Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:38])[NH:4][C@H:5]([C:9]([N:11]1[CH2:15][C@@H:14]([O:16][CH3:17])[CH2:13][C@H:12]1[C:18]1[NH:19][CH:20]=[C:21]([C:23]2[CH:28]=[CH:27][C:26](B3OC(C)(C)C(C)(C)O3)=[CH:25][CH:24]=2)[N:22]=1)=[O:10])[CH:6]([CH3:8])[CH3:7].[C:39]([O:43][C:44]([N:46]1[CH2:51][CH2:50][N:49]([C:52]2[CH:57]=[CH:56][C:55]([C:58](=[O:73])[NH:59][C:60]3[CH:65]=[C:64]([O:66][C:67]([F:70])([F:69])[F:68])[C:63](Br)=[CH:62][C:61]=3[Cl:72])=[CH:54][N:53]=2)[C@H:48]([CH3:74])[CH2:47]1)=[O:45])([CH3:42])([CH3:41])[CH3:40].O.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1>[C:39]([O:43][C:44]([N:46]1[CH2:51][CH2:50][N:49]([C:52]2[CH:57]=[CH:56][C:55]([C:58](=[O:73])[NH:59][C:60]3[C:61]([Cl:72])=[CH:62][C:63]([C:26]4[CH:27]=[CH:28][C:23]([C:21]5[N:22]=[C:18]([C@@H:12]6[CH2:13][C@H:14]([O:16][CH3:17])[CH2:15][N:11]6[C:9](=[O:10])[C@@H:5]([NH:4][C:3]([O:2][CH3:1])=[O:38])[CH:6]([CH3:7])[CH3:8])[NH:19][CH:20]=5)=[CH:24][CH:25]=4)=[C:64]([O:66][C:67]([F:70])([F:69])[F:68])[CH:65]=3)=[CH:54][N:53]=2)[C@H:48]([CH3:74])[CH2:47]1)=[O:45])([CH3:42])([CH3:40])[CH3:41]
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)CCN1c1ccc(C(=O)Nc2cc(OC(F)(F)F)c(Br)cc2Cl)cn1
Reactant: COC(=O)N[C@H](C(=O)N1C[C@@H](OC)C[C@H]1c1nc(-c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)c[nH]1)C(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: COC(=O)N[C@H](C(=O)N1C[C@@H](OC)C[C@H]1c1nc(-c2ccc(-c3cc(Cl)c(NC(=O)c4ccc(N5CCN(C(=O)OC(C)(C)C)C[C@H]5C)nc4)cc3OC(F)(F)F)cc2)c[nH]1)C(C)C
Temperature: 90 °C
Yield: 20.3 %

Procedure:
To a solution of [(S)-1-((2S,4S)-4-methoxy-2-{4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-phenyl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamic acid methyl ester (100 mg, 0.19 mmol, Preparation 27) and (R)-4-[5-(4-bromo-2-chloro-5-trifluoromethoxy-phenylcarbamoyl)-pyridin-2-yl]-3-methyl-piperazine-1-carboxylic acid tert-butyl ester (110 mg, 0.19 mmol) dissolved in toluene (1.18 mL) and water (0.43 mL) was added potassium carbonate (127 mg, 0.92 mmol). The reaction mixture was sparged under nitrogen for 15 min and Pd(dppf)Cl2CH2Cl2 (13.55 mg, 0.017 mmol) was added and the reaction mixture was sparged with nitrogen and heated at 90° C. overnight, cooled to RT, diluted with EtOAc and washed with water and brine to produce a dark colored solid, which was purified by silica gel chromatography (12 g silica, EtOAc/hexanes 40 to 100%) to produce the title intermediate (35.3 mg, 21% yield) as a yellowish colored solid. (m/z): [M+H]+ calcd for C44H52ClF3N8O8 913.35. found 913.3.
Reaction SMILES: [C:1]([O:6][CH2:7][CH3:8])(=[O:5])[C:2]([CH3:4])=O.[Br:9][C:10]1[CH:11]=[CH:12][C:13]([N+:18]([O-])=O)=[C:14]([CH:17]=1)[CH:15]=O.[Sn](Cl)Cl>C(O)C.[Cl-].[Zn+2].[Cl-]>[Br:9][C:10]1[CH:17]=[C:14]2[C:13](=[CH:12][CH:11]=1)[N:18]=[C:2]([C:1]([O:6][CH2:7][CH3:8])=[O:5])[CH:4]=[CH:15]2
Reactant: CCOC(=O)C(C)=O
Reactant: O=Cc1cc(Br)ccc1[N+](=O)[O-]
Agent: Cl[Sn]Cl
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CCO
Product: CCOC(=O)c1ccc2cc(Br)ccc2n1
Temperature: 70 °C
Yield: 14.1 %

