Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br.[F:2][C:3]1[CH:9]=[C:8]([F:10])[C:7]([O:11][CH3:12])=[CH:6][C:4]=1[NH2:5].C(N(CC)CC)C.C(O[CH:23]=[C:24]([C:30](=[O:43])[C:31]1[CH:36]=[C:35]([F:37])[C:34]([N+:38]([O-:40])=[O:39])=[C:33]([CH3:41])[C:32]=1F)[C:25]([O:27][CH2:28][CH3:29])=[O:26])C>C(Cl)(Cl)Cl>[F:2][C:3]1[CH:9]=[C:8]([F:10])[C:7]([O:11][CH3:12])=[CH:6][C:4]=1[N:5]1[C:32]2[C:31](=[CH:36][C:35]([F:37])=[C:34]([N+:38]([O-:40])=[O:39])[C:33]=2[CH3:41])[C:30](=[O:43])[C:24]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:23]1
Reactant: COc1cc(N)c(F)cc1F
Reactant: CCOC=C(C(=O)OCC)C(=O)c1cc(F)c([N+](=O)[O-])c(C)c1F
Agent: Br
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1cn(-c2cc(OC)c(F)cc2F)c2c(C)c([N+](=O)[O-])c(F)cc2c1=O
Reaction time: 0.17 h
Yield: 46.5 %

Procedure:
2,4-Difluoro-5-methoxyaniline monohydrobromide (780 mg) and a solution of triethylamine (328 mg) in chloroform (10 ml) were added dropwise to a solution of ethyl 3-ethoxy-2-(2',5'-difluoro-3'-methyl-4'-nitrobenzoyl)acrylate (2.0 g) in chloroform (10 ml) at 0° C. After the mixture was stirred for 10 minutes, the solvent and the like were distilled off. Anhydrous potassium carbonate (510 mg) was added to a solution of the whole amount of the residue in N,N-dimethylformamide (10 ml), and the mixture was stirred at 70° C. for 5 hours. Ethyl acetate and water were added to the reaction mixture to collect an organic layer. After the organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off. Ethanol was added to the residue to disperse it therein, and filtration was conducted to obtain the title compound (660 mg) as a pale yellow powder.
Reaction SMILES: [Br-].[C:2]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([OH:4])=[O:3].[CH2:29]([O:31][C:32]1[CH:39]=[CH:38][C:35]([CH:36]=O)=[CH:34][CH:33]=1)[CH3:30]>C1COCC1>[CH2:29]([O:31][C:32]1[CH:39]=[CH:38][C:35]([CH:36]=[CH:9][CH2:8][CH2:7][CH2:6][CH2:5][C:2]([OH:4])=[O:3])=[CH:34][CH:33]=1)[CH3:30]
Reactant: CCOc1ccc(C=O)cc1
Reactant: O=C(O)CCCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Product: CCOc1ccc(C=CCCCCC(=O)O)cc1
Yield: 64 %

Procedure:
This compound was synthesized from 5-carboxypentyltriphenylphosphonium bromide (9.50 g, 20 mmol) and p-ethoxybenzaldehyde (3.00 g, 20 mmol) in THF (100 mL) by a Wittig reaction. Crystallization (hexanes-ethyl acetate) afforded the product (3.18 g, 64%) as white crystals (mp 62-63° C.), IR: 3450-2500, 1720 cm-1 ; 1H-NMR: 1.40 (t, 3H), 1.50 (m, 2H), 1.70 (m, 2H), 2.38 (m, 4H), 4.00 (q, 2H), 5.72+6.05 (m, 1H), 6.32 (t, 1H), 7.05 (q, 4H), 10.10 (bs, 1H). Anal. Calcd. for C15H20O3 : C, 72.55, H, 8.12% Found: C, 72.53, H, 8.15%. Z:E=45:55.
Reaction SMILES: F[C:2]1[C:7]([F:8])=[C:6]([CH3:9])[C:5]([F:10])=[C:4]([F:11])[N:3]=1.[C:12]([C:14]1[CH:15]=[C:16]([OH:20])[CH:17]=[CH:18][CH:19]=1)#[N:13].C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C>[F:8][C:7]1[C:2]([O:20][C:16]2[CH:15]=[C:14]([CH:19]=[CH:18][CH:17]=2)[C:12]#[N:13])=[N:3][C:4]([F:11])=[C:5]([F:10])[C:6]=1[CH3:9]
Reactant: Cc1c(F)c(F)nc(F)c1F
Reactant: N#Cc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: Cc1c(F)c(F)nc(Oc2cccc(C#N)c2)c1F
Temperature: 45 °C

