Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N1C=CC=CC=1.[CH3:7][S:8]([O:11]S(C)(=O)=O)(=[O:10])=[O:9].O[CH2:17][CH2:18][CH2:19][N:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22]([C:29]2[C:30](=[O:54])[NH:31][C:32](=[O:53])[C:33]=2[C:34]2[C:42]3[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=3)[N:36]([C:43]3[CH:52]=[CH:51][C:50]4[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=4)[CH:44]=3)[CH:35]=2)=[N:21]1.Cl>C1COCC1>[CH3:7][S:8]([O:11][CH2:17][CH2:18][CH2:19][N:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22]([C:29]2[C:30](=[O:54])[NH:31][C:32](=[O:53])[C:33]=2[C:34]2[C:42]3[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=3)[N:36]([C:43]3[CH:52]=[CH:51][C:50]4[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=4)[CH:44]=3)[CH:35]=2)=[N:21]1)(=[O:10])=[O:9]
Reactant: CS(=O)(=O)OS(C)(=O)=O
Reactant: O=C1NC(=O)C(c2nn(CCCO)c3ccccc23)=C1c1cn(-c2ccc3ccccc3c2)c2ccccc12
Agent: Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CS(=O)(=O)OCCCn1nc(C2=C(c3cn(-c4ccc5ccccc5c4)c4ccccc34)C(=O)NC2=O)c2ccccc21
Temperature: 50 °C
Reaction time: 0.25 h

Procedure:
Following the procedure of Example 26, pyridine (0.7 g, 8.35 mmol) and methanesulfonic anhydride (1.09 g, 6.26 mmol) were added to Compound 84 (1.07 g, 2.09 mmol) (prepared in Example 24) in THF (20 mL). The mixture was heated at 50° C. for 2 h, then cooled to rt. Another portion of THF (10 mL) was added, followed by addition of 1 N HCl (10 mL). The mixture was stirred for 15 min, then extracted with EtOAc several times. The combined EtOAc layers were washed once with 1 N HCl (10 mL), water (2×20 mL) and saturated NaCl (20 mL), then dried (Na2SO4) and evaporated in vacuo to obtain a 3-[1-[3-[(methylsulfonyl)oxy]propyl]-1H-indazol-3-yl]-4-[1-(2-napthalenyl)-1H-indol-3-yl]-1H-pyrrole-2,5-dione analog of Compound 26a (1.1 g, 92%) as a reddish solid. ES-MS m/z 591 (MH+).
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH2:16][CH:17]([CH3:19])[CH3:18])[CH3:15])[C:11]([Cl:20])=[CH:10][C:9]=1[N+:21]([O-])=O)([CH3:4])([CH3:3])[CH3:2].O.O.Cl[Sn]Cl>>[C:1]([O:5][C:6](=[O:24])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH2:16][CH:17]([CH3:18])[CH3:19])[CH3:15])[C:11]([Cl:20])=[CH:10][C:9]=1[NH2:21])([CH3:2])([CH3:4])[CH3:3]
Reactant: CC(C)CN(C)c1cc(NC(=O)OC(C)(C)C)c([N+](=O)[O-])cc1Cl
Agent: Cl[Sn]Cl
Solvent: O
Product: CC(C)CN(C)c1cc(NC(=O)OC(C)(C)C)c(N)cc1Cl