Procedure:
Ethyl pyruvate (535.4 mg, 4.61 mmol) was added to 5-Bromo-2-nitro-benzaldehyde (1.01 g, 4.39 mmol) in ethanol (22 mL) at room temperature under argon. Then, tin(II)chloride (4.16 g, 21.95 mmol) was added to the reaction mixture, followed by the addition of zinc(II)chloride (2.99 g, 21.95 mmol), and finally activated 4 Å molecular sieve pellets (1.01 g). The mixture was heated at 70° C. in an oil bath for twenty hours, then allowed to cool to room temperature, and carefully quenched with saturated sodium bicarbonate. Ethyl acetate was added, and the mixture was filtered through Celite®. The filtrate was extracted with ethyl acetate, and the organic layer was dried over anhydrous magnesium sulfate, then filtered and concentrated. The residue was purified by silica gel chromatography eluting with dichloromethane and subsequently a second silica gel chromatography purification eluting with 1:4 ethyl acetate:hexanes to give 173.6 mg (14%) of ethyl 6-bromo-2-quinolinecarboxylate as a solid. 1H NMR (400 MHz, d6-DMSO): δ 8.55 (d, J=9 Hz, 1H), 8.42 (d, J=2 Hz, 1H), 8.16 (d, J=9 Hz, 1H), 8.11 (d, J=9 Hz, 1H), 7.98 (dd, J=9, 2 Hz, 1H), 4.42 (q, J=7 Hz, 2H), 1.37 (t, J=7 Hz, 3H). ESI-LCMS m/z 280 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:13]=[C:12]2[C:14]([C:17]3[CH:18]=[C:19]([N:23]4[CH2:28][CH2:27][CH:26]([NH:29]C(=O)OC(C)(C)C)[CH2:25][CH2:24]4)[CH:20]=[N:21][CH:22]=3)=[CH:15][NH:16][C:11]2=[CH:10][CH:9]=1.Cl>CO.C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:13]=[C:12]2[C:14]([C:17]3[CH:18]=[C:19]([N:23]4[CH2:24][CH2:25][CH:26]([NH2:29])[CH2:27][CH2:28]4)[CH:20]=[N:21][CH:22]=3)=[CH:15][NH:16][C:11]2=[CH:10][CH:9]=1
Reactant: CC(C)(C)OC(=O)NC1CCN(c2cncc(-c3c[nH]c4ccc(-c5ccccc5F)nc34)c2)CC1
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: NC1CCN(c2cncc(-c3c[nH]c4ccc(-c5ccccc5F)nc34)c2)CC1
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
A solution of tert-butyl 1-(5-(5-(2-fluorophenyl)-1-tosyl-1H-pyrrolo[3,2-b]pyridin-3-yl)pyridin-3-yl)piperidin-4-ylcarbamate (125 mg, 0.195 mmol) in THF (3 mL) was treated with NaOH 10N (0.195 mL, 1.948 mmol). The reaction was heated to reflux at 80° C. After 4 h, the solution was cooled to 23° C., concentrated in vacuo and purified by silica gel chromatography (eluent: 1-5% MeOH/DCM), affording tert-butyl 1-(5-(5-(2-fluorophenyl)-1H-pyrrolo[3,2-b]pyridin-3-yl)pyridin-3-yl)piperidin-4-ylcarbamate (69 mg, 73%). MS (ESI, pos. ion) m/z: 488.2 (M+1). A solution of tert-butyl 1-(5-(5-(2-fluorophenyl)-1H-pyrrolo[3,2-b]pyridin-3-yl)pyridin-3-yl)piperidin-4-ylcarbamate (64 mg, 0.131 mmol) in MeOH (3 mL) and DCM (0.500 mL) was treated with HCl, 36.5-38.0% (0.109 mL, 1.313 mmol). The reaction was heated to 50° C. After 2 h 30 min, the reaction was cooled to 23° C. and concentrated. The residue (as HCl salt) was free-based using a Silicycle Si-propylsulfonic acid ion exchange column (catalog # R51230B). The compound was diluted in MeOH and added to a pad of the resin (wetted and flushed with 10 mL MeOH). It was flushed with MeOH (50 mL), and then the product was “released” using 2.0 M NH3 in MeOH solution (50 ml). The final filtrate was concentrated, affording 1-(5-(5-(2-fluorophenyl)-1H-pyrrolo[3,2-b]pyridin-3-yl)pyridin-3-yl)piperidin-4-amine. MS (ESI, pos. ion) m/z: 388.3 (M+1).
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][CH:5]1[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1.[Cl:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[NH:17][C:16]([C:21]([NH:23][CH:24]([CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:25](O)=[O:26])=[O:22])=[CH:15]2>>[CH2:28]([CH:24]([NH:23][C:21]([C:16]1[NH:17][C:18]2[C:14]([CH:15]=1)=[CH:13][C:12]([Cl:11])=[CH:20][CH:19]=2)=[O:22])[C:25]([N:8]1[CH2:9][CH2:10][CH:5]([O:4][CH2:3][O:2][CH3:1])[CH2:6][CH2:7]1)=[O:26])[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: COCOC1CCNCC1
Reactant: O=C(NC(Cc1ccccc1)C(=O)O)c1cc2cc(Cl)ccc2[nH]1
Product: COCOC1CCN(C(=O)C(Cc2ccccc2)NC(=O)c2cc3cc(Cl)ccc3[nH]2)CC1

