Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:3]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:4]=[C:5]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]#[CH:13])[N:6]=1.[N:21]([CH2:24][CH2:25][NH:26][C:27](=[O:39])[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])=[N+:22]=[N-:23]>>[NH2:1][C:2]1[N:3]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:4]=[C:5]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]2[N:23]=[N:22][N:21]([CH2:24][CH2:25][NH:26][C:27](=[O:39])[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])[CH:13]=2)[N:6]=1
Reactant: CCCCCCCCCCCC(=O)NCCN=[N+]=[N-]
Reactant: C#CCCCCCc1cn(C(=O)OC(C)(C)C)c(N)n1
Product: CCCCCCCCCCCC(=O)NCCn1cc(CCCCCc2cn(C(=O)OC(C)(C)C)c(N)n2)nn1

Procedure:
tert-butyl 2-amino-4-(hept-6-ynyl)-1H-imidazole-1-carboxylate (0.107 g, 0.387 mmol) was reacted with N-(2-azidoethyl)dodecanamide (0.104 g, 0.387 mmol) following the general click procedure to give tert-butyl 2-amino-4-(5-(1-(2-dodecanamidoethyl)-1H-1,2,3-triazol-4-yl)pentyl)-1H-imidazole-1-carboxylate 1H NMR (300 MHz, CDCl3) δ 7.36 (s, 1H), δ 6.94 (s, 1H), δ 6.49 (s, 1H), δ 6.23 (s, 2H), δ 4.46 (t, 2H), δ 3.74 (q, 2H), δ 2.68 (t, 2H0, δ 2.34 (t, 2H), δ 2.16 (t, 2H), δ 1.54 (m, 13H), δ 1.47 (m, 2H), δ 1.24 (m, 18H), δ 0.87 (t, 3H) ppm; 13C NMR (75 MHz, CDCl3) δ 174.3, 150.4, 149.5, 148.3, 138.5, 121.9, 106.5, 84.9, 49.5, 39.5, 36.6, 34.1, 32.1, 29.8, 29.8, 29.7, 29.6, 29.5, 29.3, 28.9, 28.2, 28.1, 29.0, 26.9. 25.6, 22.9, 14.3 ppm; HRMS (ESI) calcd for C29H51N7O3 (M+) 545.4053. found 545.4053, which was subsequently deprotected to give N-(2-(4-(5-(2-amino-1H-imidazol-4-yl)pentyl)-1H-1,2,3-triazol-1-yl)ethyl)dodecanamide hydrochloride (0.155 g, 83% yield). 1H NMR (400 MHz, CD3OD) δ 8.31 (s, 1H), δ 6.49 (s, 1H), δ 4.63 (s, 2H), δ 3.97 (s, 2H), δ 2.81 (s, 2H), δ 2.51 (t, 2H), δ 2.51 (t, 2H), δ 2.14 (t, 2H), δ 1.76 (s, 2H), δ 1.67 (s, 2H), δ 1.51 (s, 2H), δ 1.44 (s, 2H), δ 1.26 (bs, 16H), δ 0.71 (s, 3H) ppm; 13C NMR (100 MHz, CD3OD) δ 175.6, 159.4, 147.3, 127.6, 108.5, 51.3, 48.6, 38.8, 35.8, 31.9, 29.6, 29.5, 29.4, 29.3, 29.2, 28.2, 28.1, 27.7, 24.8, 24.2, 23.9, 22.6, 22.5, 13.4, 13.3 ppm; HRMS (ESI) calcd for C24H43N7O (M+) 445.3429. found 445.3524.
Reaction SMILES: [Br:1]Br.[CH:3]1([C@H:6]([NH:14][C:15]([C:17]2[C:26]3[C:21](=[C:22]([F:27])[CH:23]=[CH:24][CH:25]=3)[C:20](=[O:28])[N:19]([CH2:29][CH2:30][CH3:31])[C:18]=2[CH3:32])=[O:16])[C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[CH:8]=2)[CH2:5][CH2:4]1>ClCCCl>[CH:3]1([C@H:6]([NH:14][C:15]([C:17]2[C:26]3[C:21](=[C:22]([F:27])[CH:23]=[CH:24][CH:25]=3)[C:20](=[O:28])[N:19]([CH2:29][CH2:30][CH3:31])[C:18]=2[CH2:32][Br:1])=[O:16])[C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[CH:8]=2)[CH2:5][CH2:4]1
Reactant: BrBr
Reactant: CCCn1c(C)c(C(=O)N[C@H](c2cccc(F)c2)C2CC2)c2cccc(F)c2c1=O
Solvent: ClCCCl
Product: CCCn1c(CBr)c(C(=O)N[C@H](c2cccc(F)c2)C2CC2)c2cccc(F)c2c1=O
Temperature: 60 °C
Reaction time: 0.25 h

