Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:4]1[CH2:8][C@H:7]([O:9][CH2:10][CH3:11])[C@H:6]([NH:12][C:13]2[C:18]([CH2:19][CH3:20])=[N:17][C:16]([C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=3[Cl:28])=[C:15]([CH2:29][CH3:30])[N:14]=2)[CH2:5]1)(=[O:3])C.ClC1C=C(Cl)C=CC=1C1N=C(CC)C(N[C@H]2[C@@H:52]([O:53]CC)CNC2)=NC=1CC.ClC(OC)=O>>[Cl:28][C:22]1[CH:23]=[C:24]([Cl:27])[CH:25]=[CH:26][C:21]=1[C:16]1[N:17]=[C:18]([CH2:19][CH3:20])[C:13]([NH:12][C@H:6]2[C@@H:7]([O:9][CH2:10][CH3:11])[CH2:8][N:4]([C:1]([O:53][CH3:52])=[O:3])[CH2:5]2)=[N:14][C:15]=1[CH2:29][CH3:30]
Reactant: CCO[C@H]1CN(C(C)=O)C[C@H]1Nc1nc(CC)c(-c2ccc(Cl)cc2Cl)nc1CC
Reactant: CCO[C@H]1CNC[C@H]1Nc1nc(CC)c(-c2ccc(Cl)cc2Cl)nc1CC
Agent: COC(=O)Cl
Product: CCO[C@H]1CN(C(=O)OC)C[C@H]1Nc1nc(CC)c(-c2ccc(Cl)cc2Cl)nc1CC

Procedure:
Following the procedure for the preparation of N-[(cis)-1-acetyl-4-ethoxypyrrolidin-3-yl]-5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-amine but substituting 5-(2,4-dichlorophenyl)-N-[(3R,4S)-4-ethoxypyrrolidin-3-yl]-3,6-diethylpyrazin-2-amine and methyl chloroformate, and making non-critical variations provided the title compound as an oil: 1H NMR (400 MHz, CDCl3) δ) 7.49, 7.34-7.26, 5.20, 4.73, 4.09, 3.95, 3.74, 3.60, 3.50, 3.39, 3.31, 3.26, 2.69, 2.47, 1.32-1.25, 1.15; IR (diffuse reflectance) 2971 (s), 2350 (w), 2341 (w), 2063 (w), 1940 (w), 1921 (w), 1710 (s), 1568, 1551, 1499, 1466 (s), 1452 (s), 1392 (s), 1373, 1102, cm−1; HRMS (FAB) calcd for C22H28Cl2N4O3+H 467.1617, found 467.1619. Anal. Calcd for C22H28Cl2N4O3: C, 56.54; H, 6.04; N, 11.99. Found: C, 56.64; H, 6.27; N, 11.92.
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1[CH:5]=[C:6]([O:10]COCCOC)[CH:7]=[CH:8][CH:9]=1.Cl[C:18]1[O:19][C:20]2[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=2[N:22]=1>>[O:19]1[C:20]2[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=2[N:22]=[C:18]1[N:2]([CH2:3][C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1)[CH3:1]
Reactant: Clc1nc2ccccc2o1
Reactant: CNCc1cccc(OCOCCOC)c1
Product: CN(Cc1cccc(O)c1)c1nc2ccccc2o1
Temperature: 140 °C

Procedure:
MS (ESI) 255 (M+H)+. Prepared from 3-[(methylamino)-methyl]-(2-methoxyethoxy-methoxy)benzene (example 28) and 2-chloro-benzoxazole. Also, omit heating to 140° C. Reaction stirred at room temperature.
Reaction SMILES: [C:1]1([C:7]#[CH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(NC(C)C)(C)C.I[C:17]1[CH:22]=[CH:21][C:20]([O:23][C:24](=[O:33])[N:25]([CH3:32])[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[CH:19][CH:18]=1>[Cu]I.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[C:1]1([C:7]#[C:8][C:17]2[CH:18]=[CH:19][C:20]([O:23][C:24](=[O:33])[N:25]([CH3:32])[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[CH:21][CH:22]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CN(C(=O)Oc1ccc(I)cc1)c1ccccc1
Reactant: C#Cc1ccccc1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: [Cu]I
Agent: [Pd]
Solvent: CC(C)NC(C)C
Product: CN(C(=O)Oc1ccc(C#Cc2ccccc2)cc1)c1ccccc1
Temperature: 70 °C
Reaction time: 8 h
Yield: 41 %

