Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O=[N+]([O-])[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[Ce+4].[NH4+].[NH4+].C(#N)C.C[O:32][C:33]1[C:41]([O:42][CH3:43])=[C:40]([O:44][CH3:45])[C:39]([O:46]C)=[C:38]2[C:34]=1[CH2:35][CH:36]([CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][OH:56])[CH2:37]2>O>[OH:56][CH2:55][CH2:54][CH2:53][CH2:52][CH2:51][CH2:50][CH2:49][CH2:48][CH:36]1[CH2:35][C:34]2[C:33](=[O:32])[C:41]([O:42][CH3:43])=[C:40]([O:44][CH3:45])[C:39](=[O:46])[C:38]=2[CH2:37]1
Reactant: COc1c2c(c(OC)c(OC)c1OC)CC(CCCCCCCCO)C2
Agent: O=[N+]([O-])[O-]
Agent: [Ce+4]
Agent: [NH4+]
Solvent: CC#N
Solvent: O
Product: COC1=C(OC)C(=O)C2=C(CC(CCCCCCCCO)C2)C1=O
Reaction time: 0.25 h
Yield: 26.2 %

Procedure:
A water (1.0 ml) solution of CAN (463 mg, 0.845 mmols) was dropwise added to an acetonitrile (3.0 ml) solution of 8-(4,5,6,7-tetramethoxyindan-2-yl)octanol (138 mg, 0.338 mmols) with cooling with ice and stirring was continued for 15 minutes. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, and then dried. The solvent was evaporated out in vacuo, and the resulting crude product was purified by silica gel column chromatography (hexane:ethyl acetate=4:1 to 2:1) followed by recrystallization from hexane-diethyl ether to obtain the entitled compound (29.8 mg) as crystals.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([S:11][C:12]#N)=[CH:7][C:6]=1[N+:14]([O-:16])=[O:15])(=[O:3])[CH3:2].CN(C)[CH:19]=[O:20].[BH4-].[Na+].COCCl>O>[C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([S:11][CH2:12][O:20][CH3:19])=[CH:7][C:6]=1[N+:14]([O-:16])=[O:15])(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc(SC#N)cc1[N+](=O)[O-]
Reactant: CN(C)C=O
Agent: COCCl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Product: COCSc1ccc(NC(C)=O)c([N+](=O)[O-])c1
Reaction time: 1 h

Procedure:
2.37 G. of 1-acetamido-2-nitro-4-thiocyanatobenzene in 10 ml. dimethylformamide is treated, under nitrogen, with 0.38 g. sodium borohydride at 20°-30° C. After one hour at 20°-30° C., 1.6 ml. of chloromethyl methyl ether is added. The mixture is stirred for a further 3 hour period, then diluted with water. The crude product is filtered off and recrystallized from cyclohexane, yielding 1-acetamido-2-nitro-4-methoxymethylthiobenzene.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([I:9])[CH:8]=1)[NH2:5].[C:10]([N:17]1[CH:21]=[CH:20]N=[CH:18]1)(N1C=CN=C1)=[O:11].[CH3:22][O:23][C:24]1[CH:25]=[C:26]2C(=[CH:31][C:32]=1[C:33]([F:36])([F:35])[F:34])NCC2.O>ClCCl.CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([NH:5][C:10]([N:17]2[C:18]3[C:26](=[CH:25][C:24]([O:23][CH3:22])=[C:32]([C:33]([F:35])([F:36])[F:34])[CH:31]=3)[CH2:20][CH2:21]2)=[O:11])[CH:6]=[C:7]([I:9])[CH:8]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Nc1cc(F)cc(I)c1
Reactant: COc1cc2c(cc1C(F)(F)F)NCC2
Solvent: CN(C)C=O
Solvent: O
Solvent: ClCCl
Product: COc1cc2c(cc1C(F)(F)F)N(C(=O)Nc1cc(F)cc(I)c1)CC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 40 %