Procedure:
Bromine (400 mg, 2.5 mmol) in 0.5 ml 1,2-dichloroethane was added to 8-fluoro-3-methyl-1-oxo-2-propyl-1,2-dihydro-isoquinoline-4-carboxylic acid [(S)-cyclopropyl-(3-fluoro-phenyl)-methyl]-amide (344 mg, 0.84 mmol, see example 3) in 1,2-dichloroethane (20 mL) at 60° C. The reaction mixture was stirred for 15 minutes at 60° C. The reaction mixture was concentrated in vacuo to give crude 3-bromomethyl-8-fluoro-1-oxo-2-propyl-1,2-dihydro-isoquinoline-4-carboxylic acid [(S)-cyclopropyl-(3-fluoro-phenyl)-methyl]-amide, which was used in the next step without purification. LC-MS (m/z) 489.5 (MH+); tR=1.55.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:24]([NH:26][C@H:27]([C:34]([NH:36][C@@H:37]([CH2:45][CH:46]([CH3:48])[CH3:47])[C@@H:38]([OH:44])[CH2:39][C:40]([NH:42][NH2:43])=[O:41])=[O:35])[CH2:28][C:29]1[N:33]=[CH:32][NH:31][CH:30]=1)=[O:25])[CH2:13][C:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][CH:15]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:49]([CH2:57][CH2:58][CH2:59][C:60](O)=[O:61])(=[O:56])[C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1.ON1C(=O)CCC1=O>CN(C)C=O>[CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:24]([NH:26][C@H:27]([C:34]([NH:36][C@@H:37]([CH2:45][CH:46]([CH3:48])[CH3:47])[C@@H:38]([OH:44])[CH2:39][C:40]([NH:42][NH:43][C:60](=[O:61])[CH2:59][CH2:58][CH2:57][C:49](=[O:56])[C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1)=[O:41])=[O:35])[CH2:28][C:29]1[N:33]=[CH:32][NH:31][CH:30]=1)=[O:25])[CH2:13][C:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][CH:15]=1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)CCCC(=O)c1ccccc1
Reactant: CC(C)C[C@H](NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@H](Cc1cccc2ccccc12)NC(=O)OCc1ccccc1)[C@@H](O)CC(=O)NN
Agent: O=C1CCC(=O)N1O
Solvent: CN(C)C=O
Product: CC(C)C[C@H](NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@H](Cc1cccc2ccccc12)NC(=O)OCc1ccccc1)[C@@H](O)CC(=O)NNC(=O)CCCC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 75.7 %

Procedure:
66 mg (0.1 mmole) of 4(S)-[N-benzyloxycarbonyl-3-(1-naphthyl)-L-alanyl-L-histidyl]amino-3(S)-hydroxy-6-methylheptanoic acid hydrazide (prepared as described in Example 5) were dissolved in 3 ml of dimethylformamide, and then 31 mg (0.1 mmole) of N-hydroxysuccinimide 4-benzoylbutyrate were added and the mixture was stirred for 2 days at room temperature. The resulting reaction mixture was concentrated by evaporation under reduced pressure, and water was added to the resulting residue. After the water had been added to the residue, the precipitate was separated by filtration. It was washed with water, and the powder obtained after drying was washed with ethyl acetate, to give 63 mg of the title compound as a white powdery solid melting at 158°-160°, [α]27 -44.4° (C=0.5, methanol).
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([CH3:24])=[C:6]([C:17]2[CH:18]=[N:19][C:20]([Cl:23])=[CH:21][CH:22]=2)[C:7]=1[C:8]1[C:13]([F:14])=[CH:12][C:11]([F:15])=[CH:10][C:9]=1[F:16].[CH3:25][O-:26].[Na+].CO>O>[Cl:23][C:20]1[N:19]=[CH:18][C:17]([C:6]2[C:7]([C:8]3[C:13]([F:14])=[CH:12][C:11]([F:15])=[CH:10][C:9]=3[F:16])=[C:2]([O:26][CH3:25])[N:3]=[N:4][C:5]=2[CH3:24])=[CH:22][CH:21]=1
Reactant: C[O-]
Reactant: Cc1nnc(Cl)c(-c2c(F)cc(F)cc2F)c1-c1ccc(Cl)nc1
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1nnc(C)c(-c2ccc(Cl)nc2)c1-c1c(F)cc(F)cc1F

