Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][N:7]([C:24](=[O:30])[C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH:8]([CH:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)[C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[C:33](Cl)(=[O:46])[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45]>>[CH2:28]([O:27][C:25](=[O:26])[C:24]([N:7]([CH:8]([CH:19]1[CH2:23][CH2:22][CH2:21][CH2:20]1)[C:9]1[CH:10]=[CH:11][C:12]([C:15]([F:16])([F:17])[F:18])=[CH:13][CH:14]=1)[CH2:6][C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:33](=[O:46])[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45])=[CH:32][CH:31]=1)=[O:30])[CH3:29]
Reactant: CCCCCCCCCCCCC(=O)Cl
Reactant: CCOC(=O)C(=O)N(Cc1ccc(N)cc1)C(c1ccc(C(F)(F)F)cc1)C1CCCC1
Product: CCCCCCCCCCCCC(=O)Nc1ccc(CN(C(=O)C(=O)OCC)C(c2ccc(C(F)(F)F)cc2)C2CCCC2)cc1
Yield: 76 %

Procedure:
The same procedure as employed in the preparation of Example 15 (step d) but using ethyl ((4-aminobenzyl){cyclopentyl[4-(trifluoromethyl)phenyl]methyl}amino)(oxo)acetate and tridecanoyl chloride gave the title compound as a colorless oil (76%). 1H NMR (CDCl3, 300 MHz) δ 7.52-7.21 (m, 6H), 6.95 (d, 1H, J=8.5 Hz) 6.8 (d, 1H, J=8.5 Hz), 5.30 (m, 1H), 4.47-4.05 (m, 4H), 2.85-2.60 (m, 1H), 2.45-2.26 (m, 2H), 1.80-1.10 (m, 31H), 1.05-0.86 (m, 4H). M−(LC/MS(ESI)): 643.9; M+(LC/MS(ESI)): 645.2. HPLC (Condition A), Rt: 6.85 min (HPLC purity: 98.0%).
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3[N:17]=[CH:18][N:19]=[C:20]([C:21]4[C:29]5[O:28][CH2:27][O:26][C:25]=5[CH:24]=[CH:23][C:22]=4[O:30][CH2:31][CH:32]4[CH2:34][CH2:33]4)[C:15]=3[NH:14][C:13]=2[CH3:35])=[O:11])[CH2:5][CH2:4]1.[C:36](Cl)(=[O:39])[CH2:37][CH3:38]>>[CH:32]1([CH2:31][O:30][C:22]2[CH:23]=[CH:24][C:25]3[O:26][CH2:27][O:28][C:29]=3[C:21]=2[C:20]2[C:15]3[NH:14][C:13]([CH3:35])=[C:12]([C:10]([NH:9][C@H:6]4[CH2:7][CH2:8][C@@H:3]([NH:2][C:36](=[O:39])[CH2:37][CH3:38])[CH2:4][CH2:5]4)=[O:11])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:34][CH2:33]1
Reactant: Cc1[nH]c2c(-c3c(OCC4CC4)ccc4c3OCO4)ncnc2c1C(=O)N[C@H]1CC[C@@H](N)CC1
Reactant: CCC(=O)Cl
Agent: Cl
Product: CCC(=O)N[C@H]1CC[C@@H](NC(=O)c2c(C)[nH]c3c(-c4c(OCC5CC5)ccc5c4OCO5)ncnc23)CC1

Procedure:
Starting from N-(cis-4-aminocyclohexyl)-4-[5-(cyclopropylmethoxy)-1,3-benzodioxol-4-yl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f3) and commercially available propionyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[CH2:7][C@H:8]([C:18]1[O:22][N:21]=[C:20]([C:23](OCC)=[O:24])[N:19]=1)[CH2:9][CH2:10][CH2:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)([CH3:4])([CH3:3])[CH3:2].[NH3:29]>C(O)C>[NH2:29][C:23]([C:20]1[N:19]=[C:18]([C@H:8]([CH2:9][CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:28])[O:22][N:21]=1)=[O:24]
Reactant: N
Reactant: CCOC(=O)c1noc([C@H](CCCC2CCCCC2)CC(=O)OC(C)(C)C)n1
Solvent: CCO
Product: CC(C)(C)OC(=O)C[C@@H](CCCc1ccccc1)c1nc(C(N)=O)no1