Procedure:
A mixture of 3-fluoro-5-iodoaniline (0.47 g, 1.98 mmol) and 1,1'-carbonyl diimidazole (0.33 g, 2 mmol) in dichloromethane (40 ml) was stirred at room temperature for 1 h, then evaporated to dryness. To the residue was added dimethylformamide (DMF,10 ml) and a solution of 5-methoxy-6-trifluoromethylindoline (D11, 0.44 g, 2 mmol) in DMF (5 ml). The mixture was heated at 80° C. overnight, then cooled and poured into water. The precipitate was filtered off, washed with water and dried. The crude product was chromatographed on silica gel and eluted with dichloromethane. Eluted product was recrystallised from dichloromethane to give tie title compound (0.38 g, 40%), Mp. 221-4° C.
Reaction SMILES: C([C:4]1[C:16]2[CH:15]=[CH:14][C:13]3[N:12]([C:17](=[O:22])[C:18]([F:21])([F:20])[F:19])[CH2:11][CH:10](CCl)[C:9]=3[C:8]=2[CH:7]=[CH:6][CH:5]=1)(=O)C.[N+:25]([O-])([OH:27])=[O:26]>C(Cl)Cl>[N+:25]([C:15]1[C:16]2[CH:4]=[CH:5][CH:6]=[CH:7][C:8]=2[C:9]2[CH2:10][CH2:11][N:12]([C:17](=[O:22])[C:18]([F:21])([F:20])[F:19])[C:13]=2[CH:14]=1)([O-:27])=[O:26]
Reactant: CC(=O)c1cccc2c3c(ccc12)N(C(=O)C(F)(F)F)CC3CCl
Reactant: O=[N+]([O-])O
Solvent: ClCCl
Product: O=C(N1CCc2c1cc([N+](=O)[O-])c1ccccc21)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 57 %

Procedure:
A solution of 109 (1.0 g, 2.8 mmol) in CH2Cl2 (20 mL) was treated with fuming HNO3 (6 mL). The mixture was stirred at room temperature for 30 min, and quenched with ice. The mixture was extracted with CH2Cl2 (3×50 ml) dried, and concentrated under reduced pressure. The residue was chromatographed on silica gel, eluting with EtOAc/petroleum ether (from 1:4 to 1:1) to give 6-acetyl-1 chloromethyl)-5-nitro-3-(trifluoroacetyl)-1,2-dihydro-3H-benzo[e]indole (111) (640 mg, 57%) as a brown solid: mp 182-184° C. (EtOAc/petroleum ether); 1H NMR (CDCl3) δ 9.18 (s, 1H), 9.06 (d, J=1.4 Hz, 1H), 8.28 (dd, J=8.8, 1.6 Hz, 1H), 7.95 (d, J=8.8 Hz, 1H), 4.68-4.63 (m, 1H), 4.57-4.49 (m, 1H), 4.48-4.30 (m, 1H), 3.93-3.87 (m, 1H), 3.65-3.58 (m, 1H), 2.70 (s, 3H); 13C NMR 200.4, 154.7 (q, JC-F 39.2 Hz), 148.7, 139.2, 138.2, 130.9, 130.4, 127.7, 127.5, 125.9, 119.6, 115.7, 115.6 (q, JC-F 288H), 52.7, 45.4, 42.7, 28.5. Anal. (C17H12ClF3N2O4) C, H, N.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([C:18]([C:20]2[CH:21]=[N:22][C:23](Cl)=[N:24][CH:25]=2)=[O:19])[CH:15]2[CH2:17][CH2:16]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:27][S:28]([C:31]1[CH:36]=[CH:35][C:34](B(O)O)=[CH:33][CH:32]=1)(=[O:30])=[O:29]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH:15]2[CH2:17][CH2:16]2)[C:18]([C:20]2[CH:21]=[N:22][C:23]([C:34]3[CH:35]=[CH:36][C:31]([S:28]([CH3:27])(=[O:30])=[O:29])=[CH:32][CH:33]=3)=[N:24][CH:25]=2)=[O:19])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(N(C(=O)c2cnc(Cl)nc2)C2CC2)CC1
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Product: CC(C)(C)OC(=O)N1CCC(N(C(=O)c2cnc(-c3ccc(S(C)(=O)=O)cc3)nc2)C2CC2)CC1

