvent: ClCCl
Product: CC(=O)OCCCCCCCCCCC[C@@H]1Cc2cc(OC(C)=O)ccc2[C@H]2CC[C@@]3(C)[C@@H](CCC34OCCO4)[C@H]12

Procedure:
7.85 g of 3-acetoxy-7α-(11-acetoxyundecyl)-1,3,5(10)-estratrien-17-one is stirred under reflux in 51 ml of dichloromethane and 51 ml of ethylene glycol with 24 ml of trimethyl orthoformate and 159 mg of p-toluenesulfonic acid for 0.5 hour. For working up purposes, the mixture is diluted with dichloromethane, washed with sodium bicarbonate and sodium chloride solutions, dried over sodium sulfate, concentrated to dryness under vacuum, and chromatographed on silica gel with hexane/ethyl acetate, yielding 6.5 g of pure 3-acetoxy-7α-(11-acetoxyundecyl)-17,17-ethylenedioxy-1,3,5(10)-estratriene, [α]D =13.4°, as an oil.
Reaction SMILES: [CH3:1][C:2]([NH:14][C:15]1[CH:20]=[C:19]([CH3:21])[CH:18]=[CH:17][C:16]=1[N+:22]([O-])=O)([CH3:13])[CH2:3][CH2:4][NH:5][C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9]>CO.[Pd]>[NH2:22][C:16]1[CH:17]=[CH:18][C:19]([CH3:21])=[CH:20][C:15]=1[NH:14][C:2]([CH3:13])([CH3:1])[CH2:3][CH2:4][NH:5][C:6](=[O:12])[O:7][C:8]([CH3:10])([CH3:9])[CH3:11]
Reactant: Cc1ccc([N+](=O)[O-])c(NC(C)(C)CCNC(=O)OC(C)(C)C)c1
Agent: [Pd]
Solvent: CO
Product: Cc1ccc(N)c(NC(C)(C)CCNC(=O)OC(C)(C)C)c1

Procedure:
4.71 g (14.0 mmol) tert-butyl [3-methyl-3-(5-methyl-2-nitro-phenylamino)-butyl]-carbamate are dissolved in 110 mL methanol and hydrogenated in the presence of 340 mg palladium on charcoal (10%) at ambient temperature. Then the catalyst is separated off and the solvent is distilled off. Brown solid. Yield: 3.72 g (87%); mass spectroscopy: [M+H]+=308.