Procedure:
To 2,3,5,6-tetrafluoro-4-methylpyridine (0.71 g, 4.3 mmol) dissolved in acetonitrile (5 mL) was added 3-cyanophenol (0.5 g, 4.2 mmol) and cesium carbonate (1.44 g, 4.4 mmol). The reaction was heated in an oil bath at 45° C. for 16 hours and partitioned with ether and water. The organic layer was separated, washed with brine, dried (Na2SO4), and the solvent removed in vacuo. Chromatography on silica gel with methylene chloride/hexane (7/3) gave 3-[(3,5,6-trifluoro-4-methylpyridin-2-yl)-oxy]benzonitrile; NMR (CDCl3) 7.55 (m, 2), 7.45 (m, 2), 2.24 (s, 3) ppm.
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[CH2:7]/[N:8]=[CH:9]/[CH2:10][C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:4])([CH3:3])[CH3:2].[Cl:16][C:17]1[CH:18]=[C:19](/[CH:24]=[C:25](/[C:28]2[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:29]=2[F:35])\[C:26]#[N:27])[CH:20]=[CH:21][C:22]=1[F:23].C(N(CC)CC)C>ClCCl>[C:1]([O:5][C:6]([CH:7]1[CH:24]([C:19]2[CH:20]=[CH:21][C:22]([F:23])=[C:17]([Cl:16])[CH:18]=2)[C:25]([C:28]2[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:29]=2[F:35])([C:26]#[N:27])[CH:9]([CH2:10][C:11]([CH3:14])([CH3:13])[CH3:12])[NH:8]1)=[O:15])([CH3:4])([CH3:3])[CH3:2]
Reactant: N#C/C(=C\c1ccc(F)c(Cl)c1)c1ccc(Cl)cc1F
Reactant: CC(C)(C)C/C=N/CC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)CC1NC(C(=O)OC(C)(C)C)C(c2ccc(F)c(Cl)c2)C1(C#N)c1ccc(Cl)cc1F
Yield: 23.9 %

Procedure:
In a manner similar to the method described in Example 1c, [3-methyl-but-(E)-ylideneamino]-acetic acid tert-butyl ester prepared in Example 1a (2.1 g, 10 mmol) was reacted with (Z)-3-(3-chloro-4-fluoro-phenyl)-2-(4-chloro-2-fluoro-phenyl)-acrylonitrile (2.5 g, 8 mmol) prepared in Example 69a, AgF (1.5 g, 12 mmol), and triethylamine (2.7 mL, 20 mmol) in dichloromethane (120 mL) at room temperature for 18 h to give rac-(2R,3R,4R,5S)-3-(3-chloro-4-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid tert-butyl ester as a white foam (1 g, 24%).
Reaction SMILES: [N+:1]([CH:4]=[C:5]([NH:9][CH2:10][C:11]#[CH:12])CCS)([O-:3])=[O:2].Cl[CH2:14][C:15]1[S:16][CH:17]=[CH:18][N:19]=1>>[N+:1]([CH:4]=[C:5]([NH:9][C:10]#[C:11][CH3:12])[NH:19][CH2:18][CH2:17][S:16][CH2:14][C:15]1[S:16][CH:17]=[CH:18][N:19]=1)([O-:3])=[O:2]
Reactant: ClCc1nccs1
Reactant: C#CCNC(=C[N+](=O)[O-])CCS
Product: CC#CNC(=C[N+](=O)[O-])NCCSCc1nccs1