Procedure:
The title compound is prepared from 4-[(2-chloro-pyrimidine-5-carbonyl)-cyclopropyl-amino]-piperidine-1-carboxylic acid tert-butyl ester and 4-(methanesulfonyl)phenyl boronic acid following a procedure analogous to that described in Intermediate 6. LC (method 10): tR=1.92 min; Mass spectrum (ESI−): m/z=545 [M+HCOO]−.
Reaction SMILES: F[C:2]1[CH:16]=[CH:15][C:5]2[C:6](=[O:14])[NH:7][C:8]3[C:13]([C:4]=2[CH:3]=1)=[CH:12][CH:11]=[CH:10][N:9]=3.BrC1[CH:19]=[C:20]([CH:23]=CC=1)[CH2:21]O.C(=O)([O-])[O-:27].[K+].[K+]>CN(C=O)C.CO>[C:20]([O:27][C:2]1[CH:16]=[CH:15][C:5]2[C:6](=[O:14])[NH:7][C:8]3[C:13]([C:4]=2[CH:3]=1)=[CH:12][CH:11]=[CH:10][N:9]=3)([CH3:23])([CH3:21])[CH3:19]
Reactant: O=C([O-])[O-]
Reactant: O=c1[nH]c2ncccc2c2cc(F)ccc12
Reactant: OCc1cccc(Br)c1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CO
Product: CC(C)(C)Oc1ccc2c(=O)[nH]c3ncccc3c2c1
Temperature: 150 °C
Reaction time: 0.33 h
Yield: 3.9 %

Procedure:
9-Fluoro-5H-benzo[c][1,8]naphthyridin-6-one (40 mg, 0.19 mmol), 3-bromobenzyl alcohol (105 mg, 0.56 mmol), and potassium carbonate (129 mg, 0.93 mmol) were suspended in DMF (1 mL), and stirred for 20 minutes at 150° C. in the microwave. The reaction mixture was diluted with MeOH, filtered, and purified via prep-LC-MS to provide 90 (2 mg, 3% yield) as a solid. LC-MS (M+H=381, obsd.=381). 1H NMR (400 MHz, d6-DMSO): δ 11.88 (s, 1H), 8.88 (dd, 1H), 8.50 (dd, 1H), 8.26 (d, 1H), 8.10 (d, 1H), 7.77 (m, 1H), 7.56 (m, 2H), 7.38 (m, 3H), 5.38 (s, 2H).
Reaction SMILES: [C:1](O)(=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[SH:4].[CH2:11]([NH2:14])[CH2:12][NH2:13].CO>ClC1C=CC=CC=1Cl>[NH:13]1[CH2:12][CH2:11][N:14]=[C:1]1[C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[SH:4]
Reactant: O=C(O)c1ccccc1S
Reactant: NCCN
Solvent: Clc1ccccc1Cl
Solvent: CO
Product: Sc1ccccc1C1=NCCN1
Temperature: 60 °C
Yield: 53.1 %

Procedure:
To a suspension of 20.0 g (0.112 mol) of thiosalicylic acid in 200 mL of 1,2-dichlorobenzene was added 21.6 mL (0.323 mol) of ethylenediamine. The mixture was refluxed under nitrogen for 4 h then cooled to ca. 60° C. and 50 mL of methanol was added. The solution was allowed to stand at 22° C. over night and the resulting yellow crystalline solid collected and washed with ether to give 10.6 g of pure product.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[S:9]([N:12]1[C:17]2[CH:18]=[C:19]([C:22]([NH:24][C:25]3[CH:33]=[CH:32][C:28]([C:29]([OH:31])=[O:30])=[C:27]([F:34])[CH:26]=3)=[O:23])[CH:20]=[CH:21][C:16]=2[O:15][CH2:14][CH2:13]1)(=[O:11])=[O:10].F[C:36]1C=CC(F)=C[C:37]=1S(Cl)(=O)=O>>[CH2:36]([O:30][C:29](=[O:31])[C:28]1[CH:32]=[CH:33][C:25]([NH:24][C:22]([C:19]2[CH:20]=[CH:21][C:16]3[O:15][CH2:14][CH2:13][N:12]([S:9]([C:3]4[CH:4]=[C:5]([F:8])[CH:6]=[CH:7][C:2]=4[F:1])(=[O:10])=[O:11])[C:17]=3[CH:18]=2)=[O:23])=[CH:26][C:27]=1[F:34])[CH3:37]
Reactant: O=S(=O)(Cl)c1cc(F)ccc1F
Reactant: O=C(Nc1ccc(C(=O)O)c(F)c1)c1ccc2c(c1)N(S(=O)(=O)c1cc(F)ccc1F)CCO2
Product: CCOC(=O)c1ccc(NC(=O)c2ccc3c(c2)N(S(=O)(=O)c2cc(F)ccc2F)CCO3)cc1F