Procedure:
The title compound was prepared from [4-chloro-5-(isobutyl-methyl-amino)-2-nitro-phenyl]-carbamic acid tert-butyl ester (Example C24) (5.55 g, 15.5 mmol) by reduction with SnCl2.2H2O according to the general procedure J (method b). Obtained as a pale brown solid (3.98 g, 78%).
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[CH2:9]([N:16]1[CH:22]([CH3:23])[CH2:21][CH2:20][CH2:19][CH2:18][C:17]1=[O:24])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.CN(P(N(C)C)(N(C)C)=O)C.C([C:38]([O:40][CH3:41])=[O:39])#N>C1COCC1>[CH2:9]([N:16]1[CH:22]([CH3:23])[CH2:21][CH2:20][CH2:19][CH:18]([C:38]([O:40][CH3:41])=[O:39])[C:17]1=[O:24])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: COC(=O)C#N
Reactant: CC1CCCCC(=O)N1Cc1ccccc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Product: COC(=O)C1CCCC(C)N(Cc2ccccc2)C1=O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of lithium diisopropylamide in THF (1.8 M, 10 mL, 18 mmol, 1.3 equiv) freshly prepared at −78° C. was added a solution of 1-benzyl-7-methylazepan-2-one (2-3, 3.8 g, 18 mmol, 1.0 equiv) in THF (10 mL) was added. The reaction mixture was warmed to 0° C. and stirred for 1 h, then cooled to −78° C. HMPA (3.0 mL, 17 mmol, 0.99 equiv) was added followed by methyl cyanoformate (1.8 mL, 23 mmol, 1.3 equiv). After stirring 10 minutes at −78° C. the mixture was partitioned between water (40 mL) and diethyl ether (2×40 mL). The combined organic extracts were dried over sodium sulfate and concentrated. The residue was purified by silica gel chromatography (0-100% ethyl acetate/hexanes gradient) to yield methyl 1-benzyl-7-methyl-2-oxoazepane-3-carboxylate (2-4). LRMS m/z (M+H) 276.2 found, 276.2 required.
Reaction SMILES: C(OC([N:8]1[CH:12]=[C:11](B2OC(C)(C)C(C)(C)O2)[CH:10]=[N:9]1)=O)(C)(C)C.C([O-])([O-])=O.[Na+].[Na+].Br[C:29]1[CH:30]=[C:31]([C:35]2[CH:40]=[C:39]([NH:41][CH2:42][CH2:43][C:44]3[C:52]4[C:47](=[CH:48][CH:49]=[CH:50][CH:51]=4)[NH:46][CH:45]=3)[N:38]=[C:37]([C:53]3[CH:58]=[CH:57][CH:56]=[CH:55][N:54]=3)[CH:36]=2)[CH:32]=[N:33][CH:34]=1>CN1C(=O)CCC1.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)CCCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[NH:46]1[C:47]2[C:52](=[CH:51][CH:50]=[CH:49][CH:48]=2)[C:44]([CH2:43][CH2:42][NH:41][C:39]2[N:38]=[C:37]([C:53]3[CH:58]=[CH:57][CH:56]=[CH:55][N:54]=3)[CH:36]=[C:35]([C:31]3[CH:32]=[N:33][CH:34]=[C:29]([C:11]4[CH:12]=[N:8][NH:9][CH:10]=4)[CH:30]=3)[CH:40]=2)=[CH:45]1
Reactant: CC(C)(C)OC(=O)n1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: Brc1cncc(-c2cc(NCCc3c[nH]c4ccccc34)nc(-c3ccccn3)c2)c1
Agent: Cl[Pd]Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: c1ccc(-c2cc(-c3cncc(-c4cn[nH]c4)c3)cc(NCCc3c[nH]c4ccccc34)n2)nc1