Procedure:
4-Methoxymethoxy-piperidine (1.0 mmol) and 2-[(5-chloro-1H-indole-2-carbonyl)-amino]-3-phenyl-propionic acid (1.0 mmol) were coupled according to Procedure A and the product purified by chromatography on silica gel eluted with 1:1 ethyl acetate-hexanes: Yield 241 mg, 50%; HPLC (60/40) 7.67 minutes (94%);
Reaction SMILES: [C:1]([C:3]1[C:4](F)=[C:5]([CH:19]=[C:20]([F:23])[C:21]=1[F:22])[C:6]([C:8](=[CH:14][NH:15][CH:16]1[CH2:18][CH2:17]1)[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[O:7])#[N:2].C([O-])([O-])=O.[K+].[K+]>CN(C)C=O>[C:1]([C:3]1[C:21]([F:22])=[C:20]([F:23])[CH:19]=[C:5]2[C:4]=1[N:15]([CH:16]1[CH2:18][CH2:17]1)[CH:14]=[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:6]2=[O:7])#[N:2]
Reactant: CCOC(=O)C(=CNC1CC1)C(=O)c1cc(F)c(F)c(C#N)c1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(C2CC2)c2c(C#N)c(F)c(F)cc2c1=O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of the crude product from step f, 27.6 g of K2CO3, and 80 ml of dimethylformamide are stirred at room temperature for 16 hours. The reaction mixture is poured on 750 ml ice/water and the precipitate is filtered off with suction, washed with 80 ml of cold methanol and dried.
Reaction SMILES: C([O:8][CH2:9][C@H:10]([O:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH3:61])[CH2:11][O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])C1C=CC=CC=1>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH2:13]([O:12][CH2:11][C@H:10]([CH2:9][OH:8])[O:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH3:61])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36]
Reactant: CCCCCCCCCCCCCCCCCCCCCCCCOC[C@H](COCc1ccccc1)OCCCCCCCCCCCCCCCCCCCCCCCC
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CCCCCCCCCCCCCCCCCCCCCCCCOC[C@H](CO)OCCCCCCCCCCCCCCCCCCCCCCCC
Yield: 60.8 %