Procedure:
A solution of ethyl 5-{(1R)-1-[2-(tert-butoxy)-2-oxoethyl]-4-cyclohexylbutyl}-1,2,4-oxadiazole-3-carboxylate (Preparation 27) (400 mg, 1.01 mmol) in ethanol saturated with ammonia gas (20 ml) was stirred at room temperature for 18 hours. The solvent was removed under reduced pressure and the residue was purified by column chromatography on silica gel eluting with a gradient system of hexane:ethyl acetate (90:10) gradually changing to hexane:ethyl acetate (60:40) to afford the title compound as a white solid (260 mg).
Reaction SMILES: Cl[SiH:2]1[N:6]([C:7]([CH3:10])([CH3:9])[CH3:8])[CH:5]=[CH:4][N:3]1[C:11]([CH3:14])([CH3:13])[CH3:12].[CH:15]1([NH2:18])[CH2:17][CH2:16]1>CCCCCC>[C:11]([N:3]1[CH:4]=[CH:5][N:6]([C:7]([CH3:10])([CH3:9])[CH3:8])[SiH:2]1[NH:18][CH:15]1[CH2:17][CH2:16]1)([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)N1C=CN(C(C)(C)C)[SiH]1Cl
Reactant: NC1CC1
Solvent: CCCCCC
Product: CC(C)(C)N1C=CN(C(C)(C)C)[SiH]1NC1CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 90 %

Procedure:
In an argon atmosphere, 6.22 g (26.7 mmol) of Si(tBuNCHCHNtBu)(H)Cl was dissolved in 30 mL of hexane and after adding 3.14 g (56.0 mmol) of cyclopropylamine, the mixture was stirred at room temperature for 3 hours. Insoluble matters produced were separated by filtration, and the solvent was removed by distillation from the filtrate under atmospheric pressure. The obtained residue was distilled under reduced pressure (distillation temperature: 100° C./3.7×102 Pa) to obtain 1,3-di-tert-butyl-2-cyclopropylamino-1,3-diaza-2-silacyclopent-4-ene (Si(tBuNCHCHNtBu)(H)NHcPr) as a colorless liquid (yielded amount: 6.07 g, yield: 90%).
Reaction SMILES: C(N(CC)CC)C.Cl.[NH2:9][CH2:10][CH2:11][CH2:12][C:13]([NH2:15])=[O:14].C(OP(C#N)(=O)OCC)C.[C:26]([O:30][C:31]([NH:33][C@@H:34]([CH2:50][C@@H:51]([CH:67]([CH3:69])[CH3:68])[CH2:52][C:53]1[CH:58]=[CH:57][C:56]([O:59][CH3:60])=[C:55]([O:61][CH2:62][CH2:63][CH2:64][O:65][CH3:66])[CH:54]=1)[C@@H:35]([O:42][Si:43]([C:46]([CH3:49])([CH3:48])[CH3:47])([CH3:45])[CH3:44])[CH2:36][C@@H:37]([CH3:41])[C:38](O)=[O:39])=[O:32])([CH3:29])([CH3:28])[CH3:27]>CN(C)C=O>[C:13]([CH2:12][CH2:11][CH2:10][NH:9][C:38](=[O:39])[C@H:37]([CH3:41])[CH2:36][C@H:35]([O:42][Si:43]([C:46]([CH3:47])([CH3:49])[CH3:48])([CH3:45])[CH3:44])[C@@H:34]([NH:33][C:31]([O:30][C:26]([CH3:28])([CH3:27])[CH3:29])=[O:32])[CH2:50][C@@H:51]([CH:67]([CH3:68])[CH3:69])[CH2:52][C:53]1[CH:58]=[CH:57][C:56]([O:59][CH3:60])=[C:55]([O:61][CH2:62][CH2:63][CH2:64][O:65][CH3:66])[CH:54]=1)(=[O:14])[NH2:15]
Reactant: NCCCC(N)=O
Reactant: COCCCOc1cc(C[C@@H](C[C@H](NC(=O)OC(C)(C)C)[C@H](C[C@@H](C)C(=O)O)O[Si](C)(C)C(C)(C)C)C(C)C)ccc1OC
Agent: CCOP(=O)(C#N)OCC
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COCCCOc1cc(C[C@@H](C[C@H](NC(=O)OC(C)(C)C)[C@H](C[C@@H](C)C(=O)NCCCC(N)=O)O[Si](C)(C)C(C)(C)C)C(C)C)ccc1OC
Temperature: 25 °C
Reaction time: 18 h

