Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:11][CH2:12][N:13]([CH2:16][CH3:17])[CH2:14][CH3:15])[N:6]=[C:5]3[C:18]4[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][C:19]=4[S:20][C:3]=1[C:4]=23.Br.[Br:28][CH2:29][CH2:30][NH2:31]>CCO>[BrH:28].[CH2:16]([N:13]([CH2:14][CH3:15])[CH2:12][CH2:11][N:7]1[C:8]2[CH:9]=[CH:10][C:2]([NH:1][CH2:29][CH2:30][NH2:31])=[C:3]3[S:20][C:19]4[CH:21]=[C:22]([O:25][CH3:26])[CH:23]=[CH:24][C:18]=4[C:5]([C:4]=23)=[N:6]1)[CH3:17]
Reactant: NCCBr
Reactant: CCN(CC)CCn1nc2c3c(c(N)ccc31)Sc1cc(OC)ccc1-2
Agent: Br
Solvent: CCO
Product: CCN(CC)CCn1nc2c3c(c(NCCN)ccc31)Sc1cc(OC)ccc1-2
Yield: 39.9 %

Procedure:
Reaction of a solution of 4.5 g (0.0122 mol) of 5-amino-N,N-diethyl-8-methoxy-2H[1]benzothiopyrano-[4,3,2-cd]indazole-2-ethanamine and 7.5 g (0.0366 mol) of 2-bromoethylamine, hydrobromide, in 40 ml of EtOH as described in Example 38 gave 2.4 g of product.
Reaction SMILES: [C:1]([O:5][C:6]([CH:8]1[CH2:13][CH2:12][C:11](=[CH:14][C:15]([O:17]C(C)(C)C)=[O:16])[CH2:10][CH2:9]1)=[O:7])(C)(C)[CH3:2].[H][H]>[Pd].C(O)C>[CH2:1]([O:5][C:6]([CH:8]1[CH2:13][CH2:12][CH:11]([CH2:14][C:15]([OH:17])=[O:16])[CH2:10][CH2:9]1)=[O:7])[CH3:2]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)C=C1CCC(C(=O)OC(C)(C)C)CC1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)C1CCC(CC(=O)O)CC1
Yield: 99.8 %

Procedure:
A solution of diester (B) (12.5 g, 46.3 mmol) and 10% palladium on activated carbon (5 g) in absolute ethanol (200 mL) was exposed to a hydrogen atmosphere (at balloon pressure) and stirred vigorously for lh. After removal of catalyst by filtration and concentration, the resultant colorless oil was dissolved in methylene chloride (150 mL) and TEA (75 mL) and stirred for 15 min. All volatiles were removed by rotary evaporation and the resultant colorless oil placed under high vacuum to give (C) 4-carboxymethyl-cyclohexanecarboxylic acid ethyl ester (9.9 g, 99%) as a white solid. Data for cis/trans mixture: 1H NMR (400 MHz, CD3OD) δ 4.13 (2q, 4H), 2.58 (m, 1H), 2.30-2.20 (m, 1H), 2.20 (2d, 4H), 2.05-1.80 (m, 7H), 1.80-1.55 (m, 5H), 1.50-1.38 (m, 3H), 1.32-1.25 (m, 1H), 1.25 (2t, 6H), 1.10-1.00 (m, 2H); mass spectrum m/z 215 [(M+H)+; calcd for C11H19O4: 215].
Reaction SMILES: [NH:1]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C@H:2]([C:6]([N:8]1[CH2:15][CH2:14][CH2:13][C@H:9]1[C:10]([OH:12])=O)=[O:7])[CH:3]([CH3:5])[CH3:4].CN1CCOCC1.C(OC(Cl)=O)C(C)C.[NH2:38][C@H:39]([C:43]([C:45]([C:48]([F:51])([F:50])[F:49])([F:47])[F:46])=[O:44])[CH:40]([CH3:42])[CH3:41].Cl>C(Cl)Cl>[NH:1]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C@H:2]([C:6]([N:8]1[CH2:15][CH2:14][CH2:13][C@H:9]1[C:10]([NH:38][C@H:39]([C:43]([C:45]([C:48]([F:49])([F:50])[F:51])([F:46])[F:47])=[O:44])[CH:40]([CH3:41])[CH3:42])=[O:12])=[O:7])[CH:3]([CH3:4])[CH3:5]
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCC[C@H]1C(=O)O
Reactant: CC(C)[C@H](N)C(=O)C(F)(F)C(F)(F)F
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCC[C@H]1C(=O)N[C@H](C(=O)C(F)(F)C(F)(F)F)C(C)C
Temperature: -22 °C
Reaction time: 0.33 h
Yield: 78.6 %