Procedure:
4-{[4-(2,5-Difluoro-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-2-fluoro-benzoic acid, MS (ISP): m/e=491.1 (M−H), was prepared as described for example 21, steps 1 to 8. Step 7 was performed using 2,5-difluoro-benzenesulfonyl chloride and yielded 4-{[4-(2,5-difluoro-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-2-fluoro-benzoic acid ethyl ester, which was hydrolyzed in step 8.
Reaction SMILES: [NH:1]([C:15]([O:17][CH2:18][CH:19]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:25]2[C:20]1=[CH:21][CH:22]=[CH:23][CH:24]=2)=[O:16])[C@H:2](C(O)=O)[CH2:3][CH2:4][C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CN1CC[O:69][CH2:68]C1.[NH2:72][C@H:73]([C:99]([NH:101][C@H:102]([C:106]([NH:108][C@H:109]([C:117]([O:119][CH2:120][C:121]1[CH:126]=[CH:125][CH:124]=[CH:123][CH:122]=1)=[O:118])[CH2:110][C:111](=[O:116])[O:112][CH2:113][CH:114]=[CH2:115])=[O:107])[CH:103]([CH3:105])[CH3:104])=[O:100])[CH2:74][CH2:75][CH2:76][NH:77][C:78](=[NH:98])[NH:79][S:80]([C:83]1[C:96]([CH3:97])=[C:94]([CH3:95])[C:93]2[O:92][C:89]([CH3:91])([CH3:90])[CH2:88][CH2:87][C:86]=2[C:84]=1[CH3:85])(=[O:82])=[O:81]>C(#N)C>[NH:1]([C:15]([O:17][CH2:18][CH:19]1[C:20]2[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:26]2[C:31]1=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:16])[C@H:2]([C:68]([NH:72][C@H:73]([C:99]([NH:101][C@H:102]([C:106]([NH:108][C@H:109]([C:117]([O:119][CH2:120][C:121]1[CH:126]=[CH:125][CH:124]=[CH:123][CH:122]=1)=[O:118])[CH2:110][C:111](=[O:116])[O:112][CH2:113][CH:114]=[CH2:115])=[O:107])[CH:103]([CH3:104])[CH3:105])=[O:100])[CH2:74][CH2:75][CH2:76][NH:77][C:78](=[NH:98])[NH:79][S:80]([C:83]1[C:96]([CH3:97])=[C:94]([CH3:95])[C:93]2[O:92][C:89]([CH3:90])([CH3:91])[CH2:88][CH2:87][C:86]=2[C:84]=1[CH3:85])(=[O:82])=[O:81])=[O:69])[CH2:3][CH2:4][C:5](=[O:11])[O:6][C:7]([CH3:9])([CH3:8])[CH3:10]
Reactant: CN1CCOCC1
Reactant: C=CCOC(=O)C[C@H](NC(=O)[C@@H](NC(=O)[C@@H](N)CCCNC(=N)NS(=O)(=O)c1c(C)c(C)c2c(c1C)CCC(C)(C)O2)C(C)C)C(=O)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)CC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CC#N
Product: C=CCOC(=O)C[C@H](NC(=O)[C@@H](NC(=O)[C@H](CCCNC(=N)NS(=O)(=O)c1c(C)c(C)c2c(c1C)CCC(C)(C)O2)NC(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)OCC1c2ccccc2-c2ccccc21)C(C)C)C(=O)OCc1ccccc1
Temperature: 3 °C
Reaction time: 0.5 h
Yield: 57.3 %