Procedure:
A mixture of 3-chloro-5-(6-chloro-pyridin-3-yl)-6-methyl-4-(2,4,6-trifluorophenyl)-pyridazine (Compound No. I.a.11, 700 mg), sodium methoxide (30% solution in methanol, 750 mg) and 10 ml of methanol is heated for 6 h to 60° C. Subsequently the reaction mixture is cooled, diluted with water and extracted with ethyl acetate. The combined organic layer is washed with water and brine, dried over sodium sulfate and evaporated under reduced pressure. The remainder is purified by chromatography on silica gel, using a mixture of heptane/ethyl acetate 3:1 as eluent to obtain 4-(6-chloro-pyridin-3-yl)-6-methoxy-3-methyl-5-(2,4,6-trifluoro-phenyl)-pyridazine (Compound I.a.12), m.p. 123-124° C.
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][CH:7]=[C:8]([CH3:10])[N:9]=1)(=[O:3])[CH3:2].[H-].[Na+].Cl.[CH3:14][N:15]([CH3:19])[CH2:16][CH2:17]Cl>CN(C=O)C>[CH3:10][C:8]1[N:9]=[C:5]([N:4]([CH2:17][CH2:16][N:15]([CH3:19])[CH3:14])[C:1](=[O:3])[CH3:2])[S:6][CH:7]=1
Reactant: CN(C)CCCl
Reactant: CC(=O)Nc1nc(C)cs1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)N(CCN(C)C)c1nc(C)cs1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
The reaction is run under a nitrogen atmosphere. To a stirred solution of 31.2 g. (0.20 mole) of 2-acetamido-4-methylthiazole in 300 ml. of DMF is added 9.6 g. (0.20 mole) of a 50% suspension of sodium hydride in mineral oil. The reaction is stirred for 1/2 hour as the temperature spontaneously rises to 50° C. The reaction is cooled to 35° to 40° C. and a further 12.0 g. (0.25 mole) of sodium hydride suspension added followed by 36.0 g. (0.25 mole) of 2-dimethylaminoethyl chloride HCl, added portionwise for 10 to 15 minutes. The mixture is stirred at room temperature for about 1 hour and then at steam bath temperature for 20 hours. The tan mixture is cooled to ambient temperature and filtered to remove salts. The filtrate is concentrated under reduced pressure at steam bath temperature. This gives 46.4 g. of crude product as a brown oil (containing mineral oil (10.8 g.).
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:29])[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([C:13]3[CH:21]=[C:20]4[C:16]([C:17]([C:22]5[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=5)=[N:18][NH:19]4)=[CH:15][C:14]=3[F:28])[CH:7]=2)[CH2:3][CH2:2]1.C1C=C(Cl)C=C(C(OO)=[O:38])C=1>C(Cl)(Cl)Cl>[CH:1]1([NH:4][C:5](=[O:29])[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([C:13]3[CH:21]=[C:20]4[C:16]([C:17]([C:22]5[CH:27]=[CH:26][N+:25]([O-:38])=[CH:24][CH:23]=5)=[N:18][NH:19]4)=[CH:15][C:14]=3[F:28])[CH:7]=2)[CH2:2][CH2:3]1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-c1cc2[nH]nc(-c3ccncc3)c2cc1F
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: Cc1ccc(C(=O)NC2CC2)cc1-c1cc2[nH]nc(-c3cc[n+]([O-])cc3)c2cc1F
Yield: 56.8 %