Procedure:
67 μl of triethylamine, 34 mg of 4-aminobutyric acid amide hydrochloride and 38 μl of cyanophosphonic acid diethyl ester are added in suscession to 128 mg of 5(S)-tert-butoxycarbonylamino-4(S)-tert-butyldimethylsilyloxy-7(S)-isopropyl-2(R)-methyl-8-[4-methoxy-3-(3-methoxy-propyloxy)-phenyl]-octanoic acid in 8 ml of dimethylformamide at 0° C. The reaction mixture is stirred for a further 18 hours at room temperature. The reaction mixture is concentrated by evaporation and 20 ml of 10% citric acid solution and ice are added to the residue. The mixture is extracted repeatedly with ethyl acetate and the organic phases are then washed with saturated sodium hydrogen carbonate solution and saturated sodium chloride solution. After concentration by evaporation, the residue is purified by means of FC (70 g of silica gel, dichloromethane/methanol=9:1). The title compound is obtained: Rf (dichloromethane/methanol=9:1)=0.38.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[C:10]([C:11]([NH:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[CH:9][N:8]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[C:5]2=[N:6][CH:7]=1.[F:26][C:27]1[CH:35]=[C:34]2[C:30]([CH:31]=[N:32][NH:33]2)=[CH:29][CH:28]=1.CC(C)([O-])C.[Na+]>O1CCOCC1.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:14]([NH:13][C:11]([C:10]1[C:4]2[C:5](=[N:6][CH:7]=[C:2]([N:33]3[C:34]4[C:30](=[CH:29][CH:28]=[C:27]([F:26])[CH:35]=4)[CH:31]=[N:32]3)[N:3]=2)[N:8]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[CH:9]=1)=[O:12])([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Br)nc12
Reactant: Fc1ccc2cn[nH]c2c1
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: CC(C)(C)[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CC(C)(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-n3ncc4ccc(F)cc43)nc12
Temperature: 125 °C

Procedure:
To a stirred solution of 2-bromo-N-tert-butyl-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (140 mg, 328 μmol), 6-fluoro-1H-indazole (43.0 mg, 316 mmol) in dioxane (2 mL) was added sodium tert-butoxide (66.8 mg, 695 μmol) and bis(tri-tert-butylphosphine)palladium(0) (16.1 mg, 31.6 μmol). The mixture was degassed then heated in sealed tube at 125° C. for two days. The mixture was cooled, filtered through celite, the cake washed with ethyl acetate, and the combined filtrates were concentrated in vacuo. Purification by chromatography (silica, 24 g Analogix column, 0-40% ethyl acetate in hexanes) gave N-tert-Butyl-2-(6-fluoro-1H-indazol-1-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide. 1H NMR (CDCl3) δ: 9.17 (s, 1H), 8.36 (s, 1H), 8.29 (dd, J=9.3, 2.3 Hz, 1H), 8.26 (d, J=1.0 Hz, 1H), 7.80 (dd, J=8.8, 5.0 Hz, 1H), 7.66 (s, 1H), 7.12 (td, J=8.9, 2.3 Hz, 1H), 5.72 (s, 2H), 3.54-3.63 (m, 2H), 1.62 (s, 9H), 0.90-1.00 (m, 2H), −0.03 (s, 9H).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].C[O:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:16])[CH3:15])=[CH:9][CH:8]=1.[N+](C)([O-])=O.[Br:21][CH:22]([CH2:26][CH2:27][CH2:28][CH3:29])[C:23](Cl)=[O:24]>ClCCl>[Br:21][CH:22]([CH2:26][CH2:27][CH2:28][CH3:29])[C:23]([C:8]1[CH:9]=[C:10]([NH:13][C:14](=[O:16])[CH3:15])[CH:11]=[CH:12][C:7]=1[OH:6])=[O:24]
Reactant: CCCCC(Br)C(=O)Cl
Reactant: COc1ccc(NC(C)=O)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: C[N+](=O)[O-]
Solvent: ClCCl
Product: CCCCC(Br)C(=O)c1cc(NC(C)=O)ccc1O
Temperature: 0 °C
Reaction time: 4 h
Yield: 91.6 %