Procedure:
4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrazole-1-carboxylic acid tert-butyl ester (1.1 eq, 0.12 mmol, 34 mg) is stirred in NMP (1 ml) and 2M Na2CO3 (2 eq, 0.21 mmol, 0.106 ml) for 15 minutes, under an inert atmosphere of argon. (5″-Bromo-[2,2′;4′,3″]terpyridin-6′-yl)-[2-(1H-indol-3-yl)-ethyl]-amine (Example 1.14) (1 eq, 0.11 mmol, 50 mg) and 1,4-bis(diphenylphosphino)butane-palladium(II) chloride (0.2 eq, 0.021 mmol, 12 mg) are added and the reaction mixture is flushed with argon and heated using microwave radiation at 100° C. for 2 hours. The reaction mixture is extracted into EtOAc washing with water. The organic phase is washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The crude residue is purified by reverse phase column chromatography (Isolute™ C18, 0-50% acetonitrile in water—0.1% TFA) and the appropriate fractions are combined and concentrated in vacuo. The resulting residue is dissolved in MeOH and loaded onto a SCX-2 cartridge eluting with MeOH followed by 2M NH3 in MeOH. The methanolic ammonia fractions are concentrated in vacuo and dried under vacuum to afford the title compound; [M+H]+ 458.
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]1[CH:4]=[C:5]([CH:26]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:28]=1)[C:6]([N:8]1[CH2:25][CH2:24][C:11]2([N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[Cl:22])[CH2:14][NH:13][C:12]2=[O:23])[CH2:10][CH2:9]1)=[O:7].[N:35]1[CH:40]=[CH:39][C:38](B(O)O)=[CH:37][CH:36]=1>>[F:32][C:29]([F:31])([F:30])[C:27]1[CH:26]=[C:5]([CH:4]=[C:3]([C:2]([F:1])([F:33])[F:34])[CH:28]=1)[C:6]([N:8]1[CH2:9][CH2:10][C:11]2([N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[Cl:22])[CH2:14][N:13]([C:38]3[CH:39]=[CH:40][N:35]=[CH:36][CH:37]=3)[C:12]2=[O:23])[CH2:24][CH2:25]1)=[O:7]
Reactant: OB(O)c1ccncc1
Reactant: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCC2(CC1)C(=O)NCN2c1ccccc1Cl
Product: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCC2(CC1)C(=O)N(c1ccncc1)CN2c1ccccc1Cl

Procedure:
The title compound, MS: m/e=583.0 (M+H+), was prepared in accordance with the general method of example 83 from 8-(3,5-bis-trifluoromethyl-benzoyl)-1-(2-chloro-phenyl)-1,3,8-triaza-spiro[4.5]decan-4-one and 4-pyridineboronic acid.
Reaction SMILES: [O:1]1[CH2:25][CH:2]1[CH2:3][N:4]1[CH2:9][CH2:8][N:7]([CH:10]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)[C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[CH2:6][CH2:5]1.[NH3:26]>CCO>[NH2:26][CH2:25][CH:2]([OH:1])[CH2:3][N:4]1[CH2:5][CH2:6][N:7]([CH:10]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[C:18]2[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=2)[CH2:8][CH2:9]1
Reactant: Fc1ccc(C(c2ccc(F)cc2)N2CCN(CC3CO3)CC2)cc1
Reactant: N
Solvent: CCO
Product: NCC(O)CN1CCN(C(c2ccc(F)cc2)c2ccc(F)cc2)CC1

Procedure:
A solution of 1-[1-(2,3-epoxy)propyl]-4-[bis(4-fluorophenyl)methyl]piperazine (8.9 g, 25.8 mmol) and liquid ammonia (20 mL) in EtOH (40 mL) was heated in a teflon reaction vessel in a bomb at 110° C. for 28 h. The solution was then evaporated to dryness to give about 10 g of a glass which was purified using flash chromatography on silica gel and increasing proportions of methanol in methylene chloride to give the product as an oil which solidified upon vacuum drying, 5.7 g (61%), mp 45°-47° C. IR(neat) 3350 cm-1 ; 300 MHz 1H NMR (CDCl3): δ 7.4-6.9 (m, 8H), 4.21 (s, 1H), 3.68 (br m, 1H) 2.8-2.2(m, 12H); MS 362 (MH+).
Reaction SMILES: I[C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[CH2:12]([OH:17])[C@@H:13]([OH:16])[C:14]#[CH:15].CCN(CC)CC.N#N>C(#N)C.CCOC(C)=O.[Cu]I.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>[OH:16][C@H:13]([CH2:12][OH:17])[C:14]#[C:15][C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1ccccc1I
Reactant: C#C[C@H](O)CO
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: N#N
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COC(=O)c1ccccc1C#C[C@H](O)CO
Temperature: 80 °C
Reaction time: 0.33 h
Yield: 85.7 %