Procedure:
Phenylacetylene (1.2 mmol), diisopropylamine (1.2 mmol), CuI (0.03 mmol), Pd2(dba)3 (0.03 mmol), Pd(P(t-Bu)3)2 (0.06 mmol) and methyl-phenyl-carbamic acid 4-iodo-phenyl ester (1.0 mmol) were added to a Schlenk tube under nitrogen. The Schlenk tube was evacuated and refilled with nitrogen five times. Then dioxane (2 mL) was added and the reaction mixture was stirred at 70° C. for 8 h. The crude product was purified by flash chromatography (Quad flash 12, EtOAc-heptane) giving the title compound in 41% yield as brown oil.
Reaction SMILES: F.F.F.C(N(CC)CC)C.C(N(CC)CC)C.[B-](F)(F)(F)F.CCN([S+](F)[F:29])CC.[CH:31]([N:44]1[CH2:47][C:46]([C:49]2[CH:54]=[CH:53][C:52]([C:55]3[CH2:59][C:58]([C:64]4[CH:69]=[C:68]([Cl:70])[C:67]([Cl:71])=[C:66]([Cl:72])[CH:65]=4)([C:60]([F:63])([F:62])[F:61])[O:57][N:56]=3)=[CH:51][C:50]=2[Br:73])(O)[CH2:45]1)([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>ClCCl>[CH:31]([N:44]1[CH2:45][C:46]([C:49]2[CH:54]=[CH:53][C:52]([C:55]3[CH2:59][C:58]([C:64]4[CH:69]=[C:68]([Cl:70])[C:67]([Cl:71])=[C:66]([Cl:72])[CH:65]=4)([C:60]([F:63])([F:62])[F:61])[O:57][N:56]=3)=[CH:51][C:50]=2[Br:73])([F:29])[CH2:47]1)([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: OC1(c2ccc(C3=NOC(c4cc(Cl)c(Cl)c(Cl)c4)(C(F)(F)F)C3)cc2Br)CN(C(c2ccccc2)c2ccccc2)C1
Reactant: CCN(CC)[S+](F)F
Agent: F
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: FC1(c2ccc(C3=NOC(c4cc(Cl)c(Cl)c(Cl)c4)(C(F)(F)F)C3)cc2Br)CN(C(c2ccccc2)c2ccccc2)C1
Temperature: -78 °C
Reaction time: 2 h
Yield: 91.7 %

Procedure:
Triethylamine trihydrofluoride (0.3 mL, 1.7 mmol) and triethylamine (0.11 mL, 0.8 mL) were dissolved in dichloromethane (30 mL) and cooled to −78° C. To the cooled mixture was added XtalFluor-E (310 mg, 1.4 mmol) and then 1-benzhydryl-3-(2-bromo-4-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)phenyl)azetidin-3-ol (Preparation 28, 600 mg, 0.8 mmol). Cooling was removed and the mixture was allowed to warm to room temperature with stirring for 2 hours. The reaction was poured into saturated aqueous sodium carbonate solution (100 mL) and the organic phase was separated, dried over anhydrous sodium sulfate, filtered and evaporated to dryness. Crude material was chromatographed (40 G Redi-Sep Column) eluting from 100% heptane to 20:80 EtOAc:heptane to afford the intermediate (523 mg, 87%) as a glass. 1HNMR (CDCl3) δ ppm: 7.90 (1H), 7.69-7.66 (3H), 7.47-7.21 (11H), 4.46 (1H), 4.08 (1H), 3.90-3.66 (5H); m/z (Cl) 713 ([M+H]+.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[CH:10]([C:13]1[CH:14]=[C:15]([OH:19])[CH:16]=[CH:17][CH:18]=1)([CH3:12])[CH3:11]>>[CH:10]([C:13]1[CH:14]=[C:15]([CH:16]=[CH:17][CH:18]=1)[O:19][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1)([CH3:12])[CH3:11]
Reactant: N#Cc1ccc(Br)cc1
Reactant: CC(C)c1cccc(O)c1
Product: CC(C)c1cccc(Oc2ccc(C#N)cc2)c1
Yield: 33 %