Procedure:
Dissolve Boc-Val-Pro-OH (314 mg, 1.0 mmol) in methylene chloride (4 mL) and add N-methylmorpholine (252 mg, 2.5 mmol). Cool to -22° C. and add isobutylchloroformate (136 mg, 1.0 mmol). Stir for 20 minutes and add to H-Val-CF2CF3.hydrochloride (1.1 mmol). Stir for 1 hour at -22° C., allow to warm to room temperature and stir for 3 hours. Purify by silica gel chromatography (40% ethyl acetate/hexane) to give the title compound (405 mg).
Reaction SMILES: [CH2:1]([NH:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[CH2:2][CH2:3][CH2:4][CH3:5].[CH2:12]=O>>[CH3:12][N:6]([CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])[CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: CCCCCNCCCCC
Reactant: C=O
Product: CCCCCN(C)CCCCC
Yield: 96 %

Procedure:
In a similar manner to Example 1, 314.4 g (2.0 mol) of diamylamine (technical mixture of 18.3% by weight of diisopentylamine, 61.0% by weight of di-n/i-pentylamine and 19.2% by weight of di-n-pentylamine, remainder: 1.5% by weight) and 330.2 g (3.2 mol) of formaldehyde (29.1%) are reacted in a 1 l autoclave; a maximum pressure of 2.5 MPa is established at a temperature of 120° C. After the crude amine (aqueous and organic phase) has been degassed at a maximum temperature of 102° C., the water is removed on a water separator. The remaining organic phase is subsequently distilled. 329.1 g of N-methyldiamylamine having a purity of 91.8% are isolated, corresponding to a yield of 88.3% of theory.
Reaction SMILES: [C:1]1([O:11][CH2:12][CH2:13][CH2:14][N:15]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[CH3:30])=[C:16]2[C:31]([O:33]CC)=[O:32])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.O1CCOCC1>[Li+].[OH-]>[CH3:30][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=1[C:17]1[C:18]2[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:15]([CH2:14][CH2:13][CH2:12][O:11][C:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:4]=[CH:3][CH:2]=2)[C:16]=1[C:31]([OH:33])=[O:32]
Reactant: CCOC(=O)c1c(-c2ccccc2C)c2ccccc2n1CCCOc1cccc2ccccc12
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Product: Cc1ccccc1-c1c(C(=O)O)n(CCCOc2cccc3ccccc23)c2ccccc12

Procedure:
A mixture of EXAMPLE 31D in 1N LiOH:dioxane (0.5 mL: 2 mL) was heated under microwave conditions (CEM Discover) at 130° C. for 30 minutes. The mixture was quenched with 1NHCl aqueous mixture (0.5 mL) and extracted with ethyl acetate. The extract was dried (Na2SO4), filtered, and concentrated. The concentrate was purified by reverse phaseHPLC (Zorbax SB-C18, 20-100% acetonitrile/water/0.1% trifluoroacetic acid). 1H NMR (400 MHz, DMSO-d6) δ 12.73 (bs, 1H), 8.23 (d, 1H), 7.87 (d, 1H), 7.66 (d, 1H), 7.52 (m, 3H), 7.38 (t, 1H), 7.26 (m, 4H), 7.12 (m, 2H), 7.04 (m, 1H), 6.87 (d, 2H), 4.91 (t, 2H), 4.19 (t, 2H), 2.38 (m, 2H), 2.01 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][C@H:6]([N:13]1[C:17]([CH2:18][NH:19]C=O)=[CH:16][NH:15][C:14]1=[S:22])[CH2:7]2.[ClH:23].CS(C)=O>C(O)(C)C>[ClH:23].[NH2:19][CH2:18][C:17]1[N:13]([C@H:6]2[CH2:5][CH2:4][C:3]3[C:8](=[CH:9][C:10]([F:12])=[CH:11][C:2]=3[F:1])[CH2:7]2)[C:14](=[S:22])[NH:15][CH:16]=1
Reactant: O=CNCc1c[nH]c(=S)n1[C@H]1CCc2c(F)cc(F)cc2C1
Agent: Cl
Solvent: CS(C)=O
Solvent: CC(C)O
Product: NCc1c[nH]c(=S)n1[C@H]1CCc2c(F)cc(F)cc2C1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 79.8 %