Procedure:
The product of Step A is reacted in a non-reactive solvent with about an equimolar amount of 2-chloromethylthiazole and about one equivalent of base, and the title product is thereby produced.
Reaction SMILES: O[C:2]1[N:7]2[N:8]=[C:9]([CH2:11][CH3:12])[N:10]=[C:6]2[N:5]=[C:4]([CH3:13])[CH:3]=1.P(Cl)(Cl)([Cl:16])=O.C([O-])([O-])=O.[Na+].[Na+]>O>[Cl:16][C:2]1[N:7]2[N:8]=[C:9]([CH2:11][CH3:12])[N:10]=[C:6]2[N:5]=[C:4]([CH3:13])[CH:3]=1
Reactant: CCc1nc2nc(C)cc(O)n2n1
Reactant: O=P(Cl)(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: CCc1nc2nc(C)cc(Cl)n2n1

Procedure:
The titled compound (Intermediate 5), was obtained by refluxing a suspension of Intermediate 4 (0.3 g, 1.684 mmol) in phosphorus oxychloride (ALDRICH, 1.88 mL, 20.2 mmol) for 2 h and then, adding the reaction mixture slowly to a mixture of water and ice. The solution was neutralized with solid Na2CO3 and extracted with DCM (25 mL). The aqueous layer was further extracted with DCM (2×5 mL) and the combined organic layers were washed with water (20 mL), then with brine (20 mL), and then dried over MgSO4. Solvent was removed under reduced pressure and the crude product was purified (silica gel column, eluting with Hexane/EtOAc mixtures from 100:0 to 40:60%) to obtain Intermediate 5 as a white solid.
Reaction SMILES: [C:1](O)(=[S:3])[CH3:2].[O:5]1[C:16]2[C:8](=[CH:9][C:10](=[CH:14][CH:15]=2)[CH2:11]C=C)[O:7][CH2:6]1.[OH-].[Na+].S(=O)(=O)(O)O>C(O)C.O>[O:5]1[C:16]2[CH:15]=[CH:14][C:10]([CH2:11][CH2:2][CH2:1][SH:3])=[CH:9][C:8]=2[O:7][CH2:6]1
Reactant: C=CCc1ccc2c(c1)OCO2
Reactant: CC(O)=S
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: SCCCc1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 66.4 %

Procedure:
25 g of thioacetic acid was added to 53.5 g of safrole in portions, while stirring the mixture at a room temperature or under cooling with ice/water. The reaction was carried out for 30 minutes. A solution of 20 g of sodium hydroxide in a mixture comprising 100 ml of water and 200 ml of ethanol was added to the reaction mixture. The obtained mixture was heated under reflux for 20 minutes, cooled, neutralized with dilute sulfuric acid and extracted with 1 l of benzene. The extract was washed with water and the benzene layer was dried over anhydrous sodium sulfate and purified by silica gel column chromatography (hexane) to obtain 42.8 g of the title compound as a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:15][CH2:14][CH2:13][C@H:12]2[C:16]#[N:17])(=[O:10])=[O:9])=[CH:4][CH:3]=1.Cl.[NH2:19][OH:20]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([N:11]2[CH2:15][CH2:14][CH2:13][C@H:12]2/[C:16](=[N:19]/[OH:20])/[NH2:17])(=[O:10])=[O:9])=[CH:6][CH:7]=1
Reactant: NO
Reactant: N#C[C@@H]1CCCN1S(=O)(=O)c1ccc(F)cc1
Agent: Cl
Product: N/C(=N\O)[C@@H]1CCCN1S(=O)(=O)c1ccc(F)cc1

Procedure:
The title compound was prepared by the method of Preparation 4 from (2S)-1-[(4-fluorophenyl)sulfonyl]-2-pyrrolidinecarbonitrile [see Preparation 51] and hydroxylamine hydrochloride to afford the title compound as a white solid.
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[NH:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH2:6][NH2:7].[C:16]([C:20]1[CH:29]=[CH:28][C:23]([CH2:24][N:25]=[C:26]=[O:27])=[CH:22][CH:21]=1)([CH3:19])([CH3:18])[CH3:17]>CN(C=O)C.ClCCl>[C:16]([C:20]1[CH:29]=[CH:28][C:23]([CH2:24][NH:25][C:26](=[O:27])[NH:7][CH2:6][C:5]2[CH:8]=[CH:9][C:10]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])=[C:3]([F:2])[CH:4]=2)=[CH:22][CH:21]=1)([CH3:19])([CH3:17])[CH3:18]
Reactant: CC(C)(C)c1ccc(CN=C=O)cc1
Reactant: CS(=O)(=O)Nc1ccc(CN)cc1F
Agent: Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)(C)c1ccc(CNC(=O)NCc2ccc(NS(C)(=O)=O)c(F)c2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 68 %