Procedure:
3-O-Benzyl-1,2-di-O-tetracosyl-Sn-glycerol (1.47 g) was reacted in a mixture (30 ml) of toluene-ethyl acetate (1:1) by the general procedure according to 15-B to obtain the title compound (0.80 g, 66%) as white solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:10])[CH3:9].[Br:11]CC(C1C=C(Cl)C=CC=1Cl)=O>>[Br:11][CH2:9][C:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[Br:1])=[O:10]
Reactant: O=C(CBr)c1cc(Cl)ccc1Cl
Reactant: CC(=O)c1ccccc1Br
Product: O=C(CBr)c1ccccc1Br
Yield: 57 %

Procedure:
This compound was prepared from 1-(2-bromo-phenyl)-ethanone (2.5 g, 12.6 mmol) in the manner described for 2-bromo-1-(2,5-dichlorophenyl)ethanone (Method I-2), affording 1.98 g (57%) of 2-bromo-1-(2-bromo-phenyl)-ethanone as a clear oil. 1H-NMR (CD2Cl2) δ 8.13 (t, J=2 Hz, 1H), 7.92 (dm, J=8 Hz, 1H), 7.78 (dm, J=8 Hz, 1H), 7.42 (t, J=8 Hz, 1H), 4.49 (s, 2H); TLC Rf=0.38, 15%, ethyl acetate-hexanes.
Reaction SMILES: [C:1]([N:3]=[C:4](OC1C=CC=CC=1)[NH:5][C:6]1[CH:7]=[N:8][CH:9]=[N:10][CH:11]=1)#[N:2].[CH3:19][C@@H:20]([NH2:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CN(C=O)C>[C:1]([N:3]=[C:4]([NH:27][C@@H:20]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH3:19])[NH:5][C:6]1[CH:11]=[N:10][CH:9]=[N:8][CH:7]=1)#[N:2]
Reactant: N#CN=C(Nc1cncnc1)Oc1ccccc1
Reactant: C[C@@H](N)c1ccccc1
Solvent: CN(C)C=O
Product: C[C@@H](NC(=NC#N)Nc1cncnc1)c1ccccc1
Reaction time: 18 h

Procedure:
A stirred mixture of N'-cyano-N-(5-pyrimidyl)-O-phenylisourea (0.5 g, 0.00209 mol), (R)-α-methylbenzylamine (1.0 mL) and DMF (4 mL) was kept, under nitrogen, at ambient temperature for 18 hours and concentrated in vacuo. The residue was allowed to crystallize from EtOAc-tert-butyl methyl ether. The solid was triturated with Et2O and tert-butyl methyl ether and crystallized from EtOAc to give product: NMR (CDCl3) δ1.61 (d, 3H), 4.92 (m, 1H), 6.05 (broad s, 1H), 7.38 (m, 6H), 8.56 (s, 2H), 8.97 (s, 1H); IR (Nujol) 3262, 3109, 3054, 2174, 1600, 1570 cm-1 ; MS m/z (relative intensity) 266 (M+, 100), 251 (24.3), 161 (4.0), 146 (33.0), 120 (40.5), 105 (100).
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]#[N:20])[C:3]=1[S:21][C:22]([F:25])([F:24])[F:23].[CH:26](OCC)(OCC)[O:27][CH2:28][CH3:29]>CC1C=CC=CC=1>[C:19]([C:4]1[C:3]([S:21][C:22]([F:25])([F:24])[F:23])=[C:2]([N:1]=[CH:26][O:27][CH2:28][CH3:29])[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:15])([F:16])[F:17])=[CH:9][C:8]=2[Cl:18])[N:5]=1)#[N:20]
Reactant: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1SC(F)(F)F
Reactant: CCOC(OCC)OCC
Solvent: Cc1ccccc1
Product: CCOC=Nc1c(SC(F)(F)F)c(C#N)nn1-c1c(Cl)cc(C(F)(F)F)cc1Cl