Procedure:
A mixture of (S)-N-[3-(5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)-2-thioxo-2,3-dihydro-1H-imidazol-4-ylmethyl]formamide (19.1 g, 59.0 mmol), prepared as in Example 30, and 25 mL of concentrated hydrochloric acid (12.0M, 25 mL, 300 mmol) in 400 mL of isopropanol was heated to reflux over 12 minutes and stirred for 1 hour 40 minutes. The mixture was distilled removing 150 mL of isopropanol. The mixture was gradually cooled to room temperature and stirred for 3 hours 45 minutes. The material was isolated by filtration and the filter residue was washed with 75 mL of isopropanol. Drying in vacuo at 110° to 125° C. with a nitrogen bleed gave (S)-5-aminomethyl-1-(5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)-1,3-dihydroimidazole-2-thione hydrochloride (15.6 g, 47.1 mmol), m.p. 251.9° C. [α]D +10.2° C. (c=0.500, DMSO).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@@H:12]([CH2:13][CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[C@H:11]([C@H:20](OS(N2C=CN=C2)=O)[C@@H:21]([CH:37]([CH3:39])[CH3:38])[C:22]([N:24]2[C@H:28]([CH3:29])[C@H:27]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[O:26][C:25]2=[O:36])=[O:23])[O:10][C:9]1([CH3:49])[CH3:48])=[O:7])([CH3:4])([CH3:3])[CH3:2].C([SnH](CCCC)CCCC)CCC>C1(C)C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[C@@H:12]([CH2:13][CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[C@H:11]([CH2:20][C@H:21]([CH:37]([CH3:38])[CH3:39])[C:22]([N:24]2[C@H:28]([CH3:29])[C@H:27]([C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)[O:26][C:25]2=[O:36])=[O:23])[O:10][C:9]1([CH3:48])[CH3:49])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)[C@@H](C(=O)N1C(=O)O[C@@H](c2ccccc2)[C@H]1C)[C@@H](OS(=O)n1ccnc1)[C@@H]1OC(C)(C)N(C(=O)OC(C)(C)C)[C@H]1CC1CCCCC1
Agent: CCCC[SnH](CCCC)CCCC
Solvent: Cc1ccccc1
Product: CC(C)[C@@H](C[C@@H]1OC(C)(C)N(C(=O)OC(C)(C)C)[C@H]1CC1CCCCC1)C(=O)N1C(=O)O[C@@H](c2ccccc2)[C@H]1C
Yield: 90.5 %

