Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[C:22]([C:26]([OH:28])=O)=[CH:21][CH:20]=[CH:19]2.[CH3:29][C:30]1[CH:35]=[CH:34][C:33]([NH2:36])=[C:32]([NH2:37])[CH:31]=1>>[NH2:37][C:32]1[CH:31]=[C:30]([CH3:29])[CH:35]=[CH:34][C:33]=1[NH:36][C:26]([C:22]1[C:23]2[C:18](=[CH:17][C:16]([O:15][C:6]3[C:5]4[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=4)[N:9]=[CH:8][N:7]=3)=[CH:25][CH:24]=2)[CH:19]=[CH:20][CH:21]=1)=[O:28]
Reactant: COc1cc2ncnc(Oc3ccc4c(C(=O)O)cccc4c3)c2cc1OC
Reactant: Cc1ccc(N)c(N)c1
Product: COc1cc2ncnc(Oc3ccc4c(C(=O)Nc5ccc(C)cc5N)cccc4c3)c2cc1OC
Yield: 82 %

Procedure:
The title compound (39.4 mg, 82% yield) was prepared as a brown solid from 6-(6,7-dimethoxyquinazolin-4-yloxy)-1-naphthoic acid (37.6 mg, 0.1 mmol) and 4-methyl-o-phenylenediamine (14.6 mg, 0.12 mmol) by an analogous procedure to that described in example 16. 1H NMR (DMSO-d6) (isomer ratio 0.77/0.23) δ 2.21 (s, 1H, Ar—CH3), 4.01 (s, 6H, 2×OCH3), 4.77 (s, 0.23×2H, benzene-NH2), 4.89 (s, 0.77×2H, benzene-NH2), 6.46 (d, J=7.6 Hz, 0.77×1H, Ar—H), 6.64 (s, 0.77×1H, Ar—H), 6.73 (d, J=7.9 Hz, 0.23×1H, Ar—H), 6.81 (s, 0.23×1H, Ar—H), 7.24 (d, J=8.1 Hz, 1H, Ar—H), 7.41 (s, 1H, Ar—H), 7.58-7.66 (m, 3H, Ar—H), 7.85 (d, J=6.7 Hz, 1H, Ar—H), 7.97 (s, 1H, Ar—H), 8.08 (d, J=7.9 Hz, 1H, Ar—H), 8.38 (d, J=9.0 Hz, 1H, Ar—H), 8.54 (s, 1H, Ar—H), 9.77 (s, 1H, benzene-NH). LC-MS (m/z) 481 (M+1).
Reaction SMILES: [CH2:1]([O:4][C:5]([NH:7][CH2:8][CH:9]([CH:12]([O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16])[CH3:13])[CH2:10][NH2:11])=[O:6])[CH:2]=[CH2:3].Cl[C:23]([O:25][CH2:26][CH:27]=[CH2:28])=[O:24].[OH-].[Na+]>O1CCCC1.O>[CH2:1]([O:4][C:5]([NH:7][CH2:8][CH:9]([CH2:10][NH:11][C:23]([O:25][CH2:26][CH:27]=[CH2:28])=[O:24])[CH:12]([O:14][Si:15]([C:18]([CH3:20])([CH3:19])[CH3:21])([CH3:16])[CH3:17])[CH3:13])=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)NCC(CN)C(C)O[Si](C)(C)C(C)(C)C
Reactant: C=CCOC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: C=CCOC(=O)NCC(CNC(=O)OCC=C)C(C)O[Si](C)(C)C(C)(C)C