Procedure:
Aluminium chloride (20.00 g, 150 mmol) was carefully added to a stirred solution of N-(4-methoxyphenyl)acetamide [3a] (8.26 g, 50.0 mmol) in dichloromethane (30 mL) at 0-5° C. (ice/water bath). Nitromethane (8.2 mL, 150 mmol) was added to the mixture in one portion. A solution of 2-bromohexanoyl chloride (12.81 g, 60.0 mmol) in dichloromethane (20 mL) was added dropwise to the stirred mixture at room temperature. The obtained mixture was stirred for 4 hours at the same temperature. Aluminum chloride (6.67 g, 50.0 mmol) was added in one portion to the stirred mixture at room temperature. The mixture was stirred overnight at the same temperature. The mixture was carefully poured into ice/water mixture. The mixture was extracted with ethyl acetate (150 mL then 2×50 mL). The combined organic layers were washed with brine (50 mL), dried over sodium sulfate, filtered and evaporated under reduced pressure at 50° C. (water bath). The residue (21.20 g) was stirred with hexane (150 mL) for 1 hour at room temperature. The precipitated solids were filtered off, washed on the filter with hexane and dried at 50° C. (water bath) to the constant weight to give 15.03 g (91.6%) of N-[3-(2-bromohexanoyl)-4-hydroxyphenyl]acetamide [6a] as yellow crystals with mp 137-138° C. (toluene).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][CH2:11][C:12]([OH:14])=O.C(Cl)(=O)C([Cl:18])=O>C(OCC)C.CN(C)C=O>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][CH2:11][C:12]([Cl:18])=[O:14]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)CCCc1ccc(Cl)cc1Cl
Solvent: CN(C)C=O
Solvent: CCOCC
Product: O=C(Cl)CCCc1ccc(Cl)cc1Cl

Procedure:
By the method of Example 1, Step B, 9.79 g (0.042 mole) of 4-(2,4-dichlorophenyl)butanoic acid and 5.8 g (0.050 mole) of oxalyl chloride are reacted in 75 mL of diethyl ether and two drops of N,N-dimethylformamide, yielding 4-(2,4-dichlorophenyl)butanoic acid chloride.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C@H:4](/[CH:5]=[CH:6]/[C:7]([O:9][CH3:10])=[O:8])[C@H:3]1[C:11](Cl)=[O:12].[CH2:15]([OH:17])[CH3:16]>C1C=CC=CC=1.C(Cl)(Cl)Cl>[CH3:1][C:2]1([CH3:14])[C@H:4](/[CH:5]=[CH:6]/[C:7]([O:9][CH3:10])=[O:8])[C@H:3]1[C:11]([O:17][CH2:15][CH3:16])=[O:12]
Reactant: CCO
Reactant: COC(=O)/C=C/[C@@H]1[C@@H](C(=O)Cl)C1(C)C
Solvent: c1ccccc1
Solvent: ClC(Cl)Cl
Product: CCOC(=O)[C@@H]1[C@@H](/C=C/C(=O)OC)C1(C)C