Procedure:
To a solution of Fmoc-Glu(tBu) (6.73 g, 15.8 mmol) and benzotriazolyloxy-tris[pyrrolidino]-phosphonium hexafluoroacetate (PyBOP, 8.18 g, 15.8 mmol) in 105 mL acetonitrile at 2° C. is added N-methylmorpholine (1.58 g, 15.8 mmol) and the reaction mixture is stirred at 2-4° C. for 30 minutes. A solution of L)Arg(Pmc)-Val-Asp(OAllyl)-OBzl (12.4 g, 15.8 mmole) in 70 mL acetonitrile is added at 2° .C over 20 minutes. N-methylmorpholine is then added to achieve pH 7. Cooling is ceased, and the mixture is allowed to warm to ambient temperature, then stirred is continued for a total of 3 hours. The milky reaction mixture is filtered (slow) and the white residue is dried in the filter overnight to afford 10.8 g of Fmoc-Glu(OBut)-Arg(Pmc)-Val-Asp(Allyl)-OBzl. The filtrate is concentrated to give a gum, which is taken up in 30 mL acetonitrile and allowed to stand for 48 hours, producing an additional 3.45 g of product. The total yield of Fmoc-Glu(OtBu)-Arg(Pmc)-Val-Asp(OAllyl)-OBzl is 14.3 g. (Mcalc 1192; M+1obsvd 1192.4)
Reaction SMILES: [CH:1]([C:3]1[C:4]([O:14][CH2:15][C:16]2[CH:39]=[CH:38][C:19]([O:20][CH2:21][C:22]3[N:23]=[C:24]([C:28]4[S:32][C:31]([C:33]([O:35][CH2:36][CH3:37])=[O:34])=[CH:30][CH:29]=4)[O:25][C:26]=3[CH3:27])=[C:18]([O:40][CH3:41])[CH:17]=2)=[N:5][N:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:7]=1)=O.[Cl-].[CH2:43]([C:45]1[S:46][CH:47]=[C:48]([CH2:50][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[N:49]=1)[CH3:44].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH2:43]([C:45]1[S:46][CH:47]=[C:48](/[CH:50]=[CH:1]\[C:3]2[C:4]([O:14][CH2:15][C:16]3[CH:39]=[CH:38][C:19]([O:20][CH2:21][C:22]4[N:23]=[C:24]([C:28]5[S:32][C:31]([C:33]([O:35][CH2:36][CH3:37])=[O:34])=[CH:30][CH:29]=5)[O:25][C:26]=4[CH3:27])=[C:18]([O:40][CH3:41])[CH:17]=3)=[N:5][N:6]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH:7]=2)[N:49]=1)[CH3:44]
Reactant: CCc1nc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cs1
Reactant: CCOC(=O)c1ccc(-c2nc(COc3ccc(COc4nn(-c5ccccc5)cc4C=O)cc3OC)c(C)o2)s1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(-c2nc(COc3ccc(COc4nn(-c5ccccc5)cc4/C=C\c4csc(CC)n4)cc3OC)c(C)o2)s1
Temperature: 25 °C
Reaction time: 15 h
Yield: 28 %