Procedure:
5-Amino-3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-4-trifluoromethylthiopyrazole (4.0 g) was added to triethyl orthoformate (19.0 ml) and p-toluene/-sulphonic acid (0.019 g) added. The mixture was heated under reflux for 21 hours, cooled, and the triethyl orthoformate evaporated in vacuo to give a brown oil as residue. This was purified by chromatography eluting with a mixture of dichloromethane and hexane (1:1). Evaporation of the eluates in vacuo gave 3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-5-ethoxymethyleneamino-4-trifluoromethylthiopyrazole as a colourless solid, m.p. 70-71.5° C.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:7]([CH:10]([CH3:12])[CH3:11])=[CH:6][C:3]=1[C:4]#[N:5].F[C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=1[N+:21]([O-:23])=[O:22].O.[OH-].[Li+]>CS(C)=O>[F:20][C:17]1[CH:18]=[CH:19][C:14]([NH:1][C:2]2[CH:9]=[CH:8][C:7]([CH:10]([CH3:12])[CH3:11])=[CH:6][C:3]=2[C:4]#[N:5])=[C:15]([N+:21]([O-:23])=[O:22])[CH:16]=1
Reactant: CC(C)c1ccc(N)c(C#N)c1
Reactant: O=[N+]([O-])c1cc(F)ccc1F
Agent: [Li+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: CC(C)c1ccc(Nc2ccc(F)cc2[N+](=O)[O-])c(C#N)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 80.8 %

Procedure:
Heat a solution of 2-amino-5-isopropyl-benzonitrile (1.482 g, 9.25 mmol) with 1,4-difluoro-2-nitro-benzene (1.47 g, 9.25 mmol) and lithium hydroxide monohydrate (0.78 g, 18.50 mmol) in DMSO (20 ml) to 70° C. for 38 hours. Cool the reaction to ambient temperature and then pour into approximately 200 ml of ice water and stir for one hour. The title compound precipitates and collection by filtration to obtain 2.236 g (7.47 mmol, 81% yield) of the title compound as an orange amorphous solid: Mass Spectrum (m/e): 300(M+1).
Reaction SMILES: ClC(OC(Cl)C)=O.C1(C[N:15]2[CH2:20][CH:19]=[C:18]([C:21]3[CH:26]=[CH:25][C:24]([NH:27][C:28]([C:30]4[C:31]([C:36]5[CH:41]=[CH:40][C:39]([C:42]([F:45])([F:44])[F:43])=[CH:38][CH:37]=5)=[CH:32][CH:33]=[CH:34][CH:35]=4)=[O:29])=[CH:23][CH:22]=3)[CH2:17][CH2:16]2)C=CC=CC=1>ClCCCl>[NH:15]1[CH2:16][CH:17]=[C:18]([C:21]2[CH:22]=[CH:23][C:24]([NH:27][C:28]([C:30]3[C:31]([C:36]4[CH:37]=[CH:38][C:39]([C:42]([F:43])([F:44])[F:45])=[CH:40][CH:41]=4)=[CH:32][CH:33]=[CH:34][CH:35]=3)=[O:29])=[CH:25][CH:26]=2)[CH2:19][CH2:20]1
Reactant: O=C(Nc1ccc(C2=CCN(Cc3ccccc3)CC2)cc1)c1ccccc1-c1ccc(C(F)(F)F)cc1
Agent: CC(Cl)OC(=O)Cl
Solvent: ClCCCl
Product: O=C(Nc1ccc(C2=CCNCC2)cc1)c1ccccc1-c1ccc(C(F)(F)F)cc1
Reaction time: 0.5 h
Yield: 126.2 %