Procedure:
A solution of the resultant product from Example 1E (6.50 g, 9.33 mmol) in 275 ml of dry toluene was degassed with argon for 30 min, then warmed to reflux (under argon). A solution of tri-n-butyltin hydride (5.43 g, 18.6 mmol) in 75 ml of dry, degassed toluene was added dropwise over 15 min. After an additional 2 h of reflux, the reaction was cooled, concentrated and purified by flash chromatography (5% EtOAc-hexanes) to afford 4.82 g (90%) of the title compound as a white foam. 1H NMR(CDCl3) 0.90 (d, 3H), 0.92 (d, 3H), 0.9-1.1 (bm, 3H), 1.06 (d, 3H), 1.15-1.35 (bm, 3H), 1.51 (s, 9H), 1.57-2.14 (several bm, 16H total), 3.84 (m, 1H), 3.97 (m, 1H), 4.85 (dq, 1H), 5.68 (d, 1 H), 7.3-7.46 (m, 5H). Mass spectrum: (M+H)+=571.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[CH3:5][O:6][C:7](=[O:17])[C:8]1[CH:13]=[CH:12][C:11]([CH2:14]Br)=[CH:10][C:9]=1[Cl:16]>CN(C)C=O>[CH3:5][O:6][C:7](=[O:17])[C:8]1[CH:13]=[CH:12][C:11]([CH2:14][N:1]=[N+:2]=[N-:3])=[CH:10][C:9]=1[Cl:16]
Reactant: [N-]=[N+]=[N-]
Reactant: COC(=O)c1ccc(CBr)cc1Cl
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(CN=[N+]=[N-])cc1Cl
Temperature: 50 °C
Reaction time: 8 h
Yield: 89.1 %

Procedure:
Add sodium azide (2.44 g, 37.49 mmol) to crude 4-bromomethyl-2-chloro-benzoic acid methyl ester (7.6 g, 28.84 mmol) in anhydrous dimethylformamide (100 mL) at room temperature under argon gas. Stir the reaction mixture at 50° C. overnight. Quench the reaction mixture with water and extract with ether (3×). Combine the organic layers, wash with brine, dry over sodium sulfate, and concentrate to provide the crude product (5.8 g, 25.7 mmol).
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH2:16][CH3:17])[CH3:15])[C:11]([CH3:18])=[CH:10][C:9]=1[NH2:19])([CH3:4])([CH3:3])[CH3:2].C([O:25][C:26](=O)[CH2:27][C:28](=[O:48])[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([N:35]2[C:39]([CH2:40][O:41][CH:42]3[CH2:47][CH2:46][CH2:45][CH2:44][O:43]3)=[CH:38][N:37]=[N:36]2)[CH:30]=1)(C)(C)C>>[C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH2:16][CH3:17])[CH3:15])[C:11]([CH3:18])=[CH:10][C:9]=1[NH:19][C:26](=[O:25])[CH2:27][C:28](=[O:48])[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([N:35]2[C:39]([CH2:40][O:41][CH:42]3[CH2:47][CH2:46][CH2:45][CH2:44][O:43]3)=[CH:38][N:37]=[N:36]2)[CH:30]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-n2nncc2COC2CCCCO2)c1
Reactant: CCN(C)c1cc(NC(=O)OC(C)(C)C)c(N)cc1C
Product: CCN(C)c1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-n3nncc3COC3CCCCO3)c2)cc1C

Procedure:
The title compound was prepared from [2-amino-5-(ethyl-methyl-amino)-4-methyl-phenyl]-carbamic acid tert-butyl ester (Example J25) (279 mg, 1.0 mmol) and (RS)-3-oxo-3-{3-[5-(tetrahydro-pyran-2-yloxymethyl)-[1,2,3]triazol-1-yl]-phenyl}-propionic acid tert-butyl ester (Example K5) (402 mg, 1.0 mmol) according to the general procedure M. Obtained as a yellow foam (400 mg, 66%).
Reaction SMILES: [NH2:1][C:2]1([C:11]2[N:16]=[CH:15][C:14]([C:17]#[N:18])=[C:13]([S:19]([CH3:21])=O)[N:12]=2)[O:10][C:6]2=[CH:7][CH:8]=[CH:9][C:5]2=[CH:4][CH2:3]1.SC[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=1.C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1([C:11]2[N:16]=[CH:15][C:14]([C:17]#[N:18])=[C:13]([S:19][CH2:21][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=3)[N:12]=2)[O:10][C:6]2=[CH:7][CH:8]=[CH:9][C:5]2=[CH:4][CH2:3]1
Reactant: CS(=O)c1nc(C2(N)CC=C3C=CC=C3O2)ncc1C#N
Reactant: SCCc1ccccn1
Solvent: COCCOC
Solvent: C1CCC2=NCCCN2CC1
Product: N#Cc1cnc(C2(N)CC=C3C=CC=C3O2)nc1SCCc1ccccn1