Procedure:
A solution of methyl 2-iodobenzoate (2.312 ml, 15.26 mmol), (2S)-3-butyne-1,2-diol (1.380 g, 16.03 mmol), and Et3N (10.64 ml, 76 mmol) in Acetonitrile (25.2 ml) was degassed with N2 for 10 min and treated with CuI (0.581 g, 3.05 mmol) and Pd(PPh3)4 (0.264 g, 0.229 mmol) and the reaction mixture was heated to 80° C. After 20 min, the reaction mixture was cooled to ambient temperature. The reaction mixture was diluted with EtOAc and washed with saturated aqueous NH4Cl, water and brine. The organic phase was dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (ethyl acetate-hexanes 0-100%) to afford the title compound (2.88 g, 13.08 mmol, 86% yield) as a beige solid: Rt=0.54 min, ES+ MS: 221 (M+1).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([O:8][CH:9]2[CH2:14][CH2:13][N:12]([C:15](OC(C)(C)C)=O)[CH2:11][CH2:10]2)=[CH:4][CH:3]=1.[CH3:22][C:23]1(C)[CH2:25][O:24]1>ClCCl.FC(F)(F)C(O)=O>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([O:8][CH:9]2[CH2:10][CH2:11][N:12]([CH2:15][C:23]([CH3:25])([OH:24])[CH3:22])[CH2:13][CH2:14]2)=[CH:4][CH:3]=1
Reactant: CC1(C)CO1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(Cl)nc2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(O)CN1CCC(Oc2ccc(Cl)nc2)CC1
Reaction time: 3 h
Yield: 85 %

Procedure:
To a stirred solution of tert-butyl 4-((6-chloropyridin-3-yl)oxy)piperidine-1-carboxylate (1.0 g, 3.2 mmol) in dichloromethane (10 mL), trifluoroacetic acid (3 mL) was added at 0° C. and stirred for 3 h. The reaction mixture was concentrated in vacuo and resultant residue was dissolved in MeOH (5 mL), 2,2-dimethyloxirane (0.246 g, 3.2 mmol) was added and stirred at room temperature for 10-12 h. The reaction mixture was concentrated in vacuo to give the title product (0.775, 85%); MS: 285.0 (M+1).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([N:10]2[N:14]=[C:13]([CH2:15][CH3:16])[C:12]([CH3:17])=[N:11]2)[CH:7]=[CH:6][C:3]=1[CH:4]=O.[N+:18]([C:21]1[CH:26]=[CH:25][C:24]([CH2:27][C:28](OCC)=[O:29])=[CH:23][CH:22]=1)([O-:20])=[O:19].N1CCCCC1.C(O)(=O)C>C(O)C>[N+:18]([C:21]1[CH:22]=[CH:23][C:24]([C:27]2[C:28](=[O:29])[O:1][C:2]3[C:3]([CH:4]=2)=[CH:6][CH:7]=[C:8]([N:10]2[N:14]=[C:13]([CH2:15][CH3:16])[C:12]([CH3:17])=[N:11]2)[CH:9]=3)=[CH:25][CH:26]=1)([O-:20])=[O:19]
Reactant: CCOC(=O)Cc1ccc([N+](=O)[O-])cc1
Reactant: CCc1nn(-c2ccc(C=O)c(O)c2)nc1C
Solvent: CC(=O)O
Solvent: CCO
Solvent: C1CCNCC1
Product: CCc1nn(-c2ccc3cc(-c4ccc([N+](=O)[O-])cc4)c(=O)oc3c2)nc1C
Yield: 55 %