Procedure:
A mixture of ethyl 5-{4-[(4-[{(4-formyl-1-phenyl-1H-pyrazol-3-yl)oxy}methyl]-2-methoxyphenoxy)methyl]-5-methyl-1,3-oxazol-2-yl}thiophene-2-carboxylate (1.80 g), [(2-ethyl-1,3-thiazol-4-yl)methyl]triphenylphosphonium chloride (1.99 g), anhydrous potassium carbonate (0.65 g) and N,N-dimethylformamide (50 mL) was stirred at room temperature for 15 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate-hexane (2:3, v/v) to give ethyl 5-[4-({4-[({4-[(Z)-2-(2-ethyl-1,3-thiazol-4-yl)ethenyl]-1-phenyl-1H-pyrazol-3-yl}oxy)methyl]-2-methoxyphenoxy}methyl)-5-methyl-1,3-oxazol-2-yl]thiophene-2-carboxylate as colorless crystals (0.60 g, yield 28%). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 118-119° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[Cl:17])[CH2:5][N:6]1[CH2:11][CH2:10][O:9][CH:8]([CH2:12][NH2:13])[CH2:7]1.[F:18][C:19]1[CH:20]=[C:21]([CH2:26][C:27](O)=[O:28])[CH:22]=[CH:23][C:24]=1[F:25]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[Cl:17])[CH2:5][N:6]1[CH2:11][CH2:10][O:9][CH:8]([CH2:12][NH:13][C:27](=[O:28])[CH2:26][C:21]2[CH:22]=[CH:23][C:24]([F:25])=[C:19]([F:18])[CH:20]=2)[CH2:7]1
Reactant: NCC1CN(Cc2ccc(Cl)c(Cl)c2)CCO1
Reactant: O=C(O)Cc1ccc(F)c(F)c1
Product: O=C(Cc1ccc(F)c(F)c1)NCC1CN(Cc2ccc(Cl)c(Cl)c2)CCO1
Yield: 23 %

Procedure:
Example 6 was prepared in an analogous manner to Example 1 using a mixture of Intermediate 1 (0.055 g) and (3,4-difluorophenyl)acetic acid (0.034 g) to give the title compound (0.0195 g).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[Br:11][C:12]1[N:17]=[CH:16][C:15]2[CH:18]=[C:19]([C:21]3[CH:22]=[N:23][N:24]([CH3:26])[CH:25]=3)[NH:20][C:14]=2[CH:13]=1.Br[CH2:28][CH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1.[H-].[Na+]>CN(C=O)C.O.CCOC(C)=O>[Br:11][C:12]1[N:17]=[CH:16][C:15]2[CH:18]=[C:19]([C:21]3[CH:22]=[N:23][N:24]([CH3:26])[CH:25]=3)[N:20]([CH2:28][CH:29]3[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]3)[C:14]=2[CH:13]=1
Reactant: BrCC1CCCCC1
Reactant: Cn1cc(-c2cc3cnc(Br)cc3[nH]2)cn1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: Cn1cc(-c2cc3cnc(Br)cc3n2CC2CCCCC2)cn1
Temperature: 60 °C
Reaction time: 8 h
Yield: 59.5 %

Procedure:
NaHMDS (1 M solution in THF, 217 mL, 0.217 mmol) was added to a solution of 6-bromo-2-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[3,2-c]pyridine (Preparation 22, 50 mg, 0.180 mmol) in DMF (790 mL). The reaction mixture was then stirred for 10 minutes at room temperature before the addition of (bromomethyl)cyclohexane (38 mL, 0.271 mmol) and was stirred overnight at 60° C. NaH (60% in mineral oil) (14.4 mg, 0.361 mmol) and bromomethylcyclohexane (76 mL, 0.542 mmol) were then added. The reaction mixture was stirred for 1 hour at 60° C. before being diluted with water and EtOAc. The layers were separated and the aqueous layer was extracted with EtOAc. The combined organic layers were dried (Na2SO4), filtered and concentrated under reduced pressure. The crude was purified via Biotage silica gel column chromatography eluting with (DCM/EtOAc 99/1 to 80/20) to afford the title product as a colourless oil (40 mg, 59%). 1H NMR (500 MHz, CDCl3) d 0.84-0.94 (m, 2H), 1.06-1.17 (m, 3H), 1.43-1.50 (m, 2H), 1.61-1.69 (m, 3H), 1.70-1.78 (m, 1H), 3.95 (d, J=7.5 Hz, 2H), 4.02 (s, 3H), 6.52 (d, J=0.9 Hz, 1H), 7.41 (t, J=0.9 Hz, 1H), 7.57 (s, 1H), 7.66 (s, 1H), 8.58 (d, J=0.9 Hz, 1H). LC (Method B)-MS (ESI, m/z) tR 3.14 min, 373 [(M+H+), 100%].
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([NH:6][CH3:7])=[O:5].C([Li])CCC.[CH3:17][N:18]([CH3:29])[CH2:19][CH2:20][C:21]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:22].[Cl-].[NH4+]>CCCCCC.O1CCCC1>[CH3:29][N:18]([CH3:17])[CH2:19][CH2:20][C:21]([OH:22])([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[CH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([NH:6][CH3:7])=[O:5]
Reactant: CN(C)CCC(=O)c1ccccc1
Reactant: CNC(=O)c1ccccc1C
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CNC(=O)c1ccccc1CC(O)(CCN(C)C)c1ccccc1
Temperature: 5 °C