Procedure:
Use a method similar to Preparation 32 (Step 1), using 4-bromobenzonitrile (2.0 g, 11.3 mmol) and 3-isopropylphenol (3.08 g, 22.6 mmol) to give 4-(3′-isopropylphenoxy)-benzonitrile (885 mg, 33%). MS (ES+) m/z: 255 (M+NH4)+.
Reaction SMILES: Cl.COCCOCCOC.II.[CH2:13]([O:15][C:16](=[O:19])[CH2:17]Br)[CH3:14].[C:20](#[N:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>[Zn]>[CH2:13]([O:15][C:16](=[O:19])[CH:17]=[C:20]([NH2:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH3:14]
Reactant: CCOC(=O)CBr
Reactant: N#Cc1ccccc1
Agent: Cl
Agent: II
Agent: [Zn]
Solvent: COCCOCCOC
Product: CCOC(=O)C=C(N)c1ccccc1
Temperature: 25 °C
Reaction time: 17 h
Yield: 95 %

Procedure:
21 g of (97.2%) zinc dust are treated, according to Example 4, with 2% (by weight) aqueous hydrochloric acid. The zinc activated in this manner is placed into 75 ml of diethylene glycol dimethyl ether, and 0.6 g of iodine is added. There is then added at 25° C. (if necessary with external cooling) a mixture of 16.7 ml of bromoacetic acid ethyl ester and 15.4 ml of benzonitrile. The mixture is stirred for 17 hours at room temperature, and subsequently processed basically analogously to Example 2. The β-aminocinnamic acid ethyl ester is obtained in 95% yield. When in the above Example the solvent diethylene glycol dimethyl ether is replaced by toluene or diethyl ether, the procedure being otherwise the same, there are likewise obtained good yields of β-aminocinnamic acid ethyl ester.
Reaction SMILES: [N+:1]([C:4]1[CH:27]=[CH:26][C:7]([CH2:8][O:9][C:10]([C:12]2[N:13]=[C:14]([N:17]3[CH2:20][CH:19](OS(C)(=O)=O)[CH2:18]3)[S:15][CH:16]=2)=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:28]([O-:31])(=[S:30])[CH3:29].[K+]>CN(C)C=O>[C:28]([S:30][CH:19]1[CH2:20][N:17]([C:14]2[S:15][CH:16]=[C:12]([C:10]([O:9][CH2:8][C:7]3[CH:26]=[CH:27][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=3)=[O:11])[N:13]=2)[CH2:18]1)(=[O:31])[CH3:29]
Reactant: CS(=O)(=O)OC1CN(c2nc(C(=O)OCc3ccc([N+](=O)[O-])cc3)cs2)C1
Reactant: CC([O-])=S
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)SC1CN(c2nc(C(=O)OCc3ccc([N+](=O)[O-])cc3)cs2)C1
Temperature: 90 °C
Reaction time: 4 h
Yield: 10 %

Procedure:
To a solution of 1-(4-p-nitrobenzyloxycarbonyl-1,3-thiazol-2-yl)-3-methanesulfonyloxyazetidine (776 mg, 1.88 mmol) (obtained as described in Reference Example 2(7)) in dimethylformamide (35 ml) was added potassium thioacetate (860 mg, 7.53 mmol) at room temperature. The mixture was stirred in an oil bath (90° C.) for 4 hours. After checking the completion of the reaction, the reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate solution. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using n-hexane:ethyl acetate (1:1) as the eluant to afford 3-acetylthio-1-(4-p-nitrobenzyloxycarbonyl-1,3-thiazol-2-yl)azetidine (73.8 mg, yield 11%) as a pale brown solid.
Reaction SMILES: COC1C=CC(C[NH:8][C:9]2[C:14]([C:15]([F:18])([F:17])[F:16])=[CH:13][CH:12]=[C:11]([CH3:19])[N:10]=2)=CC=1>FC(F)(F)C(O)=O>[CH3:19][C:11]1[N:10]=[C:9]([NH2:8])[C:14]([C:15]([F:18])([F:16])[F:17])=[CH:13][CH:12]=1
Reactant: COc1ccc(CNc2nc(C)ccc2C(F)(F)F)cc1
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(C(F)(F)F)c(N)n1