Procedure:
From 2-amino-4-benzofuran-2-yl-6-methanesulfinyl-pyrimidine-5-carbonitrile, 2-mercaptoethylpyridine and DBU in DME. ES-MS m/e (%:374 (M+H+, 100).
Reaction SMILES: [CH:1]1[C:14]2[CH2:13][C@H:12]3[NH:15][CH2:16][CH2:17][C@:6]4([C@H:11]3[CH2:10][CH2:9][CH2:8][CH2:7]4)[C:5]=2[CH:4]=[C:3]([C:18](=[O:20])[CH3:19])[CH:2]=1.C(=O)([O-])[O-].[K+].[K+].[CH:27]1([CH2:31]Cl)[CH2:30][CH2:29][CH2:28]1>CN(C)C=O>[C:18]([C:3]1[CH:2]=[CH:1][C:14]2[CH2:13][C@H:12]3[N:15]([CH2:31][CH:27]4[CH2:30][CH2:29][CH2:28]4)[CH2:16][CH2:17][C@@:6]4([C:5]=2[CH:4]=1)[C@H:11]3[CH2:10][CH2:9][CH2:8][CH2:7]4)(=[O:20])[CH3:19]
Reactant: ClCC1CCC1
Reactant: CC(=O)c1ccc2c(c1)[C@@]13CCCC[C@H]1[C@@H](C2)NCC3
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)c1ccc2c(c1)[C@@]13CCCC[C@H]1[C@@H](C2)N(CC1CCC1)CC3
Temperature: 25 °C
Yield: 76 %

Procedure:
To a mixture of 1.7 g, (-)-1-(morphinan-3-yl)ethanone, 1.5 g of potassium carbonate and 40 ml dimethylformamide, was added 1.2 g of cyclobutylmethyl chloride. After the mixture had been heated at 100°-110° for 16 hours it was cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure and the residue was dissolved in 120 ml of ether. The ether solution was washed with water (2×20 ml), dried over magnesium sulfate and removal of the solvent gave 1.6 g (76%) of crude (-)-3-acetyl-N-cyclobutylmethylmorphinan. For analysis, a sample of this compound was distilled, bp 200°-210° (0.05 mm), [α]25D-80.64° (c 1.03, MeOH).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7]Cl)=[CH:5][CH:4]=1.[P:11]([O:18]CC)([O:15][CH2:16][CH3:17])[O:12][CH2:13][CH3:14]>>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][P:11](=[O:18])([O:15][CH2:16][CH3:17])[O:12][CH2:13][CH3:14])=[CH:5][CH:4]=1
Reactant: COc1ccc(CCl)cc1
Reactant: CCOP(OCC)OCC
Product: CCOP(=O)(Cc1ccc(OC)cc1)OCC

Procedure:
4-methoxybenzylchloride and triethyl phosphite were reacted for 5 hrs at 150° C. Then the excessive triethylphosphite and a by product ethyl chloride were removed by reduced-pressure distillation to prepare diethyl 4-methoxybenzylphosphonate.
Reaction SMILES: [C:1]1([C:7]2[O:11][C:10]([SH:12])=[N:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(C(C)C)CC)(C)C.[CH2:22](Br)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[OH-].[Na+]>CCO>[CH2:22]([S:12][C:10]1[O:11][C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[N:8][N:9]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: Sc1nnc(-c2ccccc2)o1
Reactant: BrCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: c1ccc(CSc2nnc(-c3ccccc3)o2)cc1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 92.3 %