Procedure:
A solution of N-cyclopropyl-3-[5-fluoro-3-(4-pyridinyl)-1H-indazol-6-yl]-4-methylbenzamide (Example 1, 9.3 mg) and m-CPBA (20 mg) in chloroform (2 ml) was stirred under nitrogen at 60° C. for 1 h. The mixture was applied to an Isolute amino cartridge (1 g) and eluted with chloroform/methanol (100:0 and 90:10 to give the title compound as a yellow solid (5.5 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:12]([N:14]3[CH2:19][CH2:18][CH2:17][CH:16]([CH2:20]OS(C)(=O)=O)[CH2:15]3)=[O:13])[CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH3:26][O:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[N:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1.C(N(CC)CC)C>C(#N)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:12]([N:14]3[CH2:19][CH2:18][CH2:17][CH:16]([CH2:20][N:37]4[CH2:38][CH2:39][N:34]([C:29]5[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=5[O:27][CH3:26])[CH2:35][CH2:36]4)[CH2:15]3)=[O:13])[CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: COc1ccccc1N1CCNCC1
Reactant: CS(=O)(=O)OCC1CCCN(C(=O)C2(c3ccc(Cl)cc3)CCC2)C1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COc1ccccc1N1CCN(CC2CCCN(C(=O)C3(c4ccc(Cl)cc4)CCC3)C2)CC1
Temperature: 25 °C
Yield: 43.1 %

Procedure:
To a solution of 2 (1.0 g, 2.60 mmol) in acetonitrile (25 mL) was added 1-(2-methoxyphenyl)piperazine (0.55 g, 2.86 mmol) and triethylamine (2 mL). The reaction was stirred and refluxed for 20 h. After cooling to room temperature, most of solvent was removed by rotary evaporation. The reaction mixture was partitioned between dichloromethane and water (50 mL each), and the organic layer was washed with sat. sodium carbonate (50 mL) and water. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated by rotary evaporation. The organic residue was purified by flash chromatography on silica gel, eluting with dichloromethane/2.0 M ammonia in ethyl alcohol (96:4) to give 3 (0.54 g, 43%) as a light brown solid; C28H36ClN3O2, LRMS (m/z)=483 (MH+).
Reaction SMILES: [C:1]([O:9]CC)(=O)[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[H-].[Na+].[CH2:14]([N:21]1[C:26]2[N:27]=[CH:28][CH:29]=[CH:30][C:25]=2[C:24](=O)[O:23]C1=O)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.Cl>CC(N(C)C)=O>[CH2:6]([O:5][C:3]([C:2]1[C:1](=[O:9])[N:21]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:26]2[C:25]([C:24]=1[OH:23])=[CH:30][CH:29]=[CH:28][N:27]=2)=[O:4])[CH3:7]
Reactant: O=c1oc(=O)n(Cc2ccccc2)c2ncccc12
Reactant: CCOC(=O)CC(=O)OCC
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CCOC(=O)c1c(O)c2cccnc2n(Cc2ccccc2)c1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 72.5 %