Procedure:
1-Chloroethyl chloroformate (0.078 mol) was added dropwise to a stirring mixture of intermediate (20) (0.039 mol) in 1,2-dichloro-ethane (500 ml). The mixture was stirred for 30 minutes and then stirred and refluxed overnight. The solvent was evaporated. Methanol (500 ml) was added. The mixture was stirred and refluxed overnight. The solvent was evaporated. The residue was triturated in DIPE. The precipitate was filtered off and dried, yielding 20.8 g of N-[4-(1,2,3,6-tetrahydro-4-pyridinyl)phenyl]-4′-(trifluoro-methyl )-[1,1′-biphenyl]-2-carboxamide (intermediate 21).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].[N+:9]([C:12]1[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=1[C:14](Cl)=[O:15])([O-:11])=[O:10]>>[N+:9]([C:12]1[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=1[C:14]([NH:5][C:4]1[CH:6]=[CH:7][CH:8]=[C:2]([Cl:1])[CH:3]=1)=[O:15])([O-:11])=[O:10]
Reactant: O=C(Cl)c1ccccc1[N+](=O)[O-]
Reactant: Nc1cccc(Cl)c1
Product: O=C(Nc1cccc(Cl)c1)c1ccccc1[N+](=O)[O-]
Yield: 98 %

Procedure:
Using the procedure described in Example 93, Part A, 3-chloroaniline (9.4 mmol) and 2-nitrobenzoyl chloride (10.4 mmol) yielded 2.55 g (98%) of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:17]=[CH:16][C:15](I)=[CH:14][C:3]=1/[CH:4]=[CH:5]/[C:6]1[C:11]([CH3:12])=[CH:10][CH:9]=[CH:8][C:7]=1[CH3:13].[CH2:19]([OH:22])[CH:20]=[CH2:21]>>[CH3:13][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]([CH3:12])[C:6]=1/[CH:5]=[CH:4]/[C:3]1[CH:14]=[C:15]([CH2:21][CH2:20][CH:19]=[O:22])[CH:16]=[CH:17][C:2]=1[F:1]
Reactant: Cc1cccc(C)c1/C=C/c1cc(I)ccc1F
Reactant: C=CCO
Product: Cc1cccc(C)c1/C=C/c1cc(CCC=O)ccc1F

Procedure:
(E)-2-(2-Fluoro-5-iodostyryl)-1,3-dimethylbenzene was coupled with allyl alcohol according to the method in Example 42. Purification by flash chromatography (40% CH2Cl2-hexanes) gave (E)-3-(3-(2,6-dimethylstyryl)-4-fluorophenyl)propanal as an oil. Yield (0.115 g, 52%): 1H NMR (400 MHz, DMSO-d6) δ 9.72 (t, J=1.2 Hz, 1H), 7.64 (dd, J=7.2, 2.4 Hz, 1H), 7.27 (d, J=16.8 Hz, 1H), 7.09-7.19 (m, 2H), 7.06 (s, 3H), 6.67 (d, J=16.8 Hz, 1H), 2.78-2.89 (m, 4H), 2.31 (s, 6H).
Reaction SMILES: [CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([C:36]3[NH:40][C:39]([C:41]4[S:42][CH:43]=[CH:44][N:45]=4)=[CH:38][CH:37]=3)[CH2:14][C@H:15]3[CH2:35][CH2:34][C:17]4(O[C@H](C5C=CC=CC=5)[C@@H](C5C=CC=CC=5)[O:18]4)[CH2:16]3)=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.S(=O)(=O)(O)O.C(=O)([O-])O.[Na+]>O1CCOCC1>[CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([C:36]3[NH:40][C:39]([C:41]4[S:42][CH:43]=[CH:44][N:45]=4)=[CH:38][CH:37]=3)[CH2:14][C@H:15]3[CH2:35][CH2:34][C:17](=[O:18])[CH2:16]3)=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1
Reactant: O=S(=O)(c1ccc(C(C[C@H]2CCC3(C2)O[C@H](c2ccccc2)[C@@H](c2ccccc2)O3)c2ccc(-c3nccs3)[nH]2)cc1)C1CC1
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: C1COCCO1
Product: O=C1CC[C@H](CC(c2ccc(S(=O)(=O)C3CC3)cc2)c2ccc(-c3nccs3)[nH]2)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 43.4 %