Procedure:
5-Phenyl-[1,3,4]oxadiazole-2-thiol (Aldrich, 3.1 g, 17.4 mmol) was added to EtOH (30 mL) and cooled to 0° C. while stirring. Diisopropylethylamine (3.1 mL, 17.4 mmol) was then added and the mixture became a clear solution. Benzyl bromide (2.08 mL, 17.4 mmol) was added and the resulting mixture was allowed to warm to room temperature while stirring. After 45 min, a thick white precipitate formed. The mixture was stirred an additional 1 hr followed by the addition of 1M NaOH (3 mL). The mixture was filtered, washed with 1M NaOH (2×20 mL), 3% citric acid (2×20 mL), H2O (2×20 mL) and the precipitate was dried under vacuum to afford 4.31 g (92%) 2-benzylsulfanyl-5-phenyl-[1,3,4]oxadiazole as a white solid. 1H NMR (CDCl3, 300 MHz) δ 4.57 (s, 2H), 7.37 (m, 3H), 7.48 (m, 5H), 7.99 (m, 2H); MS (DCl/NH3) m/z 269 (M+H)+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([NH:7][C:8]([NH2:10])=[S:9])=[CH:3][CH:2]=1.[CH2:11]([O:13][C:14](=[O:19])[C:15](=O)[CH2:16]Br)[CH3:12]>CO>[CH2:11]([O:13][C:14]([C:15]1[N:10]=[C:8]([NH:7][C:4]2[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=2)[S:9][CH:16]=1)=[O:19])[CH3:12]
Reactant: NC(=S)Nc1ccncc1
Reactant: CCOC(=O)C(=O)CBr
Solvent: CO
Product: CCOC(=O)c1csc(Nc2ccncc2)n1
Yield: 79.8 %

Procedure:
2-(Pyridin-4-ylamino)-thiazole-4-carboxylic acid ethyl ester (200 mg) was prepared according to General Procedure B using pyridin-4-yl-thiourea (154 mg) and 3-bromo-2-oxo-propionic acid ethyl ester (200 mg) in methanol (2 mL). The crude product was used without further purification.
Reaction SMILES: [SH:1][C:2]1[N:3]([CH3:12])[C:4](=[O:11])[C:5]2[S:10][CH:9]=[CH:8][C:6]=2[N:7]=1.[OH-].[Na+].O.[Cl:16][C:17]1[CH:32]=[C:31]([Cl:33])[CH:30]=[CH:29][C:18]=1[C:19]([C:21]1[CH:28]=[CH:27][C:24]([CH2:25]Br)=[CH:23][CH:22]=1)=[O:20]>C(O)C.O>[Cl:16][C:17]1[CH:32]=[C:31]([Cl:33])[CH:30]=[CH:29][C:18]=1[C:19]([C:21]1[CH:22]=[CH:23][C:24]([CH2:25][S:1][C:2]2[N:3]([CH3:12])[C:4](=[O:11])[C:5]3[S:10][CH:9]=[CH:8][C:6]=3[N:7]=2)=[CH:27][CH:28]=1)=[O:20]
Reactant: Cn1c(S)nc2ccsc2c1=O
Reactant: O=C(c1ccc(CBr)cc1)c1ccc(Cl)cc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cn1c(SCc2ccc(C(=O)c3ccc(Cl)cc3Cl)cc2)nc2ccsc2c1=O
Temperature: 60 °C
Reaction time: 1 h
Yield: 72.6 %

Procedure:
To a solution of 2-mercapto-3-methylthieno[3,2-d]-pyrimidin-4(3H)-one (1.0 g) and 1N-sodium hydroxide/water (5.5 ml) in ethanol (20 ml) was added 4-(2,4-dichlorobenzoyl)benzyl bromide (1.91 g) and the mixture was stirred at 60° C. for 1 hour. This reaction mixture was poured in water and the resulting crystals were collected by filtration, rinsed with water, and recrystallized from ethyl acetate to provide the title compound as colorless solid (1.69 g).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:33])[C:10]1[C:15]([F:16])=[C:14]([F:17])[C:13]([N:18]2[CH2:22][CH2:21][C@H:20]([NH:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:19]2)=[C:12]([F:31])[C:11]=1F)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:34]1([NH2:37])[CH2:36][CH2:35]1>CS(C)=O>[CH2:1]([O:8][C:9](=[O:33])[C:10]1[C:15]([F:16])=[C:14]([F:17])[C:13]([N:18]2[CH2:22][CH2:21][C@H:20]([NH:23][C:24]([O:26][C:27]([CH3:30])([CH3:28])[CH3:29])=[O:25])[CH2:19]2)=[C:12]([F:31])[C:11]=1[NH:37][CH:34]1[CH2:36][CH2:35]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCN(c2c(F)c(F)c(C(=O)OCc3ccccc3)c(F)c2F)C1
Reactant: NC1CC1
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N[C@H]1CCN(c2c(F)c(F)c(C(=O)OCc3ccccc3)c(NC3CC3)c2F)C1
Yield: 86.2 %