Procedure:
Diethyl malonate (0.6 mL, 4 mmol) was added slowly to a suspension of NaH (60% in mineral oil, 164 mg, 4.1 mmol) in dimethylacetamide (20 mL) and stirred at room temperature for 0.5 h under inert atmosphere. 1-Benzyl-1H-pyrido[2,3-d][1,3]oxazine-2,4-dione (2) (1 g, 4 mmol) was added to the solution and heated at 110° C. for 4 h (TLC control). The solution was cooled and poured into ice water. The pH of the solution was adjusted to 3 by cold 10% HCl. The solids formed were filtered, washed by excess water, and dried in a vacuum oven to yield 940 mg (72%) of 1-benzyl-4-hydroxy-2-oxo-1,2-dihydro-[1,8]-naphthyridine-3-carboxylic acid ethyl ester (3) as white solids. MP: 143° C.; 1H-NMR (DMSO-d6): δ 1.29 (t, J=6.9 Hz, 3H), 4.31 (q, J=6.9 Hz, 2H), 5.55 (s, 2H), 7.23 (m, 5H), 7.36 (m, 1H), 8.45 (dd, J=1.5, 7.5 Hz, 1H), 8.70 (dd, J=1.5, 7.5 Hz, 1H); EIMS: 325 (M+1), 347 (M+23).
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6]([C@H:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][CH3:17])=[O:15])[C@@H:10]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][C:26]([F:29])([F:28])[F:27])=[CH:21][CH:20]=2)[CH2:9]1)=[O:7])C.[OH-].[Na+].[NH2:33]O.Cl>CO.O>[O:3]=[C:4]1[CH:5]=[C:6]([C@H:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][CH3:17])=[O:15])[C@@H:10]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][C:26]([F:29])([F:28])[F:27])=[CH:21][CH:20]=3)[CH2:9]2)[O:7][NH:33]1
Reactant: NO
Reactant: CCOC(=O)CC(=O)[C@H]1CCN(C(=O)OC)[C@@H](Cc2ccc(OC(F)(F)F)cc2)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COC(=O)N1CC[C@H](c2cc(=O)[nH]o2)C[C@@H]1Cc1ccc(OC(F)(F)F)cc1
Temperature: -40 °C
Reaction time: 0.33 h
Yield: 61.4 %

Procedure:
Cis-methyl 4-(3-ethoxy-3-oxopropanoyl)-2-(4-(trifluoromethoxy)benzyl)piperidine-1-carboxylate (2.475 g, 5.74 mmol) was dissolved in MeOH (20 mL) and cooled to −40° C. under nitrogen. Sodium hydroxide (1.687 mL, 5.74 mmol) dissolved in water (2.000 mL) was added during 10 min and the yellow solution continued to stir at −40° C. for 20 min. Hydroxylamine (50% by weight in water, 0.352 mL, 5.74 mmol) was added during 8 min. The resulting solution was stirred at −40° C. for 3 h. The mixture was then rapidly poured into a prewarmed (80° C.) solution of 6 M hydrogen chloride (29.5 mL, 177.28 mmol) and the mixture continued to stir at 80° C. for 20 min. The solvent was evaporated and DCM/water added. The phases were separated and the organic phase passed through a phase separator and evaporated to yield a white solid. The compound was purified by preparative HPLC on a Kromasil C8 column (10 μm 250×50 ID mm) using a gradient of 10-60% Acetonitrile in H2O/MeCN/AcOH 95/5/0.2 buffer over 30 minutes with a flow of 100 mL/min. Cis-methyl 4-(3-oxo-2,3-dihydroisoxazol-5-yl)-2-(4-(trifluoromethoxy)benzyl)piperidine-1-carboxylate (1.41 g, 61.4%) was isolated. MS m/z 401 (M+H)+
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:18]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[C:10]([NH2:19])[C:9]=2[N:8]=[CH:7]1.[F:20][C:21]([F:34])([F:33])[CH2:22][O:23][C:24]1[N:29]=[CH:28][C:27]([C:30](Cl)=[O:31])=[CH:26][CH:25]=1>>[NH2:19][C:10]1[C:9]2[N:8]=[CH:7][N:6]([CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:30](=[O:31])[C:27]3[CH:26]=[CH:25][C:24]([O:23][CH2:22][C:21]([F:33])([F:34])[F:20])=[N:29][CH:28]=3)[C:18]=2[C:17]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:11]=1
Reactant: O=C(Cl)c1ccc(OCC(F)(F)F)nc1
Reactant: NCCCCn1cnc2c(N)nc3ccccc3c21
Product: Nc1nc2ccccc2c2c1ncn2CCCCNC(=O)c1ccc(OCC(F)(F)F)nc1