Procedure:
Using the procedure of Example 3, 2.7 g of (1R,trans) 2,2-dimethyl-3-[(E)-3-methoxy-3-oxo-1-propenyl]-cyclopropane-1-carboxylic acid chloride in 12.5 ml of benzene and 1 ml of ethanol were reacted to obtain 1.31 g of ethyl (1R,trans) 2,2-dimethyl-3-[(E)-3-methoxy-3-oxo-1-propenyl]-cyclopropane-1-carboxylate with a specific rotation of [α]D20 =+93°±1.5° (c=1% in chloroform).
Reaction SMILES: [CH:1]#[C:2][C@H:3]([OH:9])[CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].I[C:11]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:12]=1/[C:13](=[CH:21]/[C:22]1[NH:23][CH:24]=[CH:25][C:26]=1[O:27][CH3:28])/[C:14](=[O:20])[NH:15]2>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.CN(C=O)C.CCN(CC)CC>[OH:9][C@H:3]([CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[C:2]#[C:1][C:11]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:12]=1/[C:13](=[CH:21]/[C:22]1[NH:23][CH:24]=[CH:25][C:26]=1[O:27][CH3:28])/[C:14](=[O:20])[NH:15]2
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2cccc(I)c21
Reactant: C#C[C@H](O)CCCCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCCCC[C@@H](O)C#Cc1cccc2c1/C(=C/c1[nH]ccc1OC)C(=O)N2

Procedure:
Using Method C above, (R)-(+)-1-octyn-3-ol (61 mg, 0.48 mmol) (Aldrich) was coupled with (Z)-1,3-dihydro-4-iodo-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (146 mg, 0.4 mmol) (Starting Material 2 supra) using (Ph3P)2PdCl2 (20 mg) and CuI (10 mg) as catalyst in DMF (2 mL) and Et3N (2 mL) as solvent at 70° C. for 15 h to yield (R)-(Z)-1,3-dihydro-4-(3-hydroxy-1-octynyl)-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one. (Yield 91 mg, 62%).
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:14])[N:4]([CH2:12][CH3:13])[C:5](=[O:11])[N:6]([CH2:9][CH3:10])[C:7]=1[NH2:8].[Br:15][C:16]1[CH:17]=[C:18]([CH:24]=[CH:25][C:26]=1[O:27][CH3:28])[CH:19]=[CH:20][C:21](O)=O>>[Br:15][C:16]1[CH:17]=[C:18]([CH:24]=[CH:25][C:26]=1[O:27][CH3:28])/[CH:19]=[CH:20]/[C:21]1[NH:1][C:2]2[C:3](=[O:14])[N:4]([CH2:12][CH3:13])[C:5](=[O:11])[N:6]([CH2:9][CH3:10])[C:7]=2[N:8]=1
Reactant: COc1ccc(C=CC(=O)O)cc1Br
Reactant: CCn1c(N)c(N)c(=O)n(CC)c1=O
Product: CCn1c(=O)c2[nH]c(/C=C/c3ccc(OC)c(Br)c3)nc2n(CC)c1=O
Yield: 17.1 %

Procedure:
Substantially the same procedure as in Example 7 was repeated using 2.00 g (10.1 mmol) of 5,6-diamino-1,3-diethyluracil and 2.72 g (10.6 mmol) of 3-bromo-4methoxycinnamic acid. Then, the resultant crude crystals were recrystallized from dioxane to give 726 mg (yield 17%) of Compound 118 as pale brown needles.
Reaction SMILES: C(OC(=O)[NH:7][C@@H:8]([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C@H:9]([OH:32])[CH2:10][N:11]([S:20]([C:23]1[CH:31]=[CH:30][C:26]2[O:27][CH2:28][O:29][C:25]=2[CH:24]=1)(=[O:22])=[O:21])[CH2:12][C:13]([CH3:19])([CH3:18])[CH2:14][CH2:15][C:16]#[N:17])(C)(C)C.[C:41]([OH:47])([C:43]([F:46])([F:45])[F:44])=[O:42]>C(Cl)Cl>[F:44][C:43]([F:46])([F:45])[C:41]([OH:47])=[O:42].[NH2:7][C@@H:8]([CH2:33][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)[C@H:9]([OH:32])[CH2:10][N:11]([CH2:12][C:13]([CH3:19])([CH3:18])[CH2:14][CH2:15][C:16]#[N:17])[S:20]([C:23]1[CH:31]=[CH:30][C:26]2[O:27][CH2:28][O:29][C:25]=2[CH:24]=1)(=[O:21])=[O:22]
Reactant: CC(C)(CCC#N)CN(C[C@@H](O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C)S(=O)(=O)c1ccc2c(c1)OCO2
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(CCC#N)CN(C[C@@H](O)[C@@H](N)Cc1ccccc1)S(=O)(=O)c1ccc2c(c1)OCO2
Reaction time: 0.5 h