Procedure:
A solution of 4-[(S)-3-(tert-butoxycarbonylamino)pyrrolidin-1-yl]-2,3,5,6-tetrafluorobenzoic acid benzyl ester (Example 2d, 2.5 g, 5.3 mmol), cyclopropylamine (40 mL, 577 mmol), and dimethyl sulfoxide (20 mL) in a sealed glass tube is heated at 80° C. for 24 hours. The excess amine is removed by blowing in compressed air, and the solution is then concentrated under high vacuum. The residue is purified by column chromatography (1:1:7 ethyl acetate/chloroform/hexanes) to afford the title compound as a solid (2.31 g). 1H NMR (CDCl3): δ 7.47–7.27 (m, 5H), 7.12 (bs, 1H), 5.30 (s, 2H), 4.78–4.62 (m, 1H), 4.35–4.17 (m, 1H), 3.96–3.56 (m, 3H), 3.54–3.39 (m, 1H), 2.91–2.73 (m, 1H), 2.24–2.02 (m, 1H), 1.96–1.77 (m, 1H), 1.45 (s, 9H), 0.69–0.56 (m, 2H), 0.53–0.40 (m, 2H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][NH:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([N:24]3[CH:28]=[CH:27][N:26]=[CH:25]3)=[CH:20][CH:19]=2)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].Cl.[N:31]1[CH:36]=[CH:35][CH:34]=[C:33]([S:37](Cl)(=[O:39])=[O:38])[CH:32]=1>>[C:1]([O:5][C:6](=[O:29])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][N:16]([CH2:17][C:18]2[CH:19]=[CH:20][C:21]([N:24]3[CH:28]=[CH:27][N:26]=[CH:25]3)=[CH:22][CH:23]=2)[S:37]([C:33]2[CH:32]=[N:31][CH:36]=[CH:35][CH:34]=2)(=[O:39])=[O:38])[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)COc1cccc(CNCc2ccc(-n3ccnc3)cc2)c1
Reactant: O=S(=O)(Cl)c1cccnc1
Agent: Cl
Product: CC(C)(C)OC(=O)COc1cccc(CN(Cc2ccc(-n3ccnc3)cc2)S(=O)(=O)c2cccnc2)c1

Procedure:
The title compound of Step A was prepared from {3-[(4-imidazol-1-yl-benzylamino)-methyl]-phenoxy}-acetic acid tert-butyl ester, prepared in Step A of Example 13l, and pyridine-3-sulfonyl chloride hydrochloride, of Preparation 2, following the method described in Example 3, Step B. 1H NMR (400 MHz, CDCl3)δ 9.04 (d, 1H), 8.80 (dd, 1H), 8.06 (d, 1H), 7.83 (s, 1H), 7.44 (dd, 1H), 7.22 (m, 6H), 7.11 (t, 1H), 6.73 (dd, 1H), 6.64 (m, 2H), 4.39 (s, 2H), 4.38 (s, 2H), 4.32 (s, 2H), 1.47 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[NH:11][C:10]([C:20]3[CH:21]=[C:22]([CH:30]=[CH:31][C:32]=3[O:33][CH3:34])[CH2:23][N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)=[N:9]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:42](Cl)(=[O:46])[CH:43]([CH3:45])[CH3:44]>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH:12]([C:13]3[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=3)[N:11]([C:42](=[O:46])[CH:43]([CH3:45])[CH3:44])[C:10]([C:20]3[CH:21]=[C:22]([CH2:23][N:24]4[CH2:29][CH2:28][O:27][CH2:26][CH2:25]4)[CH:30]=[CH:31][C:32]=3[O:33][CH3:34])=[N:9]2)=[CH:4][CH:3]=1
Reactant: COc1ccc(CN2CCOCC2)cc1C1=NC(c2ccc(Cl)cc2)C(c2ccc(Cl)cc2)N1
Reactant: CC(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(CN2CCOCC2)cc1C1=NC(c2ccc(Cl)cc2)C(c2ccc(Cl)cc2)N1C(=O)C(C)C
Reaction time: 12 h