Procedure:
According to the general method of Example 14, 1-(4-aminobutyl)-1H-imidazo[4,5-c]quinolin-4-amine and 6-(2,2,2-trifluoroethoxy)pyridine-3-carbonyl chloride were combined to provide N3-[4-(4-amino-1H-imidazo[4,5-c]quinolin-1-yl)butyl]-6-(2,2,2-trifluoroethoxy)nicotinamide as a white crystalline solid, m.p. 192.0-194.0° C. (decomposition). 1H NMR (300 MHz, DMSO-d6) δ8.62 (d, J=1.9 Hz, 1H), 8.58 (t, J=5.6 Hz, 1H), 8.25 (s, 1H), 8.15 (dd, J=8.6, 2.4 Hz, 1H), 8.06 (d, J=7.6 Hz, 1H), 7.64 (d, J=7.8 Hz, 1H), 7.45 (t, J=7.1 Hz, 1H), 7.24 (t, J=7.1 Hz, 1H), 7.04 (d, J=8.6 Hz, 1H), 6.82 (broad s, 2H), 5.06 (q, J=9.1 Hz, 2H), 4.64 (t, J=6.9 Hz, 2H), 3.30 (m, 2H), 1.91 (m, 2H), 1.60 (m, 2H); MS (EI) m/e 458.1678 (458.1678 calcd for C22H21N6O2F3).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[C:3]=1[F:19].C([Li])CCC.C([O:28][B:29](OC(C)C)[O:30]C(C)C)(C)C>C1COCC1>[F:1][C:2]1[C:3]([F:19])=[C:4]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH:5]=[CH:6][C:7]=1[B:29]([OH:30])[OH:28]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: CCCCCOCCCCOc1cccc(F)c1F
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCCCOCCCCOc1ccc(B(O)O)c(F)c1F
Reaction time: 2 h

Procedure:
To a solution of 1,2-difluoro-3-(4-pentyloxybutoxy)-benzene (24), (1 equi.) in THF (5 mL/mmole), butyllithium (1.3 equi.) was added at −78° C. The reaction mixture was stirred at that temperature for 2 hr,. Then triisopropylborate (1 equi.) was added at that temperature. The reaction mixture was stirred at that temperature for 1 h and at room temperature for 10 h, quenched with water, extracted with ethyl acetate, washed with brine, dried over MgSO4, and concentrated in vacuo. Purification by recrystallization from hexane gave 2,3-difluoro-4-(4-pentyloxybutoxy)phenylboronic acid (25), as a white solid (75%).
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].[C:6]([SiH2:10][O:11][C:12]([CH3:23])([CH3:22])[C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][C:20]=1[Cl:21])[CH2:16][NH2:17])([CH3:9])([CH3:8])[CH3:7].CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:5][O:4][C:2](=[O:3])[NH:17][CH2:16][C:15]1[CH:18]=[CH:19][C:20]([Cl:21])=[C:13]([C:12]([CH3:23])([CH3:22])[O:11][SiH2:10][C:6]([CH3:9])([CH3:8])[CH3:7])[CH:14]=1
Reactant: CC(C)(C)[SiH2]OC(C)(C)c1cc(CN)ccc1Cl
Reactant: COC(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)NCc1ccc(Cl)c(C(C)(C)O[SiH2]C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 75 %

Procedure:
Methyl chloroformate (1.98 mL, 25.2 mmol) was added to a sol. of 3-(tert-butyl-dimethyl-silanyloxymethyl)-4-chloro-benzylamine (6.00 g, 20.9 mmol) and DIPEA (7.33 mL, 42.0 mmol) in CH2Cl2 (100 mL) at rt. The mixture was stirred for 1 h at rt, and more CH2Cl2 was added. The mixture was washed with aq. sat. NH4Cl, aq. 1M NaOH, and brine. The org. layer was dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the crude by FC (EtOAc/heptane 1:5) yielded the title compound (5.39 g, 75%). LC-MS: tR=1.02 min; ES+: 344.38.
Reaction SMILES: [Cl:1][C:2]1[N:3]([CH2:10][C@:11]2([CH3:14])[CH2:13][O:12]2)[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1.[N:15]1([CH:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1.O>CN(C=O)C>[N:15]1([CH:21]2[CH2:26][CH2:25][N:24]([CH2:13][C@:11]([CH3:14])([OH:12])[CH2:10][N:3]3[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=[C:2]3[Cl:1])[CH2:23][CH2:22]2)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: C1CCN(C2CCNCC2)CC1
Reactant: C[C@@]1(Cn2cc([N+](=O)[O-])nc2Cl)CO1
Solvent: O
Solvent: CN(C)C=O
Product: C[C@](O)(CN1CCC(N2CCCCC2)CC1)Cn1cc([N+](=O)[O-])nc1Cl
Temperature: 70 °C
Reaction time: 5 h
Yield: 74.2 %