Procedure:
N-(4-Methoxybenzyl)-6-methyl-3-(trifluoromethyl)pyridin-2-amine (100 mg, 338 μmol, Eq: 1.00) in trifluoroacetic acid (2 ml) was heated under reflux for 30 min. The mixture was concentrated. The crude product (120 mg, pink solid) was used in the next step without further purification. MS: m/z=218.2 (M+H+)
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:8]=[C:7]([P:9]([OH:12])(=[O:11])[OH:10])[CH:6]=[C:5]([P:13]([OH:16])(=[O:15])[OH:14])[CH:4]=1.[C:17](Cl)(Cl)=[S:18]>O>[N:2]([C:3]1[CH:8]=[C:7]([P:9]([OH:10])(=[O:12])[OH:11])[CH:6]=[C:5]([P:13]([OH:16])(=[O:14])[OH:15])[CH:4]=1)=[C:17]=[S:18]
Reactant: S=C(Cl)Cl
Reactant: Nc1cc(P(=O)(O)O)cc(P(=O)(O)O)c1
Agent: Cl
Solvent: O
Product: O=P(O)(O)c1cc(N=C=S)cc(P(=O)(O)O)c1
Temperature: 20 °C
Reaction time: 2.5 h

Procedure:
Aniline-3,5-diphosphonic acid hydrochloride(500 mg, 1.73 mmole) was dissolved in water(5 ml) and thiophosgene(600 mg, 5.2 mmole) was added and the mixture stirred vigorously at 20° C. for 2.5 hours. Volatiles were removed in vacuo and the residue was dissolved in water(10 ml), filtered and lyophilised. 490 mg. 96%
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([C:10](=[CH:13][N:14](C)C)[C:11]#[N:12])=[O:9])=[CH:6][C:5]([N+:17]([O-:19])=[O:18])=[CH:4][N:3]=1>C(O)C.[OH-].[NH4+]>[N+:17]([C:5]1[CH:6]=[C:7]2[C:2](=[N:3][CH:4]=1)[NH:12][CH:11]=[C:10]([C:13]#[N:14])[C:8]2=[O:9])([O-:19])=[O:18]
Reactant: CN(C)C=C(C#N)C(=O)c1cc([N+](=O)[O-])cnc1Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: CCO
Product: N#Cc1c[nH]c2ncc([N+](=O)[O-])cc2c1=O
Yield: 111.9 %

Procedure:
A solution of 22.4 g (79.8 mmol) of 2-(2-chloro-5-nitro-pyridine-3-carbonyl)-3-dimethylamino-acrylonitrile was refluxed in a mixture of 500 ml of ethanol and 180 ml of conc. ammonium hydroxide for 2 hr. The mixture was cooled and solid was collected which was washed with ether. Concentrating the filtrate gave a second crop which was collected and washed with ether. Solids were combined. After drying, 19.3 g of the title compound was obtained as a yellow solid: mass spectrum (electrospray, m/e): M−H 215 (negative mode).
Reaction SMILES: [CH3:1][O:2][CH:3]([O:12][CH3:13])[C:4]([CH3:11])(OC(=O)C)[CH:5]=[CH2:6]>[Cu]Cl>[C:3]([O:12][CH2:6][CH:5]=[C:4]([CH3:11])[CH:3]([O:2][CH3:1])[O:12][CH3:13])(=[O:2])[CH3:4]
Reactant: C=CC(C)(OC(C)=O)C(OC)OC
Agent: Cl[Cu]
Product: COC(OC)C(C)=CCOC(C)=O
Temperature: 147 °C
Yield: 81.4 %