Procedure:
To a solution of 11.4 g of crude 2-(N-allyloxycarbonylaminomethyl)-3-(t-butyldimethylsilyloxy)butylamine in 67 ml of tetrahydrofuran and 56 ml of water was added 2.8 ml of allyl chloroformate dropwise, while keeping pH 8-8.5 with 4N sodium hydroxide solution. The reaction mixture was extracted three times with chloroform, and the combined organic layer was washed with brine and dried over anhydrous magnesium sulfate. Evaporation of the solvent followed by column chromatography on silica gel (hexane:ethyl acetate=1:1) gave 5.34 g of 1-allyloxycarbonylamino-2-(N-allyloxycarbonylaminomethyl)- 3-t-butyldimethylsilyloxybutane.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[N:2]1.Cl[C:7]1[N:8]=[C:9]([NH:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([Cl:27])[CH:20]=2)[C:10]2[CH:15]=[C:14]([CH3:16])[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([Cl:27])[CH:20]=3)[C:10]3[CH:15]=[C:14]([CH3:16])[S:13][C:11]=3[N:12]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: c1cn[nH]c1
Reactant: COc1ccc(CNc2nc(Cl)nc3sc(C)cc23)cc1Cl
Product: COc1ccc(CNc2nc(-n3cccn3)nc3sc(C)cc23)cc1Cl

Procedure:
Following the procedure of Example 97, the reaction of pyrazole with 2-chloro-6-methyl-4-(3-chloro-4-methoxybenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(pyrazol-1-yl)-6-methyl-4-(3-chloro-4-methoxybenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [Br:1][C:2]1[C:10]2[N:9]=[C:8]([N:11]3[CH2:16][CH2:15][N:14]([C:17]4[C:22]([C:23]([F:26])([F:25])[F:24])=[CH:21][CH:20]=[CH:19][N:18]=4)[CH2:13][CH2:12]3)[NH:7][C:6]=2[CH:5]=[C:4]([C:27]([F:30])([F:29])[F:28])[CH:3]=1.[CH3:31][Si:32]([CH3:39])([CH3:38])[CH2:33][CH2:34][O:35][CH2:36]Cl>C(Cl)Cl>[Br:1][C:2]1[C:10]2[N:9]=[C:8]([N:11]3[CH2:12][CH2:13][N:14]([C:17]4[C:22]([C:23]([F:24])([F:25])[F:26])=[CH:21][CH:20]=[CH:19][N:18]=4)[CH2:15][CH2:16]3)[N:7]([CH2:36][O:35][CH2:34][CH2:33][Si:32]([CH3:39])([CH3:38])[CH3:31])[C:6]=2[CH:5]=[C:4]([C:27]([F:30])([F:28])[F:29])[CH:3]=1
Reactant: C[Si](C)(C)CCOCCl
Reactant: FC(F)(F)c1cc(Br)c2nc(N3CCN(c4ncccc4C(F)(F)F)CC3)[nH]c2c1
Solvent: ClCCl
Product: C[Si](C)(C)CCOCn1c(N2CCN(c3ncccc3C(F)(F)F)CC2)nc2c(Br)cc(C(F)(F)F)cc21

Procedure:
4-Bromo-6-trifluoromethyl-2-[4-(3-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-1H-benzoimidazole (2 g, 4 mmol, Example 7) in CH2Cl2 (20 mL) reacted with 2-(trimethylsilyl)ethoxymethyl chloride (660 mg, 4 mmol, Aldrich) under the conditions of Example 127a to give the title compound as a light-brown oil. MS (ESI, pos. ion) m/z: 564.4 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH:12]3[C:10]([C:14]([OH:16])=O)([CH2:11]3)[C:9]2=[O:17])=[CH:4][CH:3]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.CCN(C(C)C)C(C)C.[NH2:48][C:49]1[CH:78]=[CH:77][C:52]([O:53][C:54]2[CH:59]=[CH:58][N:57]=[C:56]3[CH:60]=[C:61]([C:63]4[CH:68]=[CH:67][C:66]([C:69]([N:71]5[CH2:76][CH2:75][O:74][CH2:73][CH2:72]5)=[O:70])=[CH:65][CH:64]=4)[S:62][C:55]=23)=[C:51]([F:79])[CH:50]=1>ClCCl>[F:79][C:51]1[CH:50]=[C:49]([NH:48][C:14]([C:10]23[CH2:11][CH:12]2[CH2:13][N:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[C:9]3=[O:17])=[O:16])[CH:78]=[CH:77][C:52]=1[O:53][C:54]1[CH:59]=[CH:58][N:57]=[C:56]2[CH:60]=[C:61]([C:63]3[CH:64]=[CH:65][C:66]([C:69]([N:71]4[CH2:76][CH2:75][O:74][CH2:73][CH2:72]4)=[O:70])=[CH:67][CH:68]=3)[S:62][C:55]=12
Reactant: Nc1ccc(Oc2ccnc3cc(-c4ccc(C(=O)N5CCOCC5)cc4)sc23)c(F)c1
Reactant: O=C(O)C12CC1CN(c1ccc(F)cc1)C2=O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(c1ccc(-c2cc3nccc(Oc4ccc(NC(=O)C56CC5CN(c5ccc(F)cc5)C6=O)cc4F)c3s2)cc1)N1CCOCC1
Reaction time: 8 h
Yield: 23.4 %