Procedure:
(R)-2-Chloro-1-(2-methyloxiran-2-ylmethyl)-4-nitroimidazole prepared in Example 12 (0.500 g, 2.29 mmol) and 4-piperidinopiperidine (0.425 g, 2.53 mmol) were dissolved in DMF (5 ml), and the solution was stirred at 70° C. for 5 hours. The reaction mixture was added water and extracted with ethyl acetate twice. The organic phases were combined, washed with water and a saturated saline solution, dried over sodium sulfate and then filtered. The resulting filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane/ethyl acetate=3/2) using basic silica gel to afford (S)-1-(4-piperidinopiperidin-1-yl)-3-(2-chloro-4-nitroimidazol-1-yl)-2-methyl-propan-2-ol (0.656 g, yield 74%) as a brown oil.
Reaction SMILES: Cl.[C:2]([NH2:5])(=[NH:4])[CH3:3].C[O-].[Na+].[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]1[CH:22]=[C:21]([F:23])[C:20]([CH2:24][CH:25]([C:30](=O)[CH2:31][CH2:32][CH2:33][CH3:34])[C:26](OC)=[O:27])=[C:19]([F:36])[CH:18]=1)#[N:10].O>CO>[CH2:31]([C:30]1[N:4]=[C:2]([CH3:3])[NH:5][C:26](=[O:27])[C:25]=1[CH2:24][C:20]1[C:21]([F:23])=[CH:22][C:17]([C:12]2[C:11]([C:9]#[N:10])=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:18][C:19]=1[F:36])[CH2:32][CH2:33][CH3:34]
Reactant: CCCCC(=O)C(Cc1c(F)cc(-c2ccccc2C#N)cc1F)C(=O)OC
Reactant: CC(=N)N
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CCCCc1nc(C)[nH]c(=O)c1Cc1c(F)cc(-c2ccccc2C#N)cc1F
Yield: 63.1 %

Procedure:
To a suspension of acetamidine hydrochloride (3.9 g) in methanol (30 mL) were added sodium methoxide (28% methanol solution, 12 mL) and then methyl 2-[(2′-cyano-3,5-difluorobiphenyl-4-yl)methyl]-3-oxoheptanoate (7.93 g), and the mixture was stirred for 15 hr. Water was added to the reaction mixture, and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was triturated with diisopropyl ether to give the title compound (5.11 g, 63%) as pale-yellow crystals.
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15](Br)[CH:16]=2)[CH:11]=[CH:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:19][N:20]1[C:28]2[C:23](=[CH:24][C:25](B(O)O)=[CH:26][CH:27]=2)[CH:22]=[CH:21]1>>[CH2:1]([O:8][N:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15]([C:25]3[CH:24]=[C:23]4[C:28](=[CH:27][CH:26]=3)[N:20]([CH3:19])[CH:21]=[CH:22]4)[CH:16]=2)[CH:11]=[CH:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Brc1cnc2ccn(OCc3ccccc3)c2c1
Reactant: Cn1ccc2cc(B(O)O)ccc21
Product: Cn1ccc2cc(-c3cnc4ccn(OCc5ccccc5)c4c3)ccc21