Procedure:
A solution of {(1S,2R)-3-[(Benzo[1,3]dioxole-5-sulfonyl)-(4-cyano-2,2-dimethyl-butyl)-amino]-1-benzyl-2-hydroxy-propyl}-carbamic acid tert-butyl ester (0.075 g, 0.13 mmol) in CH2Cl2 at ambient temperature was treated with TFA. After stirring 30 min solvent was removed in vacuo to give desired product as a white solid which was used directly in the next step.
Reaction SMILES: [NH2:1][C:2]1[C:10]([Cl:11])=[C:9]([O:12][CH3:13])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[C:14]([O-])([O-])=O.[K+].[K+].CI.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C=O)C>[CH3:14][O:5][C:4](=[O:6])[C:3]1[CH:7]=[CH:8][C:9]([O:12][CH3:13])=[C:10]([Cl:11])[C:2]=1[NH2:1]
Reactant: COc1ccc(C(=O)O)c(N)c1Cl
Reactant: O=C([O-])[O-]
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)c1ccc(OC)c(Cl)c1N
Reaction time: 0.5 h
Yield: 50 %

Procedure:
To a stirred solution of compound 104d (1.9 g, 9.6 mmol) in dry DMF (25 mL) was added K2CO3 (1.32 g, 9.6 mmol) at room temperature. The reaction mixture was stirred for 30 min and methyl iodide (0.77 mL, 12.4 mmol) was added. After 2 hrs at room temperature, 5% aqueous citric acid was added. The mixture was extracted with EtOAc. Organics were washed with water, dried over Na2SO4, filtered, concentrated under reduced pressure, and purified by chromatography on silica gel (petroleum ether/EtOAc) to yield compound 105d as beige solid in 50% yield.
Reaction SMILES: Cl[C:2]1[C:12]2[CH2:11][CH2:10][N:9]([C:13]3[C:18]([C:19]([F:22])([F:21])[F:20])=[CH:17][CH:16]=[CH:15][N:14]=3)[CH2:8][CH2:7][C:6]=2[N:5]=[CH:4][N:3]=1.[C:23]([C:27]1[CH:33]=[CH:32][C:30]([NH2:31])=[CH:29][CH:28]=1)([CH3:26])([CH3:25])[CH3:24]>CCCCO>[C:23]([C:27]1[CH:28]=[CH:29][C:30]([NH:31][C:2]2[C:12]3[CH2:11][CH2:10][N:9]([C:13]4[C:18]([C:19]([F:22])([F:21])[F:20])=[CH:17][CH:16]=[CH:15][N:14]=4)[CH2:8][CH2:7][C:6]=3[N:5]=[CH:4][N:3]=2)=[CH:32][CH:33]=1)([CH3:26])([CH3:24])[CH3:25]
Reactant: CC(C)(C)c1ccc(N)cc1
Reactant: FC(F)(F)c1cccnc1N1CCc2ncnc(Cl)c2CC1
Solvent: CCCCO
Product: CC(C)(C)c1ccc(Nc2ncnc3c2CCN(c2ncccc2C(F)(F)F)CC3)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 87.9 %