Procedure:
564 parts of 1,1-dimethoxy-2-methyl-2-acetoxy-but-3-ene and 0.3 parts of copper (I) chloride were heated, with stirring, at 147° C., under a pressure of 0.2 bar, in a reaction vessel equipped with a stirrer, an internal thermometer, and a descending condenser. During the reaction time of 7.5 hours, the low-boiling products formed distilled off continuously and the reaction temperature rose to 157° C. Subsequent working up of the reaction mixture by distillation gave 459 parts of 4,4-dimethoxy-3-methyl-crotyl acetate, corresponding to a yield of 81.4% of theory.
Reaction SMILES: N1C2C(=CC=C3C=2N=CC=C3)C=CC=1.C([O-])([O-])=O.[Cs+].[Cs+].I[C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=1.[CH3:30][C:31](=[CH2:34])[CH2:32][OH:33]>[Cu]I.C1(C)C=CC=CC=1>[CH3:34][C:31](=[CH2:30])[CH2:32][O:33][C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=1
Reactant: COc1ccc(I)cc1
Reactant: C=C(C)CO
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: Cc1ccccc1
Product: C=C(C)COc1ccc(OC)cc1
Temperature: 110 °C
Reaction time: 28 h
Yield: 78 %

Procedure:
A test tube was charged with CuI (20 mg, 0.10 mmol, 0.10 equiv), 1,10-phenanthroline (36 mg, 0.20 mmol, 0.20 equiv), Cs2CO3 (652 mg, 2.0 mmol, 2.0 equiv), 4-iodoanisole (234 mg, 1.0 mmol, 1.0 equiv), 2-methyl-2-propen-1-ol (168 μL, 2.0 mmol, 2.0 equiv) and toluene (0.5 mL). The test tube was sealed and the reaction mixture was stirred at 110° C. for 28 h. The resulting suspension was cooled to room temperature and filtered through a 0.5×1 cm pad of silica gel, eluting with diethyl ether. The filtrate was concentrated in vacuo. Purification of the residue by flash chromatography on silica gel (2×20 cm; pentane:diethyl ether 30:1) provided 139 mg (78% yield) of the title compound as a colorless solid.
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]1[C:12]2[C:7](=[CH:8][C:9](/[CH:13]=[CH:14]/[C:15]([C:17]3[CH:18]=[N:19][C:20]([S:23][CH3:24])=[N:21][CH:22]=3)=[O:16])=[CH:10][CH:11]=2)[CH2:6][CH2:5]1.[N:25]1[CH:30]=[CH:29][C:28]([CH:31]=[O:32])=[CH:27][CH:26]=1>>[CH3:1][O:2][N:3]=[C:4]1[C:12]2[C:7](=[CH:8][C:9]([CH:13]([CH2:14][C:15]([C:17]3[CH:18]=[N:19][C:20]([S:23][CH3:24])=[N:21][CH:22]=3)=[O:16])[C:31]([C:28]3[CH:29]=[CH:30][N:25]=[CH:26][CH:27]=3)=[O:32])=[CH:10][CH:11]=2)[CH2:6][CH2:5]1
Reactant: CON=C1CCc2cc(/C=C/C(=O)c3cnc(SC)nc3)ccc21
Reactant: O=Cc1ccncc1
Product: CON=C1CCc2cc(C(CC(=O)c3cnc(SC)nc3)C(=O)c3ccncc3)ccc21
Yield: 74 %