Procedure:
50.6 g (200 mmols) of the Na salt of 2-hydroxy-4-(4-ethyl-5-methyl-2H-1,2,3-triazol-2-yl)-benzaldehyde, 41.8 g (200 mmols) of ethyl 4-nitrophenylacetate and 2 ml of piperidine are refluxed in 250 ml of ethanol for 4 hours. After the mixture has been cooled, it is neutralised with glacial acetic acid, and the residue is washed with ethanol and water, and dried: 46.3 g (61.5%). Recrystallisation from toluene yields 41.4 g (55%) of 3-(4-nitrophenyl)-7-(4-ethyl-5-methyl-2H-1,2,3-triazol-2-yl)-coumarin in the form of a pale yellow crystalline powder of melting point 278°-279° C.
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[C:9]([C:11]#[N:12])[CH:8]=[CH:7][C:5]=1[NH2:6])([O-])=O.[C:13](Cl)(=[O:22])[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1>>[C:11]([C:9]1[CH:10]=[C:4]([NH:1][C:13](=[O:22])[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[C:5]([NH:6][C:13](=[O:22])[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[CH:7][CH:8]=1)#[N:12]
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: N#Cc1ccc(N)c([N+](=O)[O-])c1
Product: COc1ccc(C(=O)Nc2ccc(C#N)cc2NC(=O)c2ccc(OC)cc2)cc1

Procedure:
Using the procedures described in Example 93, Part A and Example 96, Part B, 2-nitro-4-cyanoaniline (31 mmol) and 4-anisoyl chloride yielded 500 mg (21%, three steps) of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16](S(C)=O)[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:32]=[CH:33][C:34]=3[CH3:35])[C:22]([NH:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[O:23])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:39].Cl.Cl.[NH:42]1[CH:46]=[CH:45][N:44]=[C:43]1[CH2:47][NH2:48]>C(Cl)Cl.C(N(CC)CC)C.CCOC(C)=O.[OH-].[Na+]>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([NH:48][CH2:47][C:43]3[NH:42][CH:46]=[CH:45][N:44]=3)[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:32]=[CH:33][C:34]=3[CH3:35])[C:22]([NH:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[O:23])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:39]
Reactant: Cc1ccc(C(=O)NCc2ccccc2)cc1-c1nc(S(C)=O)nc2c1ccc(=O)n2-c1c(F)cccc1F
Reactant: NCc1ncc[nH]1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: Cc1ccc(C(=O)NCc2ccccc2)cc1-c1nc(NCc2ncc[nH]2)nc2c1ccc(=O)n2-c1c(F)cccc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-[8-(2,6-Difluorophenyl)-2-(methylsulfinyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl]-4-methyl-N-(phenylmethyl)benzamide (0.084 g, 0.154 mmol) and (1H-imidazol-2-ylmethyl)amine dihydrochloride (0.039 g, 0.23 mmol) were dissolved in CH2Cl2 (5 mL) and triethylamine (0.7 mL). The resulting mixture was stirred under argon at room temperature overnight. The solvents were pumped off in vacuo, and the residue taken up in EtOAc and 1 N NaOH. The organic phase was washed with brine, dried over anhydrous Na2SO4 filtered and evaporated. The residue was flash chromatographed on silica gel (20 g) eluted with 6:1:0.05 CH2Cl2:isopropanol:NH4OH. The material isolated was not pure, and was rechromatographed on silica gel (20 g) eluted with 0-5% MeOH/CH2Cl2 to give the title compound as a white amorphous solid. mp (dec) 185-190° C. LC-MS m/z 578 (M+H)+, 1.76 min (ret time).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:17]=[CH:16][C:7]([O:8][C:9]([CH3:15])([CH3:14])[C:10]([O:12][CH3:13])=[O:11])=[CH:6][CH:5]=1.[CH:18]([C:21]1[O:25][N:24]=[C:23]([C:26]2[CH:33]=[CH:32][C:29]([CH:30]=O)=[CH:28][CH:27]=2)[N:22]=1)([CH3:20])[CH3:19].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClCCl>[CH:18]([C:21]1[O:25][N:24]=[C:23]([C:26]2[CH:27]=[CH:28][C:29]([CH2:30][NH:1][CH2:2][CH2:3][C:4]3[CH:5]=[CH:6][C:7]([O:8][C:9]([CH3:15])([CH3:14])[C:10]([O:12][CH3:13])=[O:11])=[CH:16][CH:17]=3)=[CH:32][CH:33]=2)[N:22]=1)([CH3:20])[CH3:19]
Reactant: CC(C)c1nc(-c2ccc(C=O)cc2)no1
Reactant: COC(=O)C(C)(C)Oc1ccc(CCN)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: COC(=O)C(C)(C)Oc1ccc(CCNCc2ccc(-c3noc(C(C)C)n3)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.2 %