Procedure:
To a solution of 4-chloro-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine (27 mg, 0.085 mmol) in n-BuOH (1 mL) was added 4-tert-butylaniline (27 μL, 0.17 mmol). After 2 h at 135° C., the mixture was cooled to rt, quenched with saturated aqueous (satd. aq.) NaHCO3, and extracted with EtOAc. The combined organic layers were dried (Na2SO4) and concentrated. The residue was purified (FCC) to give the title compound (33 mg, 89%). MS (ESI): mass calcd. for C24H26F3N5, 441.21; m/z found, 442.2 [M+H]+. 1H NMR (CDCl3): 8.50 (s, 1H), 8.40-8.37 (m, 1H), 7.90-7.85 (m, 1H), 7.46-7.36 (m, 4H), 6.98-6.93 (m, 1H), 6.45 (s, 1H), 3.70-3.65 (m, 2H), 3.64-3.60 (m, 2H), 3.26-3.20 (m, 2H), 3.02-2.95 (m, 2H), 1.32 (s, 9H). Alternatively, the reaction of this step may be performed in the microwave at 180° C. for 30 min.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH:8]=[C:9]([N+]([O-])=O)[CH3:10])[CH:5]=[CH:4][C:3]=1[S:14]([CH3:17])(=[O:16])=[O:15].Cl.C1C[O:22]CC1>O.[Fe]>[F:1][C:2]1[CH:7]=[C:6]([CH2:8][C:9](=[O:22])[CH3:10])[CH:5]=[CH:4][C:3]=1[S:14]([CH3:17])(=[O:16])=[O:15]
Reactant: C1CCOC1
Reactant: CC(=Cc1ccc(S(C)(=O)=O)c(F)c1)[N+](=O)[O-]
Agent: [Fe]
Agent: Cl
Solvent: O
Product: CC(=O)Cc1ccc(S(C)(=O)=O)c(F)c1
Temperature: 60 °C
Reaction time: 20 h

Procedure:
Iron powder (25 g, 0.45 mol) is added to a stirred mixture of freshly prepared 2-fluoro-1-methanesulfonyl-4-(2-nitro-propenyl)-benzene (Example 64b) (29 g, 0.112 mol) in THF (50 ml). Water (110 ml) is added and the mixture is heated to 60° C. Concentrated hydrochloric acid (50 ml) is added slowly over 1 h at 60-90° C. The reaction is then stirred at 100° C. for 20 hours then diluted with cold water (500 ml) and filtered through Celite™ filter material washing with chloroform (500 ml). The organic extract is washed with water (200 ml) followed by brine (200 ml). After drying (MgSO4) the mixture is absorbed on silica and purified by chromatography, eluting with hexane-ethyl acetate (1:1) to give the title compound.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][OH:14].[Br:15][C:16]1[C:17](Cl)=[N:18][CH:19]=[C:20]([CH:25]=1)[C:21]([O:23][CH3:24])=[O:22]>>[CH3:24][O:23][C:21](=[O:22])[C:20]1[CH:25]=[C:16]([Br:15])[C:17]([O:14][CH2:13][C:3]2[C:4]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)=[N:5][O:6][C:2]=2[CH3:1])=[N:18][CH:19]=1
Reactant: Cc1onc(-c2ccccc2)c1CO
Reactant: COC(=O)c1cnc(Cl)c(Br)c1
Product: COC(=O)c1cnc(OCc2c(-c3ccccc3)noc2C)c(Br)c1
Yield: 37 %

Procedure:
As described for example 5, (5-methyl-3-phenyl-isoxazol-4-yl)-methanol (3.60 mg, 19.0 mmol) was converted using methyl 5-bromo-6-chloronicotinate instead of 6-chloronicotinonitrile to the title compound (SiO2, heptane:ethyl acetate=90:10 to 60:40, 2.83 g, 37%) which was obtained as a white solid. MS: m/e=403.3/405.2 [M+H]′.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:12](=[O:26])[C:13]1[CH:18]=[CH:17][C:16]([N:19]2[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]2)=[N:15][CH:14]=1.[N+:27]([O-])([OH:29])=[O:28].C(OC(=O)C)(=O)C.C(=O)([O-])O.[Na+]>C(#N)C>[O:1]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:12](=[O:26])[C:13]1[CH:18]=[CH:17][C:16]([N:19]2[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]2)=[N:15][CH:14]=1)[N+:27]([O-:29])=[O:28]
Reactant: O=[N+]([O-])O
Reactant: CN1CCN(c2ccc(C(=O)NCCCCCCCCCO)cn2)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: CC(=O)OC(C)=O
Product: CN1CCN(c2ccc(C(=O)NCCCCCCCCCO[N+](=O)[O-])cn2)CC1
Reaction time: 6 h
Yield: 69 %