Procedure:
To a solution of 2-(5-{1-[4-(cyclopropylsulfonyl)phenyl]-2-[(2R,3R,7R)-2,3-diphenyl-1,4-dioxaspiro[4.4]non-7-yl]ethyl}-1H-pyrrol-2-yl)-1,3-thiazole (0.100 g) in 1,4-dioxane (2 mL) was added 4.5M aqueous sulfuric acid solution (2 mL) at room temperature, and the mixture was stirred at room temperature for 4 hr. To the reaction mixture was added saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=20:80-80:20, volume ratio), and recrystallized from diethyl ether-hexane to give the title compound (0.03 g, yield 43%) as colorless crystals. MS: 441 (MH+). melting point 165-167° C.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.Br[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.C1(C)C=CC=CC=1>[CH2:11]([O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: O=Cc1ccc(O)cc1
Reactant: CCCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: CCCCCCCCOc1ccc(C=O)cc1
Temperature: 25 °C

Procedure:
A mixture of 4-hydroxybenzaldehyde (10.0 g, 81.8 mmol), 1-bromooctane (15.8 g, 81.8 mmol), and K2CO3 (34.0 g, 0.25 mol) in DMF (150 mL) was heated to reflux for 8 hours and then cooled to room temperature. The reaction mixture was subsequently diluted in toluene. The organic layer was washed with HCl (10%), brine, and water. The solvent was concentrated in vacuo and the oil was purified by short silica gel plug (dichloromethane (DCM) in n-hexanes, 10%). Solvent was dried in vacuo to afford the product 4-octyloxy benzaldehyde as a slightly colored oil.
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:14]=[C:13]([O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17])[CH:12]=[CH:11][C:10]=1[CH:23]1[CH2:28][CH2:27][C:26](=O)[CH2:25][CH2:24]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH2:30]([NH2:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>ClCCl>[CH2:30]([N:37]=[C:26]1[CH2:27][CH2:28][CH:23]([C:10]2[CH:11]=[CH:12][C:13]([O:15][Si:16]([C:19]([CH3:21])([CH3:22])[CH3:20])([CH3:17])[CH3:18])=[CH:14][C:9]=2[O:8][Si:1]([C:4]([CH3:6])([CH3:5])[CH3:7])([CH3:2])[CH3:3])[CH2:24][CH2:25]1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(C2CCC(=O)CC2)c(O[Si](C)(C)C(C)(C)C)c1
Reactant: NCc1ccccc1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)Oc1ccc(C2CCC(=NCc3ccccc3)CC2)c(O[Si](C)(C)C(C)(C)C)c1
Reaction time: 15 h
Yield: 101.6 %

Procedure:
To a round bottomed flask was added 4-(2,4-bis{[tert-butyl(dimethyl)silyl]oxy}phenyl) cyclohexanone (817 mg). Dichloromethane (50 ml) was added followed by benzylamine (0.82 ml, 7.52 mmol) and activated 4 Å molecular sieves (10.0 g). The reaction mixture was stirred vigorously for 15 hr, then dichloromethane (50 ml) was added and the reaction mixture filtered through celite, washing with dichloromethane (50 ml). The filtrate was concentrated in vacuo affording the title compound (1.00 g, 86%) as a yellow oil. δH (CDCl3) 0.19 (6H, s), 0.26 (6H, s), 0.98 (9H, s), 1.03 (9H, s), 1.51 (1H, m), 1.72 (1H, m), 2.03 (2H, m), 2.45 (1H, m), 2.60 (1H, m), 3.04 (1H, m), 3.22 (1H, m), 4.55 (1H, d), 4.60 (1H, d), 6.31 (1H, d), 6.41 (1H, dd), 6.93 (1H, d), 7.33 (5H, m).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][C:22]=1[Cl:23])[CH2:5][C@H:6]1[CH2:10][N:9]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[C@H:8]([CH2:18][OH:19])[CH2:7]1.C(N(CC)CC)C.[CH3:31][S:32](Cl)(=[O:34])=[O:33]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][C:22]=1[Cl:23])[CH2:5][C@H:6]1[CH2:10][N:9]([C:11]([O:13][C:14]([CH3:16])([CH3:17])[CH3:15])=[O:12])[C@H:8]([CH2:18][O:19][S:32]([CH3:31])(=[O:34])=[O:33])[CH2:7]1
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1C[C@H](Cc2ccc(Cl)c(Cl)c2)C[C@H]1CO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1C[C@H](Cc2ccc(Cl)c(Cl)c2)C[C@H]1COS(C)(=O)=O
Reaction time: 9 h
Yield: 101.5 %