Procedure:
To a flask equipped with a stirrer, dropping funnel, condenser and gas inlet tube maintained under a nitrogen atmosphere there is added at room temperature 40.0 g. (0.28 mole) of o-methyl-N-methyl benzamide and 250 ml. of anhydrous tetrahydrofuran. The reaction flask is immersed in an ice bath and cooled to an internal temperature of 5° C. Stirring is initiated and 360 ml. of 1.6 M. n-butyllithium (0.616 mole) in hexane is added dropwise for about 1 hour maintaining the temperature below 8° C. The resulting red dilithio salt (compound VIII) is stirred at 5° C. for 1 additional hour and the reaction flask is then immersed in a dry-ice acetone bath and cooled to an internal temperature of -30° C. To the cold reaction mixture a solution of 49.7 g. (0.28 mole) 3-dimethylaminopropiophenone in 140 ml. anhydrous tetrahydrofuran is added dropwise in ca. 45 minutes maintaining the temperature between -30° C. and -20° C. The resulting reaction mixture is stirred at -25° C. for 1 hour, allowed to warm to -10° C. in ca. 1 hour, and then treated with 200 ml. of saturated aqueous ammonium chloride while maintaining the temperature below 0° C. The resulting solid is filtered, washed thoroughly with water and recrystallized from methylene chloride-ether (1:1) to give 2-(β-[2-dimethylaminoethyl]-β-hydroxyphenethyl)-N-methylbenzamide; m.p. 139.5 to 140.5° C.
Reaction SMILES: [CH2:1]([N:8]([CH3:17])[CH2:9][CH2:10][CH:11]([OH:16])[CH2:12][CH:13](C)C)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:18]([Mg]Cl)(C)C>>[CH2:1]([N:8]([CH3:17])[CH2:9][CH2:10][CH:11]([OH:16])[CH:12]([CH3:13])[CH3:18])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)[Mg]Cl
Reactant: CC(C)CC(O)CCN(C)Cc1ccccc1
Product: CC(C)C(O)CCN(C)Cc1ccccc1

Procedure:
Using a method similar to that for 1-(Benzyl-methyl-amino)-5-methyl-hexan-3-ol, isopropylmagnesium chloride affords the title compound: mass spectrum (ion spray) m/z=222.1(M+1); 1H NMR (CDCl3) δ 7.34-7.23 (m, 5H), 6.21 (br s, 1H), 3.63 (d, 1H), 3.51-3.47 (m, 1H), 3.42 (d, 1H), 2.81-2.74 (m, 1H), 2.59-2.54 (m, 1H), 2.19 (s, 3H), 1.72-1.47 (m, 3H), 0.95 (d, 3H), 0.89 (d, 3H).
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[C:5]1([CH3:15])[CH:10]=[CH:9][C:8]([S:11](Cl)(=[O:13])=[O:12])=[CH:7][CH:6]=1.[Cl-].[Na+]>O.C(O)C>[C:5]1([CH3:15])[CH:10]=[CH:9][C:8]([S:11]([N:1]=[N+:2]=[N-:3])(=[O:13])=[O:12])=[CH:7][CH:6]=1
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Cc1ccc(S(=O)(=O)N=[N+]=[N-])cc1
Temperature: 45 °C