Procedure:
3-fluoro-4-methanesulfonylaminobenzylamine hydrochloride (1.13 g) prepared in step 3 of Example 1 was dissolved in DMF (6 mL) and diluted with dichloromethane (35 mL). To the solution were added 4-t-butylbenzylisocyanate (1.09 g) and TEA (1.2 mL) and stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, diluted with ethylacetate (20 mL) and washed with water and saturated NaCl aqueous solution. The resulting solution was dried over anhydride MgSO4 and the remaining liquid was concentrated under reduced pressure. The residue was purified with column chromatography (n-hexane/ethyl acetate=312) to yield title compound (1.23 g, 53%).
Reaction SMILES: [N:1]1([C:7]2[C:8]3[S:30][C:29]([CH:31]=O)=[CH:28][C:9]=3[N:10]=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([O:19][SiH2:20][C:21]([CH3:27])([CH3:26])[C:22]([CH3:25])([CH3:24])[CH3:23])[CH:14]=3)[N:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH3:33][N:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH3:33][N:34]1[CH2:39][CH2:38][N:37]([CH2:31][C:29]2[S:30][C:8]3[C:7]([N:1]4[CH2:2][CH2:3][O:4][CH2:5][CH2:6]4)=[N:12][C:11]([C:13]4[CH:18]=[CH:17][CH:16]=[C:15]([O:19][SiH2:20][C:21]([CH3:26])([CH3:27])[C:22]([CH3:25])([CH3:23])[CH3:24])[CH:14]=4)=[N:10][C:9]=3[CH:28]=2)[CH2:36][CH2:35]1
Reactant: CC(C)(C)C(C)(C)[SiH2]Oc1cccc(-c2nc(N3CCOCC3)c3sc(C=O)cc3n2)c1
Reactant: CN1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CN1CCN(Cc2cc3nc(-c4cccc(O[SiH2]C(C)(C)C(C)(C)C)c4)nc(N4CCOCC4)c3s2)CC1
Reaction time: 72 h
Yield: 88 %

Procedure:
A mixture of 4-morpholin-4-yl-2-[3-(1,1,2,2-tetramethyl-propylsilanyloxy)-phenyl]-thieno[3,2-d]pyrimidine-6-carbaldehyde (6.67 g, 14.66 mmol), N-methylpiperazine (2.11 mL, 1.3 equivalents) and acetic acid (838 μL, 1.0 eq.) was stirred in 1,2-dichloroethane (70 mL) at room temperature. To this was added sodium triacetoxyborohydride (3.42 g, 1.1 equivalents) and the reaction mixture was stirred for 3 days. The reaction mixture was then quenched with aqueous sodium bicarbonate solution, extracted exhaustively with chloroform, dried (MgSO4), and the solvent removed in vacuo to yield a yellow oil. This was purified using flash chromatography (silica, ethyl acetate to ethyl acetate/methanol) to yield 6-(4-methyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-2-[3-(1,1,2,2-tetramethyl-propylsilanyloxy)-phenyl]-thieno[3,2-d]pyrimidine (6.95 g, 88%).
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5][C:6](=O)[CH:7]([O:9][C:10](=O)[C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[N:13][CH:12]=1)[CH3:8])=[O:4].C([O-])(=O)C.[NH4+:24]>C(O)C>[CH3:1][O:2][C:3](=[O:4])[CH2:5][C:6]1[N:24]=[C:10]([C:11]2[CH:12]=[N:13][C:14]([Cl:17])=[CH:15][CH:16]=2)[O:9][C:7]=1[CH3:8]
Reactant: [NH4+]
Reactant: COC(=O)CC(=O)C(C)OC(=O)c1ccc(Cl)nc1
Agent: CC(=O)[O-]
Solvent: CCO
Product: COC(=O)Cc1nc(-c2ccc(Cl)nc2)oc1C
Temperature: 80 °C
Yield: 28.2 %