Procedure:
1.67 g of N-(9-hydroxy-1-nonyl)-6-(4-methyl-1-piperazinyl)nicotinamide were suspended in 40 ml of acetonitrile and to the suspension was added dropwise under ice-cooling a mixed solution of 0.8 ml of fuming nitric acid and 1.9 ml of acetic anhydride and stirred for 6 hrs. This reaction mixture was poured into an aqueous sodium hydrogencarbonate solution, extracted with methylene chloride, washed with water and a saturated sodium chloride solution, dried over anhydrous magnesium sulfate and concentrated to give 1.30 g (69%) of the title compound. m.p. 90°-92° C.
Reaction SMILES: [F:1][CH:2]([F:5])[CH2:3][NH2:4].[Cl:6][C:7]1[CH:15]=[C:14](F)[C:13]([N+:17]([O-:19])=[O:18])=[CH:12][C:8]=1[C:9]([OH:11])=[O:10]>C1COCC1>[Cl:6][C:7]1[CH:15]=[C:14]([NH:4][CH2:3][CH:2]([F:5])[F:1])[C:13]([N+:17]([O-:19])=[O:18])=[CH:12][C:8]=1[C:9]([OH:11])=[O:10]
Reactant: NCC(F)F
Reactant: O=C(O)c1cc([N+](=O)[O-])c(F)cc1Cl
Solvent: C1CCOC1
Product: O=C(O)c1cc([N+](=O)[O-])c(NCC(F)F)cc1Cl
Temperature: 60 °C
Reaction time: 30 h

Procedure:
A mixture of 2,2-difluoroethylamine (1.65 mL, 23 mmol) and THF (50 mL) is added to a mixture of 2-chloro-4-fluoro-5-nitro-benzoic acid (5.00 g, 22 mmol), TEA (6.33 mL, 45 mmol) and 50 mL THF. The mixture is stirred overnight at rt and 30 h at 60° C., concentrated and diluted with water. The resulting precipitate is collected by filtration, washed with water and dried. Yield: 3.3 g (61%); HPLC Rt=1.14 min (method A). MS m/z: 281 [M+H]+.
Reaction SMILES: [N:1]([CH2:4][S:5]([CH3:8])(=[O:7])=[O:6])=[C:2]=[O:3].[N+:9](=[C:11]1[C:15]([CH:16]=[CH:17][C:18]2[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][CH:19]=2)=[N:14][CH:13]=[N:12]1)=[N-:10]>CS(C)=O>[CH3:8][S:5]([CH2:4][N:1]1[C:2](=[O:3])[N:12]2[CH:13]=[N:14][C:15](/[CH:16]=[CH:17]/[C:18]3[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][CH:19]=3)=[C:11]2[N:9]=[N:10]1)(=[O:7])=[O:6]
Reactant: N#Cc1ccc(C=CC2=NC=NC2=[N+]=[N-])cc1
Reactant: CS(=O)(=O)CN=C=O
Solvent: CS(C)=O
Product: CS(=O)(=O)Cn1nnc2c(/C=C/c3ccc(C#N)cc3)ncn2c1=O
Reaction time: 8 h
Yield: 3.2 %

Procedure:
Isocyanato(methylsulfonyl)methane (440 mg, 3.25 mmol) was added dropwise in the dark under nitrogen to a stirred suspension of E)-4-(2-(4-diazo-4H-imidazol-5-yl)vinyl)benzonitrile (600 mg, 2.71 mmol) in DMSO (6 mL) and the mixture was stirred overnight. The resulting solution was poured into ice and the precipitate was filtered and washed successively with water, ethyl acetate and diethyl ether. The crude product was dried under vacuum and was absorbed on silica and purified by flash chromatography using DCM:MeCN (90:10) as eluent to give the pure title compound as a bright yellow solid (31 mg, 3% yield). δH (DMSO d6): 8.95 (1H, s), 7.95-7.97 (2H, d, J=8.6), 7.84-7.87 (2H, d, J=8.6), 7.75 (2H, s), 5.76 (2H, s), 3.16 (3H, s).