Procedure:
To a stirred solution of 3-(4-fluorophenyl)-2-oxo-3-aza-bicyclo[3.1.0]hexane-1-carboxylic acid (20 mg, 0.085 mmol) in 500 uL of dichloromethane at room temperature under nitrogen was added HOBt (19.5 mg, 0.128 mmol), EDCI (24.5 mg, 0.128 mmol) and DIEA (45 uL, 0.225 mmol). After 15 minutes a solution of (4-(7-(4-amino-2-fluorophenoxy)thieno[3,2-b]pyridin-2-yl)phenyl)(morpholino)methanone (Example 129, Step A, 34 mg, 0.077 mmol) in 500 uL dichloromethane was added by pipet. After stirring overnight, the reaction was diluted to 30 mL with CH2Cl2 and washed 1×30 mL with 10% sodium carbonate solution. The organics were dried (MgSO4), filtered and concentrated. The crude product was loaded onto Biotage 12S column and eluted initially with dichloromethane and then after about 100 mL of elution, switched to 2/98 MeOH/dichloromethane. Pure product containing fractions were pooled and concentrated to a white glass (12 mg, 21% yield). LRMS (APCI pos) m/e 667.4 (M+1). 1H NMR: (CDCl3, 400 MHz): δ 10.52 (s, 1H), 8.50 (d, 1H), 7.83 (m, 1H), 7.82 (s, 1H), 7.80 (s, 2H), 7.54-7.46 (m, 4H), 7.31 (m, 1H), 7.24 (m, 1H), 7.11 (m, 2H), 6.52 (d, 1H), 4.12 (m, 1H), 3.90-3.60 (br m, 8H), 3.78 (d, 1H), 2.81 (m, 1H), 2.05 (m, 1H), 1.39 (m, 1H).
Reaction SMILES: [NH2:1][C:2](=[N:20][N+:21]([O-:23])=[O:22])[NH:3][CH2:4][CH2:5][CH2:6][C@H:7]([C:9]([NH:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=1)=[O:10])[NH2:8].[CH2:24]([CH:27]([CH2:31][CH2:32][CH3:33])[C:28](O)=[O:29])[CH2:25][CH3:26].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>O1CCCC1>[NH2:1][C:2](=[N:20][N+:21]([O-:23])=[O:22])[NH:3][CH2:4][CH2:5][CH2:6][C@H:7]([C:9]([NH:11][CH2:12][C:13]1[CH:14]=[CH:15][C:16]([OH:19])=[CH:17][CH:18]=1)=[O:10])[NH:8][C:28](=[O:29])[CH:27]([CH2:31][CH2:32][CH3:33])[CH2:24][CH2:25][CH3:26]
Reactant: NC(=N[N+](=O)[O-])NCCC[C@@H](N)C(=O)NCc1ccc(O)cc1
Reactant: CCCC(CCC)C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: C1CCOC1
Product: CCCC(CCC)C(=O)N[C@H](CCCNC(N)=N[N+](=O)[O-])C(=O)NCc1ccc(O)cc1
Yield: 65 %