Procedure:
The title compound (2.9 g, 74%) was prepared from the product of Step 2 and 4-pyridinecarboxaldehyde using the method of Example 1 Step 4; MS(ES+) m/e 447 [M+H]+.
Reaction SMILES: ClC1C(F)=CC(F)=C(C=1)C(NS(C)(=O)=O)=O.[Cl:17][C:18]1[C:19](F)=[CH:20][C:21]([F:33])=[C:22]([CH:32]=1)[C:23]([NH:25][S:26](=[O:31])(=[O:30])[N:27]([CH3:29])[CH3:28])=[O:24].[C:35]12([CH2:45][OH:46])[CH2:44][CH:39]3[CH2:40][CH:41]([CH2:43][CH:37]([CH2:38]3)C1)[CH2:42]2>>[Cl:17][C:18]1[C:19]([O:46][CH:45]2[CH2:40][CH:39]3[CH2:44][CH:35]2[CH:42]2[CH:38]3[CH2:37][CH2:43][CH2:41]2)=[CH:20][C:21]([F:33])=[C:22]([CH:32]=1)[C:23]([NH:25][S:26](=[O:31])(=[O:30])[N:27]([CH3:29])[CH3:28])=[O:24]
Reactant: OCC12CC3CC(CC(C3)C1)C2
Reactant: CN(C)S(=O)(=O)NC(=O)c1cc(Cl)c(F)cc1F
Agent: CS(=O)(=O)NC(=O)c1cc(Cl)c(F)cc1F
Product: CN(C)S(=O)(=O)NC(=O)c1cc(Cl)c(OC2CC3CC2C2CCCC32)cc1F

Procedure:
Following the procedure as described in Example 8 and making variations as required to replace 5-chloro-2,4-difluoro-N-(methylsulfonyl)benzamide with 5-chloro-N-(N,N-dimethylsulfamoyl)-2,4-difluorobenzamide and adamantan-1-ylmethanol with 2-tricyclo[5.2.1.0 {2,6}]decan-8-ol, the title compound was obtained as a colorless solid (0.03 g, 7%): 1H NMR (300 MHz, CDCl3) δ 8.70-8.58 (m, 1H), 8.10-8.03 (m, 1H), 6.70-6.58 (m, 1H), 4.27-4.09 (m, 1H), 3.03 (s, 6H), 2.28 (s, 1H), 2.17-2.10 (m, 1H), 2.02-1.65 (m, 6H), 1.65-1.56 (m, 1H), 1.54-1.39 (m, 2H), 1.36-1.17 (m, 1H), 1.13-0.90 (m, 2H); MS (ES+) m/z 431.1 (M+1), 433.1 (M+1);
Reaction SMILES: [O:1]([CH2:8][CH2:9][S:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]([OH:26])=O)=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:39][N:40]([CH3:46])[CH2:41][CH2:42][CH2:43][CH2:44][NH2:45]>C1COCC1>[CH3:39][N:40]([CH3:46])[CH2:41][CH2:42][CH2:43][CH2:44][NH:45][C:24]([C:19]1[C:18]([C:15]2[CH:14]=[CH:13][C:12]([CH2:11][S:10][CH2:9][CH2:8][O:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[CH:17][CH:16]=2)=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:26]
Reactant: CN(C)CCCCN
Reactant: O=C(O)c1ccccc1-c1ccc(CSCCOc2ccccc2)cc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CN(C)CCCCNC(=O)c1ccccc1-c1ccc(CSCCOc2ccccc2)cc1
Yield: 98.3 %

Procedure:
Prepared in the same manner as described for example 1. A solution of 4′-(2-phenoxy-ethylsulfanylmethyl)-biphenyl-2-carboxylic acid (0.85 g, 2.33 mmol, 1 eq.) in anhydrous THF was treated with 1,1′-carbonyldiimidazole (0.40 g, 2.45 mmol, 1.05 eq.) and warmed as described. The reaction was allowed to cool and then treated with 4-dimethylaminobutylamine (0.33 g, 2.80 mmol, 1.2 eq.). The reaction was treated as described in example 1 to give a yellow oil. The oil was purified by silica gel flash chromatography using 5% 2M NH3 in methanol in chloroform as the mobile phase. Fractions containing the product were pooled and the solvent removed in vacuo leaving 4′-(2-phenoxy-ethylsulfanylmethyl)-biphenyl-2-carboxylic acid (4-dimethylamino-butyl)-amide (1.06 g, 98% yield) as a light yellow oil.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:20])[N:9]([CH:11]([C:16]([NH:18][CH3:19])=[O:17])[C:12]([O:14][CH3:15])=[O:13])[CH3:10])=[CH:4][CH:3]=1.[C:21]([C:23]1[CH:28]=[CH:27][C:26]([CH:29]([NH:31][CH:32]2[CH2:34][CH2:33]2)[CH3:30])=[CH:25][CH:24]=1)#[CH:22]>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.[Cu]I.C(Cl)(Cl)Cl>[CH:32]1([NH:31][CH:29]([C:26]2[CH:25]=[CH:24][C:23]([C:21]#[C:22][C:2]3[CH:7]=[CH:6][C:5]([C:8](=[O:20])[N:9]([CH:11]([C:16]([NH:18][CH3:19])=[O:17])[C:12]([O:14][CH3:15])=[O:13])[CH3:10])=[CH:4][CH:3]=3)=[CH:28][CH:27]=2)[CH3:30])[CH2:34][CH2:33]1
Reactant: CNC(=O)C(C(=O)OC)N(C)C(=O)c1ccc(I)cc1
Reactant: C#Cc1ccc(C(C)NC2CC2)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: ClC(Cl)Cl
Product: CNC(=O)C(C(=O)OC)N(C)C(=O)c1ccc(C#Cc2ccc(C(C)NC3CC3)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 81.2 %