Procedure:
A mixture of 6-chloro-nicotinic acid 3-methoxycarbonyl-1-methyl-2-oxo-propyl ester (16.3 g, 57.1 mmol) and ammonium acetate (18.5 g, 240 mmol) in ethanol (150 mL) is heated at 80° C. for 2 h, concentrated. The residue is taken into acetic acid (330 mL) and heated to reflux overnight, concentrated. The residue is taken into ethyl acetate and washed with water, dried, concentrated, purified by column giving [2-(6-Chloro-pyridin-3-yl)-5-methyl-oxazol-4-yl]-acetic acid methyl ester (4.3 g).
Reaction SMILES: [CH2:1]([O:4][C@H:5]1[C:13]2[C:8](=[CH:9][C:10]([O:14][CH3:15])=[CH:11][CH:12]=2)[C@@H:7]([NH:16][CH2:17][C@@H:18]([OH:44])[C@@H:19]([NH:27][C:28](=[O:43])[C@@H:29]([N:33]2[CH2:37][CH2:36][C@H:35]([CH2:38][CH:39]([CH3:41])[CH3:40])[C:34]2=[O:42])[CH2:30][CH:31]=[CH2:32])[CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:6]1)C=C>C(Cl)Cl>[CH2:20]([C@@H:19]1[NH:27][C:28](=[O:43])[C@@H:29]([N:33]2[CH2:37][CH2:36][C@H:35]([CH2:38][CH:39]([CH3:40])[CH3:41])[C:34]2=[O:42])[CH2:30][CH:31]=[CH:32][CH2:1][O:4][C@@H:5]2[CH2:6][C@@H:7]([C:8]3[CH:9]=[C:10]([O:14][CH3:15])[CH:11]=[CH:12][C:13]=32)[NH:16][CH2:17][C@H:18]1[OH:44])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: C=CCO[C@@H]1C[C@H](NC[C@@H](O)[C@H](Cc2ccccc2)NC(=O)[C@H](CC=C)N2CC[C@H](CC(C)C)C2=O)c2cc(OC)ccc21
Solvent: ClCCl
Product: COc1ccc2c(c1)[C@@H]1C[C@H]2OCC=CC[C@H](N2CC[C@H](CC(C)C)C2=O)C(=O)N[C@@H](Cc2ccccc2)[C@H](O)CN1
Reaction time: 16 h
Yield: 87.6 %