Procedure:
Prepared analogously to Example 5d), but using tetrahydrofuran instead of acetonitrile, from (R)-N5 -[amino(nitroimino)methyl]-N-[(4-hydroxyphenyl)methyl]-ornithinamide, 2-propyl-pentanoic acid and TBTU in a yield of 65% of theory. Colourless crystalline substance which was further processed without purification.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH:14]([C:18]([OH:20])=O)[CH2:13]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C=CC2N(O)N=NC=2C=1.[NH2:31][C:32]1[C:33](=[O:44])[N:34]([CH3:43])[C:35]2[C:40]([C:41]=1[NH2:42])=[CH:39][CH:38]=[CH:37][CH:36]=2>>[CH2:1]([O:8][C:9](=[O:10])[NH:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH:14]([C:18](=[O:20])[NH:31][C:32]2[C:33](=[O:44])[N:34]([CH3:43])[C:35]3[C:40]([C:41]=2[NH2:42])=[CH:39][CH:38]=[CH:37][CH:36]=3)[CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(NC1CCCC(C(=O)O)C1)OCc1ccccc1
Reactant: Cn1c(=O)c(N)c(N)c2ccccc21
Agent: On1nnc2ccccc21
Product: Cn1c(=O)c(NC(=O)C2CCCC(NC(=O)OCc3ccccc3)C2)c(N)c2ccccc21
Yield: 23.2 %

Procedure:
Following procedure described for example 3, step C, 3-benzyloxycarbonylamino-cyclohexanecarboxylic acid (0.586 g, 2.11 mmol), TEA (0.21 g, 2.11 mmol), HOBt (0.286 g, 2.11 mmol), and 3,4-diamino-1-methyl-1H-quinolin-2-one (0.40 g, 2.11 mmol) were reacted to give crude amide. Column chromatography purification of the crude product resulted in pure [3-(4-amino-1-methyl-2-oxo-1,2-dihydro-quinolin-3-ylcarbamoyl)-cyclohexyl]-carbamic acid benzyl ester (0.22 g, 23% yield). 1H-NMR (CDCl3): δ 8.14 (m, 1H), 7.62 (d, 1H, J=8.4 Hz), 7.55 (t, 1H, J=3.2 Hz), 7.35 (m, 7H), 5.50 (s, 2H), 5.10 (m, 2H), 3.72 (s, 3H), 3.62 (m, 1H), 2.58 (m, 1H), 2.34 (m, 1H), 2.04 (m, 2H), 1.94 (m, 1H), 1.67 (m, 2H), 1.46 (m, 2H), 1.13 (m, 1H). MS: calculated for C25H28N4O4+H 449.2; found: 449.4.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][CH:4]=1.[N:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:33]=[CH:32][C:21]([C:22]([NH:24][C:25]3[CH:26]=[N:27][CH:28]=[CH:29][C:30]=3[NH2:31])=[O:23])=[CH:20][CH:19]=2)=[CH:14][CH:13]=1>>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([NH:31][C:30]2[CH:29]=[CH:28][N:27]=[CH:26][C:25]=2[NH:24][C:22](=[O:23])[C:21]2[CH:20]=[CH:19][C:18]([C:15]3[CH:14]=[CH:13][N:12]=[CH:17][CH:16]=3)=[CH:33][CH:32]=2)=[O:8])=[CH:5][CH:4]=1
Reactant: Nc1ccncc1NC(=O)c1ccc(-c2ccncc2)cc1
Reactant: COc1ccc(C(=O)Cl)cc1
Product: COc1ccc(C(=O)Nc2ccncc2NC(=O)c2ccc(-c3ccncc3)cc2)cc1
Yield: 4 %