Procedure:
To a solution of (2S,4R)-4-(3,4-dichlorobenzyl)-1-tert-butoxycarbonyl-2-(hydroxymethyl)pyrrolidine (1.38 g, 3.82 mmol) in methylene chloride (30 mL) was added triethylamine (0.78 mL, 5.72 mmol) followed by methanesulfonyl chloride (0.36 mL, 4.58 mmol) and the mixture was stirred at 20° for 9 hrs. Most CH2Cl2 was then removed by evaporation in vacuo, and the residue was diluted with ethyl acetate and washed with aqueous NaHCO3 followed by water. Drying with Na2SO4 followed by evaporation in vacuo gave 1.70 g of crude (2S,4R)-4-(3,4-dichlorobenzyl)-1-tert-butoxycarbonyl-2-(methanesulfonyloxymethyl)pyrrolidine, which was used without further purification.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([Cl:25])[C:5]([C:8]2([CH2:11][NH:12][C:13](=[O:24])[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[C:20]([F:23])([F:22])[F:21])[CH2:10][CH2:9]2)=[N:6][CH:7]=1.[CH:26]1([B-](F)(F)F)[CH2:28][CH2:27]1.[K+].C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1.O>[Cl:25][C:4]1[C:5]([C:8]2([CH2:11][NH:12][C:13](=[O:24])[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[C:20]([F:23])([F:22])[F:21])[CH2:10][CH2:9]2)=[N:6][CH:7]=[C:2]([CH:26]2[CH2:28][CH2:27]2)[CH:3]=1
Reactant: F[B-](F)(F)C1CC1
Reactant: O=C(NCC1(c2ncc(Br)cc2Cl)CC1)c1ccccc1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: O=C(NCC1(c2ncc(C3CC3)cc2Cl)CC1)c1ccccc1C(F)(F)F
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 44.7 %

Procedure:
150 mg of N-[[1-(5-bromo-3-chloro-2-pyridyl)cyclopropyl]methyl]-2-(trifluoromethyl)benzamide (step 4), 61 mg potassium cyclopropyltrifluoroborate and 340 mg cesium carbonate were dissolved in 3 ml of a mixture of toluene and water (3:1) in a microwave vial. The reaction mixture was degassed with argon for 1 min and 14 mg of [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) was added. The vial was sealed and the reaction mixture was then stirred at 100° C. in a microwave reactor for 30 min, then at 130° C. for 30 min. Then the mixture was cooled to ambient temperature, water was added and the reaction mixture was extracted with dichloromethane. The organic phase was dried with anhydrous sodium sulfate, filtered and concentrated. Crude material was obtained as a brown sticky solid, which was purified by flash chromatography on silica gel with heptane/ethyl acetate as a solvent. Thus, 61 mg of N-[[1-(3-chloro-5-cyclopropyl-2-pyridyl)cyclopropyl]methyl]-2-(trifluoromethyl)benzamide was obtained as a pale yellow sticky solid. 1H-NMR (CDCl3): 8.19 ppm (d, 1H), 7.65 ppm (d, 1H), 7.52 ppm (m, 2H), 7.40 ppm (d, 1H), 7.30 ppm (d, 1H), 6.20 ppm (s, 1H, broad), 3.68 ppm (d, 2H), 1.85 ppm (m, 1H), 1.05 ppm (m, 5H), 0.88 ppm (m, 1H), 0.70 ppm (m, 2H).