Procedure:
To a solution of 4-{3-[4,5-bis-(4-chloro-phenyl)-4,5-dihydro-1H-imidazol-2-yl]-4-methoxy-benzyl}-morpholine (100 mg, 0.20 mmol, as in the U.S. Provisional applications incorporated by reference herein, Example 31) in methylene chloride (10 mL) were sequentially added triethylamine (0.10 mL, 0.712 mmol) and isobutyryl chloride (42 μL, 0.392 mmol). The reaction mixture was stirred for 12 h. The solvents were removed under reduced pressure. Saturated sodium bicarbonate (2 mL) and methylene chloride (20 mL) were added and the layers were separated. The aqueous layer was extracted with methylene chloride (1×100 mL). The combined organic extracts were evaporated. Purification of the crude residue by Biotage flash chromatography eluting with 0-5% methanol in ethyl acetate gave 1-[4,5-bis-(4-chloro-phenyl)-2-(2-methoxy-5-morpholin-4-ylmethyl-phenyl)-4,5-dihydro-imidazol-1-yl]-2-methyl-propan-1-one. HR-MS (ES, m/z) calculated for C31H34N3O3Cl2[(M+H)+]566.1972, observed 566.1977.
Reaction SMILES: Cl.[CH3:2][NH:3][CH3:4].C(N(CC)CC)C.[Br:12][C:13]1[CH:14]=[C:15]([S:19](Cl)(=[O:21])=[O:20])[CH:16]=[CH:17][CH:18]=1.C(=O)([O-])O.[Na+]>C1COCC1>[Br:12][C:13]1[CH:14]=[C:15]([S:19]([N:3]([CH3:4])[CH3:2])(=[O:21])=[O:20])[CH:16]=[CH:17][CH:18]=1
Reactant: CNC
Reactant: O=S(=O)(Cl)c1cccc(Br)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CN(C)S(=O)(=O)c1cccc(Br)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 93.2 %

Procedure:
In THF (10 mL), dimethylamine hydrochloride (2.04 g, 25.0 mmol) and triethylamine (3.48 mL, 25.0 mmol) were dissolved, and 3-bromobenzenesulfonyl chloride (0.721 mL, 5.00 mmol) was added thereto at 0° C., and then, the mixture was stirred at room temperature for 1 hour. To the mixture, a saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give 3-bromo-N,N-dimethylbenzenesulfonamide (1.23 g, 4.66 mmol, yield: 93%).
Reaction SMILES: [C:1]([C:5]1[C:10]2[O:11][CH2:12][C:13]([CH3:15])([CH3:14])[C:9]=2[CH:8]=[C:7]([N+:16]([O-])=O)[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].CCCCCC.N#N>CCO.[Pd]>[NH2:16][C:7]1[CH:6]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:10]2[O:11][CH2:12][C:13]([CH3:15])([CH3:14])[C:9]=2[CH:8]=1
Reactant: CC(C)(C)c1cc([N+](=O)[O-])cc2c1OCC2(C)C
Agent: [Pd]
Agent: N#N
Solvent: CCO
Solvent: CCCCCC
Product: CC(C)(C)c1cc(N)cc2c1OCC2(C)C
Reaction time: 3 h

Procedure:
A mixture of 7-tert-butyl-3,3-dimethyl-5-nitro-2,3-dihydrobenzo[b]furan (2.2 g, 8.8 mmol) and 10% Pd on charcoal (220 mg) in EtOH (60 mL) is hydrogenated at 24° C. and 40 psi of H2 for 3 h. The reaction is monitored by TLC (EtOAC:hexane, 1:19). The reaction mixture is vented to N2, filtered through Celite, and evaporated to yield 5-amino-7-tert-butyl-3,3-dimethyl-2,3-dihydrobenzo[b]furan as a purple solid.