Procedure:
Using 4-methoxybenzoyl chloride and a similar procedure to that described for Example 2, Part C, N3-[4-(4-pyridyl)-benzoyl]-3,4-pyridinediamine (55 mg, 0.19 mmol) yielded 3.2 mg (4%) of the title compound.
Reaction SMILES: C([O:3][C:4](=[O:44])[CH2:5][C:6]1[CH:7]=[N:8][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([CH2:41][CH3:42])([C:21]3[CH:26]=[CH:25][C:24]([C:27]#[C:28][C:29]4([O:35][Si](C)(C)C)[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]4)=[C:23]([CH3:40])[CH:22]=3)[CH2:19][CH3:20])=[CH:14][C:13]=2[CH3:43])=[CH:10][CH:11]=1)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[CH2:19]([C:18]([C:15]1[CH:16]=[CH:17][C:12]([C:9]2[N:8]=[CH:7][C:6]([CH2:5][C:4]([OH:44])=[O:3])=[CH:11][CH:10]=2)=[C:13]([CH3:43])[CH:14]=1)([C:21]1[CH:26]=[CH:25][C:24]([C:27]#[C:28][C:29]2([OH:35])[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]2)=[C:23]([CH3:40])[CH:22]=1)[CH2:41][CH3:42])[CH3:20]
Reactant: CCOC(=O)Cc1ccc(-c2ccc(C(CC)(CC)c3ccc(C#CC4(O[Si](C)(C)C)CCCCC4)c(C)c3)cc2C)nc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CCC(CC)(c1ccc(C#CC2(O)CCCCC2)c(C)c1)c1ccc(-c2ccc(CC(=O)O)cn2)c(C)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 25.6 %

Procedure:
[6-(4-{1-Ethyl-1-[3-methyl-4-(1-trimethylsilanyloxy-cyclohexylethynyl)-phenyl]-propyl}-2-methyl-phenyl)-pyridin-3-yl]-acetic acid ethyl ester (Example 98-(1); 14 mg, 0.023 mmol) was dissolved in tetrahydrofuran (0.2 mL). Tetra-n-butylammonium fluoride (1 M solution in tetrahydrofuran; 0.1 mL) was added, and the mixture was stirred at room temperature for three hours. The reaction mixture was concentrated under reduced pressure, and then the residue was purified by silica gel chromatography (hexane only to hexane/ethyl acetate=1/1). The product was dissolved in methanol/tetrahydrofuran=1/1 (1 mL). A 1 N sodium hydroxide aqueous solution (0.1 mL) was added, and the mixture was stirred at room temperature for one hour. A 30% sodium dihydrogenphosphate aqueous solution (0.3 mL) was added to the reaction mixture, and then the reaction mixture was concentrated under reduced pressure. The residue was purified by preparative TLC (hexane/ethyl acetate=1/1) to give the title compound (3 mg, 25%).
Reaction SMILES: C(NC(C)C)(C)C.[Cl:8][C:9]1[CH:17]=[C:16](I)[C:12]2[O:13][CH2:14][O:15][C:11]=2[C:10]=1[NH2:19].[CH3:20][Si:21]([C:24]#[CH:25])([CH3:23])[CH3:22]>C(OCC)(=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:8][C:9]1[CH:17]=[C:16]([C:25]#[C:24][Si:21]([CH3:23])([CH3:22])[CH3:20])[C:12]2[O:13][CH2:14][O:15][C:11]=2[C:10]=1[NH2:19]
Reactant: C#C[Si](C)(C)C
Reactant: Nc1c(Cl)cc(I)c2c1OCO2
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CC(C)NC(C)C
Solvent: CCOC(C)=O
Product: C[Si](C)(C)C#Cc1cc(Cl)c(N)c2c1OCO2
Temperature: -20 °C
Reaction time: 4 h