Procedure:
Intermediate 6-2 (0.11 g), PdCl2(PPh3)2 (10 mg), CuI (5.0 mg), and TEA (28 mg) were added to a chloroform (5.0 mL) solution of N-[1-(4-ethynylphenyl)ethyl]cyclopropylamine (51 mg) as obtained in Example 14-(3), and the mixture was stirred in a nitrogen atmosphere for 2 hours at room temperature, whereafter the reaction mixture was concentrated. The resulting residue was purified by OH type silica gel chromatography (ethyl acetate) to obtain 1-[1-(cyclopropylamino)ethyl]-4-[(4-{[1-methoxy-3-(methylamino)-1,3-dioxopropan-2-yl](methyl)carbamoyl}phenyl)ethynyl]benzene (light yellow foam) (0.10 g, 85%).
Reaction SMILES: [N+:1]([C:4]1[C:12]([N+:13]([O-])=O)=[CH:11][C:7]2[O:8][CH2:9][O:10][C:6]=2[CH:5]=1)([O-:3])=[O:2]>C(O)(=O)C>[N+:1]([C:4]1[C:12]([NH2:13])=[CH:11][C:7]2[O:8][CH2:9][O:10][C:6]=2[CH:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1cc2c(cc1[N+](=O)[O-])OCO2
Solvent: CC(=O)O
Product: Nc1cc2c(cc1[N+](=O)[O-])OCO2
Temperature: 0 °C
Yield: 84.4 %

Procedure:
Compound 5,6-dinitrobenzo[d][1,3]dioxole (6.0 g, 28.3 mmol) was added to stirred glacial acetic acid (120 mL) under N2 atmosphere. After the mixture was heated to boiling, the heat source was removed and iron powder (4.75 g) added with vigorous stirring. Quick spontaneous boiling occurred, the mixture turned dark and the exothermic reaction subsided (2˜5 min). The mixture was refluxed for 10 min and poured into ice/water. The orange-red product was isolated by filtration, dissolved in glacial acetic acid, and the solution filtered while hot. The filtrate was poured into ice-cold water. The orange-red solid product was isolated by filtration and dried to provide compound 6-nitrobenzo[d][1,3]dioxol-5-amine (4.35 g, 84%). LCMS: 183 [M+1]+; 1H NMR (DMSO-d6) δ 6.06 (s, 2H), 6.51 (s, 1H), 7.36 (s, 1H), 7.73 (s, 2H).
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].C(N(C(C)C)CC)(C)C.[F:14][C:15]1[CH:16]=[C:17]([CH2:21][CH2:22][C@@H:23]2[CH2:27][CH2:26][CH2:25][NH:24]2)[CH:18]=[CH:19][CH:20]=1>C(Cl)Cl>[F:14][C:15]1[CH:16]=[C:17]([CH2:21][CH2:22][C@@H:23]2[CH2:27][CH2:26][CH2:25][N:24]2[C:1](=[O:3])[CH3:2])[CH:18]=[CH:19][CH:20]=1
Reactant: Fc1cccc(CC[C@@H]2CCCN2)c1
Reactant: CC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)N1CCC[C@H]1CCc1cccc(F)c1
Reaction time: 1.5 h