Procedure:
The entitled compound was prepared from 1-(benzyloxy)-6-bromo-1H-pyrrolo[3,2-b]pyridine and (1-methyl-1H-indol-5-yl)boronic acid according to the procedure described in Example 1.
Reaction SMILES: [N:1]1[C:6]2[NH:7][CH:8]=[CH:9][C:5]=2[C:4]([N:10]2[CH2:14][CH2:13][C@@H:12]([N:15]([CH3:26])[C:16]3[CH:21]=[CH:20][C:19]([N+:22]([O-])=O)=[C:18]([NH2:25])[N:17]=3)[CH2:11]2)=[N:3][CH:2]=1>C(O)C>[N:1]1[C:6]2[NH:7][CH:8]=[CH:9][C:5]=2[C:4]([N:10]2[CH2:14][CH2:13][C@@H:12]([N:15]([CH3:26])[C:16]3[CH:21]=[CH:20][C:19]([NH2:22])=[C:18]([NH2:25])[N:17]=3)[CH2:11]2)=[N:3][CH:2]=1
Reactant: CN(c1ccc([N+](=O)[O-])c(N)n1)[C@@H]1CCN(c2ncnc3[nH]ccc23)C1
Solvent: CCO
Product: CN(c1ccc(N)c(N)n1)[C@@H]1CCN(c2ncnc3[nH]ccc23)C1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A solution of (R)—N2-(1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrrolidin-3-yl)-N2-methyl-5-nitropyridine-2,6-diamine (320 mg, 0.90 mmol) in ethanol (35 mL) was degassed and purged with N2. Pd/C (10%, 100 mg) was added, degassed and purged with H2 and then stirred under hydrogen atmosphere at ambient temperature for 20 hours. The catalyst was removed by filtration and the filtrate was concentrated to give the title product. MS (m/z): 325 (M+H)+.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]2[CH2:13][CH2:12][C:11]([CH3:15])([CH3:14])[CH2:10][CH:9]=2)[C:5]([NH:16][C:17]([C:19]2[NH:20][C:21]([C:24]#[N:25])=[CH:22][N:23]=2)=[O:18])=[CH:4][CH:3]=1.[O:26]1[CH2:31][CH2:30][C:29](=[O:32])[CH2:28][CH2:27]1>>[CH3:14][C:11]1([CH3:15])[CH2:12][CH2:13][C:8]([C:6]2[C:5]([NH:16][C:17]([C:19]3[NH:23][CH:22]=[C:21]([C:24]#[N:25])[N:20]=3)=[O:18])=[CH:4][CH:3]=[C:2]([C:29]3([OH:32])[CH2:30][CH2:31][O:26][CH2:27][CH2:28]3)[N:7]=2)=[CH:9][CH2:10]1
Reactant: O=C1CCOCC1
Reactant: CC1(C)CC=C(c2nc(Br)ccc2NC(=O)c2ncc(C#N)[nH]2)CC1
Product: CC1(C)CC=C(c2nc(C3(O)CCOCC3)ccc2NC(=O)c2nc(C#N)c[nH]2)CC1

Procedure:
The title compound was prepared from 5-cyano-1H-imidazole-2-carboxylic acid [6-bromo-2-(4,4-dimethyl-cyclohex-1-enyl)-pyridin-3-yl]-amide (as prepared in Example 32, step (d)) and tetrahydro-pyran-4-one according to the procedure in Example 1, step (h).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:31]=[CH:32][C:33]=1[O:34][CH3:35])[CH2:5][CH:6]1[C:15]2[C:10](=[CH:11][C:12]([O:18][CH3:19])=[C:13]([O:16][CH3:17])[CH:14]=2)[CH2:9][CH2:8][N:7]1[CH2:20][C:21]([NH:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22].[CH2:36](I)[CH3:37]>>[CH2:36]([O:1][C:2]1[CH:3]=[C:4]([CH:31]=[CH:32][C:33]=1[O:34][CH3:35])[CH2:5][CH:6]1[C:15]2[C:10](=[CH:11][C:12]([O:18][CH3:19])=[C:13]([O:16][CH3:17])[CH:14]=2)[CH2:9][CH2:8][N:7]1[CH2:20][C:21]([NH:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22])[CH3:37]
Reactant: COc1ccc(CC2c3cc(OC)c(OC)cc3CCN2CC(=O)NCc2ccccc2)cc1O
Reactant: CCI
Product: CCOc1cc(CC2c3cc(OC)c(OC)cc3CCN2CC(=O)NCc2ccccc2)ccc1OC

Procedure:
prepared by reaction of 2-[1-(3-hydroxy-4-methoxy-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-benzyl-acetamide with ethyl iodide