Procedure:
Bis(triphenylphosphine)palladium(II) chloride (0.283 g), cuprous iodide (0.115 g) and diisopropylamine (0.57 ml) were added to a stirred solution of 5-chloro-7-iodo-1,3-benzodioxol-4-amine (0.600 g) and trimethylsilylacetylene (0.57 ml) in ethyl acetate (10 ml) cooled to −20° C. under a nitrogen atmosphere. The mixture was stirred for 4 hr at ambient temperature. The reaction mixture was filtered through Celite and the crude product in solution was then absorbed onto silica and purified by column chromatography using 20% dichloromethane in isohexane as eluent. There was thus obtained the title compound as an oil (0.560 g). NMR Spectrum: (CDCl3) 0.24 (s 9H), 4.03 (s, 2H), 6.02 (s, 2H), 6.91 (s, 1H); Mass Spectrum: M+H+ 268 and 270.
Reaction SMILES: [CH3:1][O:2][CH:3]1[CH2:6][N:5]([C:7]2[CH:12]=[CH:11][C:10]([N+:13]([O-])=O)=[CH:9][N:8]=2)[CH2:4]1.[C:16]1([C:22]2[O:23][C:24]([C:30]([F:33])([F:32])[F:31])=[C:25]([C:27](O)=[O:28])[N:26]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.CCN(CC)CC.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>>[CH3:1][O:2][CH:3]1[CH2:6][N:5]([C:7]2[N:8]=[CH:9][C:10]([NH:13][C:27]([C:25]3[N:26]=[C:22]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[O:23][C:24]=3[C:30]([F:32])([F:33])[F:31])=[O:28])=[CH:11][CH:12]=2)[CH2:4]1
Reactant: COC1CN(c2ccc([N+](=O)[O-])cn2)C1
Reactant: O=C(O)c1nc(-c2ccccc2)oc1C(F)(F)F
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Product: COC1CN(c2ccc(NC(=O)c3nc(-c4ccccc4)oc3C(F)(F)F)cn2)C1
Yield: 21.5 %

Procedure:
2-(3-Methoxy-azetidin-1-yl)-5-nitro-pyridine (120 mg, 0.5 mmol) was hydrogenated as above and reacted with 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (141 mg, 0.55 mmol), Et3N (352 uL, 2.5 mmol) and BOP (232 mg. 0.525 mmol). Following work-up as above, the crude material was purified by flash chromatography to yield 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [6-(3-methoxy-azetidin-1-yl)-pyridin-3-yl]-amide as a light green solid (45 mg). ES-MS calcd for C20H17F3N4O3 (m/e) 418.38, obsd 419.1 (M+H).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([C:11]1[NH:12][C:13]2[C:18]([C:19](=[O:21])[N:20]=1)=[CH:17][C:16]([C:22](OC)=[O:23])=[CH:15][CH:14]=2)[CH2:8][CH2:9][CH3:10].O>O1CCCC1>[CH2:7]([C:11]1[NH:12][C:13]2[C:18]([C:19](=[O:21])[N:20]=1)=[CH:17][C:16]([CH2:22][OH:23])=[CH:15][CH:14]=2)[CH2:8][CH2:9][CH3:10]
Reactant: CCCCc1nc(=O)c2cc(C(=O)OC)ccc2[nH]1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CCCCc1nc(=O)c2cc(CO)ccc2[nH]1
Temperature: 25 °C
Reaction time: 5 h
Yield: 44.8 %

Procedure:
To a suspension of 0.013 g of lithium aluminum hydride in 5.0 ml of tetrahydrofuran is added 0.100 g of methyl 2-butyl-1,4-dihydro-4-oxo-6-quinazolinecarboxylate followed by stirring at room temperature for 5 hours. An additional 20 mg of lithium aluminum hydride is added and stirring continued for 18 hours. An additional 20 mg of lithium aluminum hydride is added and stirring continued for an additional 8 hours. The reaction mixture is poured into 75 ml of water and extracted with ethyl acetate. The extract is evaporated in vauco to a residue which is stirred with acetone and filtered to give 0.040 g of the desired product as a white solid.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH3:15])=[N:13][N:14]=[C:10]3[C@H:9]([CH3:16])[CH2:8][N:7]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][N:18]=3)[C:6]=2[CH:24]=1.CC1(C)C(C)(C)OB([C:33]2[CH:34]=[CH:35][C:36](=[O:39])[NH:37][CH:38]=2)O1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:23][C:20]1[CH:21]=[CH:22][C:17]([N:7]2[CH2:8][C@@H:9]([CH3:16])[C:10]3=[N:14][N:13]=[C:12]([CH3:15])[N:11]3[C:5]3[CH:4]=[CH:3][C:2]([C:33]4[CH:34]=[CH:35][C:36](=[O:39])[NH:37][CH:38]=4)=[CH:24][C:6]2=3)=[N:18][CH:19]=1
Reactant: Cc1nnc2n1-c1ccc(Br)cc1N(c1ccc(Cl)cn1)C[C@H]2C
Reactant: CC1(C)OB(c2ccc(=O)[nH]c2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1nnc2n1-c1ccc(-c3ccc(=O)[nH]c3)cc1N(c1ccc(Cl)cn1)C[C@H]2C
Temperature: 130 °C
Reaction time: 0.5 h
Yield: 29.8 %