Procedure:
Hoveyda-Grubb's 2nd generation catalyst (3.01 mg, 3.55 μmol) was added to flask charge with a solution of (S)—N-((2S,3R)-4-((1S,3R)-3-(allyloxy)-6-methoxy-2,3-dihydro-1H-inden-1-ylamino)-3-hydroxy-1-phenylbutan-2-yl)-2-((S)-3-isobutyl-2-oxopyrrolidin-1-yl)pent-4-enamide (25.5 mg, 35.5 μmol, TFA salt) from step 0 (1) in DCM (4 mL) at RT. The mixture was stirred for 16 h. Evaporated to dryness. Dissolved in MeOH and filtered. Purified with reverse phase Prep-HPLC to give 17.9 mg (75%) of the (1S,4R,5S,8S,14R)-5-Benzyl-4-hydroxy-8-((S)-3-isobutyl-2-oxo-pyrrolidin-1-yl)-18-methoxy-13-oxa-2,6-diaza-tricyclo[12.6.1.015,20]henicosa-10,15(20),16,18-tetraen-7-one as the TFA salt: LC-MS (M+H)+=576.2, HRMS (M+H)+=576.3447; 1H NMR (500 MHz, CDCl3) 8 ppm 0.91 (dd, J=32.81, 5.95 Hz, 4H) 1.11 (t, J=9.77 Hz, 1H) 1.30-1.44 (m, 1H) 1.55-1.72 (m, 2H) 2.03 (dd, J=13.12, 4.58 Hz, 2H) 2.28-2.76 (m, 12H) 3.14 (s, 3H) 3.72-3.92 (m, 3H) 4.04-4.19 (m, 2H) 4.40 (s, 1H) 4.72 (d, J=4.58 Hz, 1H) 4.83-4.96 (m, 1H) 5.51-5.74 (m, 1H) 6.92-7.30 (m, 8H) 7.35 (t, J=8.39 Hz, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([NH:16][C:17](=[O:26])[C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([CH3:24])[C:19]=2I)[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([F:15])[CH:12]=2)[CH2:7]1)=[O:5])[CH3:2].[CH:27](/B(O)O)=[CH:28]\[CH3:29].C([O-])([O-])=O.[K+].[K+]>CCO.O1CCOCC1.[Pd]>[CH2:1]([O:3][C:4]([C:6]1([NH:16][C:17](=[O:26])[C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([CH3:24])[C:19]=2/[CH:27]=[CH:28]/[CH3:29])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([F:15])[CH:12]=2)[CH2:7]1)=[O:5])[CH3:2]
Reactant: C/C=C/B(O)O
Reactant: CCOC(=O)C1(NC(=O)c2cccc(C)c2I)Cc2ccc(F)cc2C1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: CCO
Product: C/C=C/c1c(C)cccc1C(=O)NC1(C(=O)OCC)Cc2ccc(F)cc2C1
Yield: 50.9 %

Procedure:
To a solution of 5-fluoro-2-(2-iodo-3-methyl-benzoylamino)-indan-2-carboxylic acid ethyl ester (400 mg, 0.85 mmol) and trans-1-propen-1-ylboronic acid (294 mg, 3.42 mmol) in EtOH (10 mL) and dioxane (5 mL) is added palladium anchored homogeneous catalyst, FibreCatPd(0) (4.84% Pd, 186 mg, 8.5% mmol) and 2M aqueous solution of K2SO4 (1.71 mL, 3.42 mmol). The resulting reaction mixture is covered with argon and run in a microwave reaction: 110° C., 7 h. After concentration in vacuo, the residue is purified by HPLC to give a pure product (153) as white solid (165 mg, 51%).
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][C:6]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([S:24]([CH3:27])(=[O:26])=[O:25])[CH:19]=3)=[CH:7][CH:8]=2)[N:3]=1.[NH2:28][C:29]1[CH:34]=[CH:33][C:32](B2OC(C)(C)C(C)(C)O2)=[CH:31][N:30]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CN(C=O)C>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.O>[CH3:27][S:24]([C:20]1[CH:19]=[C:18]([C:6]2[CH:5]=[C:4]3[C:9]([C:10]([N:12]4[CH2:17][CH2:16][O:15][CH2:14][CH2:13]4)=[N:11][C:2]([C:32]4[CH:33]=[CH:34][C:29]([NH2:28])=[N:30][CH:31]=4)=[N:3]3)=[CH:8][CH:7]=2)[CH:23]=[CH:22][CH:21]=1)(=[O:26])=[O:25]
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Reactant: CS(=O)(=O)c1cccc(-c2ccc3c(N4CCOCC4)nc(Cl)nc3c2)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CS(=O)(=O)c1cccc(-c2ccc3c(N4CCOCC4)nc(-c4ccc(N)nc4)nc3c2)c1
Temperature: 95 °C
Reaction time: 2 h
Yield: 73.2 %