Procedure:
Acetyl chloride (0.29 ml) was added to a solution of N,N-diisopropyl-N-ethylamine (0.71 ml) and (R)-2-[2-(3-fluorophenyl)ethyl]-pyrrolidine (Intermediate 233, 0.39 g) in DCM (30 ml) and the mixture was stirred for 1.5 hours. The mixture was washed with 1M HCl, dried (MgSO4) and filtered. The filtrate was evaporated to dryness to give 1-{(R)-2-[2-(3-fluorophenyl)ethyl]-pyrrolidin-1-yl}ethanone (0.48 g) as an oil.
Reaction SMILES: [CH3:1][NH2:2].[O:3]=[C:4]1[NH:9][C:8]2[CH:10]=[C:11]([C:14]([N:16]3[C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=4[O:19][CH2:18][CH:17]3[CH2:26][C:27](OCC)=[O:28])=[O:15])[CH:12]=[CH:13][C:7]=2[O:6][CH2:5]1>CO>[CH3:1][NH:2][C:27](=[O:28])[CH2:26][CH:17]1[N:16]([C:14]([C:11]2[CH:12]=[CH:13][C:7]3[O:6][CH2:5][C:4](=[O:3])[NH:9][C:8]=3[CH:10]=2)=[O:15])[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[O:19][CH2:18]1
Reactant: CCOC(=O)CC1COc2ccccc2N1C(=O)c1ccc2c(c1)NC(=O)CO2
Reactant: CN
Solvent: CO
Product: CNC(=O)CC1COc2ccccc2N1C(=O)c1ccc2c(c1)NC(=O)CO2
Temperature: 25 °C
Reaction time: 16 h
Yield: 100 %

Procedure:
Methylamine (370 mL) was added slowly into a solution of ethyl {4-[(3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl)carbonyl]-3,4-dihydro-2H-1,4-benzoxazin-3-yl}acetate (Intermediate 4, 10.7 g, 26.9 mmol) in MeOH (640 mL) at rt. The resulting mixture was stirred at rt for 16 h. The organic solvent was removed by evaporation under reduced pressure. The crude product was purified by re-crystallization from MeOH to afford the title compound (10.3 g, 100%) as a white power.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]=[CH:9][C:10]([NH:12][CH:13]([C:15]1[CH:24]=[C:23]2[C:18]([CH2:19][CH2:20][CH2:21][NH:22]2)=[CH:17][CH:16]=1)[CH3:14])=[O:11].[BH4-].[Na+].[CH3:27]O>C(O)=O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]=[CH:9][C:10]([NH:12][CH:13]([C:15]1[CH:24]=[C:23]2[C:18]([CH2:19][CH2:20][CH2:21][N:22]2[CH3:27])=[CH:17][CH:16]=1)[CH3:14])=[O:11]
Reactant: CC(NC(=O)C=Cc1ccccc1F)c1ccc2c(c1)NCCC2
Reactant: CO
Agent: [BH4-]
Agent: [Na+]
Solvent: O=CO
Product: CC(NC(=O)C=Cc1ccccc1F)c1ccc2c(c1)N(C)CCC2
Reaction time: 16 h
Yield: 91 %

Procedure:
A solution of 3-(2-fluoro-phenyl)-N-[1-(1,2,3,4-tetrahydro-quinolin-7-yl)-ethyl]-acrylamide (39 mg, 0.12 mmol) in formic acid (3 mL) was treated at 23° C. with small portions of NaBH4 (136 mg, 3.6 mmol). The reaction mixture was stirred for 16 hours, then MeOH was added and the solvent evaporated. The residue was partitioned between EtOAc and aqueous NaHCO3. The organic phase was washed with water, dried (MgSO4) and evaporated. The crude material was purified by chromatography (SiO2, 5% CH3CN in CH2Cl2) yielding 37 mg (91%) of the title compound as a tan solid.