Procedure:
To a solution of (R)-8-bromo-6-(5-chloropyridin-2-yl)-1,4-dimethyl-5,6-dihydro-4H-benzo[b][1,2,4]triazolo[4,3-d][1,4]diazepine (100 mg, 0.24 mmol) in 1,4-dioxane/H2O (10:1, 2 mL) was added 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one (65 mg, 0.29 mmol), Cesium carbonate (156 mg, 0.48 mmol) and Tetrakis(triphenylphosphine)palladium(0) (18.4 mg, 0.025 mmol). The mixture was purged with N2 and stirred in the microwave at 130° C. for 0.5 hr. After filtration, concentrated in vacuo and purification by prep-TLC (elute: DCM:MeOH=15:1) gave (R)-5-(6-(5-chloropyridin-2-yl)-1,4-dimethyl-5,6-dihydro-4H-benzo[b][1,2,4]triazolo[4,3-d][1,4]diazepin-8-yl)pyridin-2(1H)-one (30 mg, 30%).
Reaction SMILES: [NH2:1][CH:2]1[CH2:6][N:5]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:4]([C:14]([N:16]2[CH2:21][CH2:20][N:19]([C:22]3[CH:29]=[CH:28][CH:27]=[CH:26][C:23]=3[C:24]#[N:25])[CH2:18][CH2:17]2)=[O:15])[CH2:3]1.[CH3:30][O:31][C:32]1[CH:40]=[CH:39][CH:38]=[CH:37][C:33]=1[C:34](Cl)=[O:35]>>[CH2:7]([N:5]1[C@H:4]([C:14]([N:16]2[CH2:17][CH2:18][N:19]([C:22]3[CH:29]=[CH:28][CH:27]=[CH:26][C:23]=3[C:24]#[N:25])[CH2:20][CH2:21]2)=[O:15])[CH2:3][C@H:2]([NH:1][C:34](=[O:35])[C:33]2[CH:37]=[CH:38][CH:39]=[CH:40][C:32]=2[O:31][CH3:30])[CH2:6]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: COc1ccccc1C(=O)Cl
Reactant: N#Cc1ccccc1N1CCN(C(=O)C2CC(N)CN2Cc2ccccc2)CC1
Product: COc1ccccc1C(=O)N[C@H]1C[C@@H](C(=O)N2CCN(c3ccccc3C#N)CC2)N(Cc2ccccc2)C1
Yield: 7.7 %

Procedure:
As described for Example 89e, 2-[4-(4-amino-1-benzyl-pyrrolidine-2-carbonyl)-piperazin-1-yl]-benzonitrile (50.0 mg, 0.128 mmol) was converted, using 2-methoxy-benzoyl chloride instead of 2-chloro-benzoyl chloride, to the title compound (5.2 mg, 7.7%) as light yellow oil. MS m/e=524.3 [M+H]+.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]([CH3:22])[C:5](=O)[CH2:6][O:7][CH2:8][CH2:9][C:10]1[C:18]([O:19][CH3:20])=[CH:17][C:13]2[S:14][CH:15]=[CH:16][C:12]=2[CH:11]=1.Cl.O.[OH-].[Na+]>O1CCCC1.C(OCC)(=O)C>[CH3:20][O:19][C:18]1[C:10]([CH2:9][CH2:8][O:7][CH2:6][CH2:5][N:4]([CH3:22])[CH2:3][CH2:2][OH:1])=[CH:11][C:12]2[CH:16]=[CH:15][S:14][C:13]=2[CH:17]=1
Reactant: COc1cc2sccc2cc1CCOCC(=O)N(C)CCO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: COc1cc2sccc2cc1CCOCCN(C)CCO
Temperature: 5 °C
Yield: 75.3 %