Procedure:
To a 50 mL round bottom flask, 2-chloro-7-(3-methanesulfonyl-phenyl)-4-morpholin-4-yl-quinazoline (0.15 g, 0.00037 mol), 2-aminopyridine-5-boronic acid pinacol ester (0.122 g, 0.0005568 mol), cesium carbonate (0.243 g, 0.00074 mol), DMF (4 mL) and water (2 mL) were added. The reaction mixture was degassed with nitrogen for 5-10 min. To the same reaction flask, Pd(PPh3)2Cl2 (0.013 g, 0.000018 mol) was added and again degassed with nitrogen for 5-10 min. The reaction mixture was stirred at 95° C. for 2 h. The reaction mixture was cooled and diluted with ethyl acetate. The organic layer was washed with water, brine and dried over sodium sulfate. The solvent was removed under reduced pressure to afford the crude product. The crude product was purified using column chromatography (60-120 silica gel, 5% MeOH in chloroform) to yield the title compound (125 mg, 74%). LC-MS (ESI): Calculated mass: 461.2; Observed mass: 462.1 [M+H]+ (RT: 0.17 min).
Reaction SMILES: [C:1]([CH:3]([NH:8][C:9]([CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH:12]1[NH:17][C:18]([C:20]1[NH:21][C:22]2[C:27]([CH:28]=1)=[CH:26][CH:25]=[C:24]([Cl:29])[CH:23]=2)=[O:19])=[O:10])[CH2:4][CH:5]([CH3:7])[CH3:6])#[N:2].[H-].[Na+].Br[CH2:33][CH2:34][CH2:35][Cl:36]>CN(C=O)C>[C:1]([CH:3]([NH:8][C:9]([CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH:12]1[NH:17][C:18]([C:20]1[N:21]([CH2:33][CH2:34][CH2:35][Cl:36])[C:22]2[C:27]([CH:28]=1)=[CH:26][CH:25]=[C:24]([Cl:29])[CH:23]=2)=[O:19])=[O:10])[CH2:4][CH:5]([CH3:7])[CH3:6])#[N:2]
Reactant: CC(C)CC(C#N)NC(=O)C1CCCCC1NC(=O)c1cc2ccc(Cl)cc2[nH]1
Reactant: ClCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)CC(C#N)NC(=O)C1CCCCC1NC(=O)c1cc2ccc(Cl)cc2n1CCCCl
Temperature: 25 °C
Reaction time: 1 h
Yield: 63.8 %

Procedure:
To a stirred solution of 6-chloro-1H-indole-2-carboxylic acid [2-(1-cyano-3-methyl-butylcarbamoyl)-cyclohexyl]-amide from Example 18 (0.428 g, 1.03 mmol) in DMF (3.5 ml) were added NaH (60% dispersion in mineral oil) (0.062 g, 1.54 mmol) at 0° C. The slurry was then stirred at room temperature for one hour followed by the addition of 1-bromo-3-chloropropane (0.13 ml, 1.34 mmol). Reaction was stirred overnight at room temperature and partitioned between 1 N HCl and ethyl acetate. The organic layer was washed with water, brine, dried over magnesium sulfate and concentrated in vacuo. The resulting oil was chromatographed on preparatory silica plates, eluting with 2.5% MeOH/dichloromethane, and yielding 6-chloro-1-(3-chloro-propyl)-1H-indole-2-carboxylic acid [2-(1-cyano-3-methyl-butylcarbamoyl)-cyclohexyl]-amide (0.323 g, 64%). [M+H=492].
Reaction SMILES: Br[CH:2]([CH3:19])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:7][CH:6]=1.[CH2:20]([C:27]1([OH:33])[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[CH2:20]([C:27]1([OH:33])[CH2:32][CH2:31][N:30]([CH2:19][CH2:2][CH2:3][O:4][C:5]2[CH:10]=[CH:9][C:8]([O:11][CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:7][CH:6]=2)[CH2:29][CH2:28]1)[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: CC(Br)COc1ccc(OCc2ccccc2)cc1
Reactant: OC1(Cc2ccccc2)CCNCC1
Product: OC1(Cc2ccccc2)CCN(CCCOc2ccc(OCc3ccccc3)cc2)CC1