Procedure:
A solution of 35 g. (0.5 moles) of sodium azide in 200 ml of water was placed in a 2 litre Erlenmeyer flask and diluted with 400 ml of 90% aqueous ethanol. To this solution was added with stirring a warm (45° C.) solution of 96 g. (0.50 mole) of p-toluenesulfonyl chloride in 1 litre of 99% ethanol. During the addition, sodium chloride separated. The reaction mixture was stirred at room temperature for 2.5 hours. Most of the solvent is removed at 35° C. (15 mm) with a rotary evaporator. The residue was mixed with 1.2 liters of water in a separatory funnel, and the oily p-toluenesulfonyl azide separated. This oil was washed with two 100 ml portions of water and dried over anhydrous sodium sulfate. Filtration with suction gave 50 g (60%, based on p-toluenesulfonyl chloride) of pure, colorless p-toluenesulfonyl azide which completely crystallised on standing at 5°.
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:16]=[C:17]([CH2:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:18]([NH2:21])=[N:19][CH:20]=2)=[CH:11][CH:10]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Si:30]([O:37][C:38]1[CH:43]=[CH:42][C:41]([CH2:44][C:45](Cl)=[O:46])=[CH:40][CH:39]=1)([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31].O>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[Si:30]([O:37][C:38]1[CH:39]=[CH:40][C:41]([CH2:44][C:45]([NH:21][C:18]2[C:17]([CH2:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[N:16][C:15]([C:12]3[CH:11]=[CH:10][C:9]([O:8][Si:1]([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:2])[CH3:3])=[CH:14][CH:13]=3)=[CH:20][N:19]=2)=[O:46])=[CH:42][CH:43]=1)([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31]
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(CC(=O)Cl)cc1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(-c2cnc(N)c(CCc3ccccc3)n2)cc1
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: c1ccncc1
Product: CC(C)(C)[Si](C)(C)Oc1ccc(CC(=O)Nc2ncc(-c3ccc(O[Si](C)(C)C(C)(C)C)cc3)nc2CCc2ccccc2)cc1
Temperature: 50 °C
Reaction time: 20 h
Yield: 45.8 %

Procedure:
Under an argon atmosphere, to a mixture of 5-[4-(tert-butyldimethylsilyloxy)phenyl]-3-phenethylpyrazin-2-amine (7r) (403 mg, 994 μmol) and 4-(dimethylamino)pyridine (19.6 mg, 160 μmol) dissolved in anhydrous pyridine (15 mL) was added 2-[4-(tert-butyldimethylsilyloxy)phenyl]acetyl chloride (10) prepared above at 0° C. and the mixture was heated with stirring at 50° C. for 20 hours. After cooling to room temperature, to this was added water and the product was extracted with ethyl acetate (100 mL×3). The combined organic extract was washed successively with water (200 mL) and brine (200 mL), followed by drying over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the residue was purified by column chromatography (silica gel 50 g, n-hexane/ethyl acetate=3/1) to give Compound 11r (298 mg, 455 μmol, 45.8%) as a yellow oily substance. Rf=0.44 (n-hexane/ethyl acetate=2/1); 1H NMR (400 MHz, DMSO-d6) 0.12 (s, 6H), 0.20 (s, 6H), 0.91 (s, 9H), 0.93 (s, 9H), 2.83 (t, 1H, J=8.4 Hz), 2.94 (t, 1H, J=8.4 Hz), 3.59 (s, 2H), 6.72-6.79 (AA′BB′, 2H), 6.92-7.00 (AA′BB′, 2H), 7.01-7.07 (AA′BB′, 2H), 7.07-7.15 (m, 1H), 7.16-7.24 (m, 4H), 7.97-8.05 (AA′BB′, 2H), 8.81 (s, 1H), 10.44 (s, 1H); 13C NMR (67.8 MHz, DMSO-d6) 8-4.5 (2C), −4.6 (2C), 17.9, 18.0, 25.5 (6C), 32.8, 34.7, 41.7, 119.6 (2C), 120.3 (2C), 125.7, 128.1 (2C), 128.2 (4C), 128.5, 129.1, 130.2 (2C), 130.3, 136.6, 141.4, 143.8, 147.9, 150.6, 153.8, 156.6, 170.3; IR (KBr, cm−1) 525, 698, 781, 839, 914, 1007, 1169, 1258, 1362, 1416, 1443, 1510, 1605, 1661, 2857, 2930, 2955, 3225.