Procedure:
In 8 mL of tetrahydrofuran is dissolved 0.93 g of N1-(2-hydroxyethyl)-N1-methyl-2-[2-(6-methoxybenzo[b]-thiophen-5-yl)ethoxy]-acetamide. The solution is cooled to 5° C., and 6 mL of 1 mol/L solution of borane-tetrahydrofuran complex in tetrahydrofuran is dropwise added thereto. After stirring the mixture at ambient temperature overnight, 1.5 mL of 6 mol/L hydrochloric acid is dropwise added, and the resulting mixture is heated under reflux for 30 minutes. After cooling, water and ethyl acetate are added to the reaction mixture, pH is adjusted to 9.5 with 5 mol/L aqueous solution of sodium hydroxide, and the organic layer is separated. The organic layer is washed with saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, the solvent is distilled off under reduced pressure, and the residue is purified by column chromatography (eluent: chloroform:methanol=10:1 to 5:1). Thus, 0.67 g of 2-[{2-[2-(6-methoxybenzo[b]thiophen-5-yl)ethoxy]-ethyl}(methyl)amino]-1-ethanol is obtained as an oily product.
Reaction SMILES: [CH:1]1([CH2:7][CH:8]([C:12](=[O:20])[CH2:13][N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:9]([OH:11])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)CCl.[NH2:25][C:26]([CH2:37][N:38]([CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[CH3:39])([CH2:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:27]#[N:28].CN1CCOCC1>C(Cl)Cl>[CH2:40]([N:38]([CH2:37][C:26]([NH:25][C:9](=[O:11])[CH:8]([CH2:7][CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1)[C:12](=[O:20])[CH2:13][N:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1)([C:27]#[N:28])[CH2:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[CH3:39])[C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1
Reactant: O=C(O)C(CC1CCCCC1)C(=O)CN1CCOCC1
Reactant: CN(Cc1ccccc1)CC(N)(C#N)CCc1ccccc1
Solvent: CN1CCOCC1
Solvent: ClCCl
Solvent: ClCCCl
Product: CN(Cc1ccccc1)CC(C#N)(CCc1ccccc1)NC(=O)C(CC1CCCCC1)C(=O)CN1CCOCC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 24.7 %

Procedure:
2-Cyclohexylmethyl-4-morpholin-4-yl-oxo-butanoic acid (0.097 g, 0.34 mmol, 1.0 equiv) was dissolved in 10 mL of CH2Cl2 followed by addition of EDC (0.065 g, 0.34 mmol, 1.0 equiv). The solution was stirred for 15 min at which time a solution of 2-amino-2-[(benzyl-methyl-amino)-methyl]-4-phenyl-butyronitrile (0.10 g, 0.34 mmol, 1.0 equiv) in 5 mL of CH2Cl2 was added followed by N-methylmorpholine (0.137 g, 1.36 mmol, 4.0 equiv). The resulting solution was stirred at room temperature for 72 h. The volatiles were removed in vacuo and the residue was redissolved in 100 mL of EtOAc and the solution was washed 2×25 mL brine. The organic layer was evaporated to dryness and the crude product was purified by semi-prep reverse-phase HPLC using 40% CH3CN in water to 90% over a time of 25 min. The appropriate fractions were combined and concentrated to yield the desired product as a thick oil (0.047 g, 25%); MS, m/z 559=M+1.