Procedure:
The title compound, MS: m/e=432.6 (M+H+), was prepared from 1-(2-bromopropoxy)-4-(benzyloxy)-benzene and 4-benzyl-piperidin-4-ol.
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[N:11]1[C:14](=[O:15])[C:13]([CH3:17])([CH3:16])[NH:12]1)[CH2:8]2.[F:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23]Br)=[C:21]([C:27]([F:30])([F:29])[F:28])[CH:20]=1>>[F:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23][N:12]2[C:13]([CH3:17])([CH3:16])[C:14](=[O:15])[N:11]2[CH:2]2[CH:3]3[CH2:4][CH:5]4[CH2:6][CH:7]([CH2:8][CH:1]2[CH2:10]4)[CH2:9]3)=[C:21]([C:27]([F:28])([F:29])[F:30])[CH:20]=1
Reactant: CC1(C)NN(C2C3CC4CC(C3)CC2C4)C1=O
Reactant: Fc1ccc(CBr)c(C(F)(F)F)c1
Product: CC1(C)C(=O)N(C2C3CC4CC(C3)CC2C4)N1Cc1ccc(F)cc1C(F)(F)F

Procedure:
2-(Adamantan-2-yl)-4,4-dimethyl-1,2-diazetidin-3-one and 4-fluoro-2-(trifluoromethyl)benzyl bromide were used for a similar reaction and treatment as Process 6 of Example 1, and the title compound was obtained as a colorless oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([N+:9]([O-:11])=[O:10])[C:7]=1Cl.O.[NH2:13][NH2:14]>C(O)C>[Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([N+:9]([O-:11])=[O:10])[C:7]=1[NH:13][NH2:14]
Reactant: O=[N+]([O-])c1cncc(Br)c1Cl
Reactant: NN
Solvent: CCO
Solvent: O
Product: NNc1c(Br)cncc1[N+](=O)[O-]
Yield: 79.5 %

Procedure:
A solution of 3-bromo-4-chloro-5-nitro-pyridine (500 mg, 2.106 mmol), hydrazine hydrate (158.1 mg, 153.6 μL, 3.159 mmol) in ethanol (5.000 mL) was stirred at RT for 1 h. The bright yellow precipitate was filtered, washed with methanol and dried under vacuum to leave 3-bromo-4-hydrazinyl-5-nitropyridine (390 mg, 79.5%). MS (ES−) 232.8.
Reaction SMILES: CN[C@@H:3]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:4]N1CCCCC1.C([Li])CCC.Cl[Si](C)(C)C.[C:27]1(=[O:32])CCC=C1>CCOCC.[Cu]I>[CH2:16]([C@H:11]1[CH2:3][CH2:4][C:27](=[O:32])[CH2:12]1)[CH2:15][CH2:14][CH3:13]
Reactant: CN[C@H](CN1CCCCC1)c1ccccc1
Reactant: O=C1C=CCC1
Agent: [Cu]I
Agent: C[Si](C)(C)Cl
Agent: [Li]CCCC
Solvent: CCOCC
Product: CCCC[C@H]1CCC(=O)C1
Temperature: -65 °C
Reaction time: 0.08 h
Yield: 51 %

Procedure:
(S)-N-methyl-1-phenyl-2-(1-piperidinyl)ethanamine (360.0 mg, 1.65 mmol) was dissolved in ether (12 mL) and n-butyl lithium (2.5M in hexanes, 0.66 mL, 1.65 mmol) was added to the solution at -65° C. The solution was stirred for 5 min at -65° C., warmed to 0° C. and stirred for 10 min at 0° C. To a second flask was added CuI (262 mg, 1.38 mmol) and 10 mL of diethyl ether. This solution was cooled to -40° C. and treated with n-butyl lithium (0.55 mL, 1.38 mmol). The solution in the first flask was cooled to -35° C. and added via canula to the solution of n-BuCu in the second flask. The resulting solution was stirred for 15 min at -35° C., for 10 min at -30° C., and cooled to -78° C. After 5 min, chlorotrimethylsilane (0.437 mL, 3.44 mmol) was added and stirred for 15 min. 2-Cyclopentenone (112.8 mg, 1.38 mmol) was added slowly at -78° C. to the reaction mixture, which was quenched after 1 hr by adding 4N NH4Cl (15 mL) at -78° C. and extracted with ether (20 mL). The extract was washed with 1N HCl (15 mL), dried (Na2SO4) and concentrated. The oily residue was purified by column chromatography on silica gel (5:1=pentane/ether) to afford (S)-3-n-butylcyclopentanone (98.7 mg, 51% chemical yield, 44% ee, [α]D =-54.4 (c=3.00, benzene)).