Procedure:
A solution of methyl 2-[4-(2-aminoethyl)phenoxy]-2-methylpropanoate (1 g; 4.22 mmol) in dichloromethane (30 ml) was treated under nitrogen with 4-(5-isopropyl-1,2,4-oxadiazol-3-yl)benzaldehyde (0.96 g; 4.43 mmol), sodium triacetoxyborohydride (0.94 g; 4.43 mmol) and acetic acid (0.24 ml; 4.23 mmol). After stirring at rt overnight, the mixture was concentrated and partitioned between ethyl acetate and 1N NaOH. The organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated. Purification by flash chromatography using an ethyl acetate-hexane gradient (20–70%) followed by a methanol-dichloromethane gradient (1–10%) afforded the title compound (1.5 g; 81% yield).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[O:6][CH2:7][CH2:8][C:9]3[N:10]([CH:13]=[C:14]([C:16]([NH2:18])=[O:17])[N:15]=3)[C:11]=2[N:12]=1.[CH3:19][C:20]1[O:24][N:23]=[C:22]([C@:25]([OH:29])([C:27]#[CH:28])[CH3:26])[CH:21]=1>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>[OH:29][C@:25]([C:22]1[CH:21]=[C:20]([CH3:19])[O:24][N:23]=1)([CH3:26])[C:27]#[C:28][C:2]1[CH:3]=[CH:4][C:5]2[O:6][CH2:7][CH2:8][C:9]3[N:10]([CH:13]=[C:14]([C:16]([NH2:18])=[O:17])[N:15]=3)[C:11]=2[N:12]=1
Reactant: NC(=O)c1cn2c(n1)CCOc1ccc(Cl)nc1-2
Reactant: C#C[C@@](C)(O)c1cc(C)on1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: Cc1cc([C@](C)(O)C#Cc2ccc3c(n2)-n2cc(C(N)=O)nc2CCO3)no1
Yield: 21 %

Procedure:
Similar to as described in General Procedure G with the exception of replacing PdCl2(PPh3)2 with Pd (PPh3)4, 2-chloro-6,7-dihydroimidazo[1,2-d]pyrido[3,2-b][1,4]oxazepine-9-carboxamide was reacted with (R)-2-(5-methylisoxazol-3-yl)but-3-yn-2-ol (US2012/214762A1) to give the titled compound as a white solid (36 mg, 21%).
Reaction SMILES: [OH:1][C@@H:2]1[CH2:9][N:8]([C:10](=[O:22])[CH2:11][CH2:12][CH2:13][N:14]2[CH2:19][CH2:18][NH:17][C@@H:16]([CH3:20])[C:15]2=[O:21])[CH2:7][CH2:6][C:3]21[CH2:5][CH2:4]2.[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([N:30]=[C:31]=[O:32])=[CH:26][CH:25]=1>>[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([NH:30][C:31]([N:17]2[CH2:18][CH2:19][N:14]([CH2:13][CH2:12][CH2:11][C:10]([N:8]3[CH2:7][CH2:6][C:3]4([CH2:5][CH2:4]4)[C@H:2]([OH:1])[CH2:9]3)=[O:22])[C:15](=[O:21])[C@@H:16]2[CH3:20])=[O:32])=[CH:26][CH:25]=1
Reactant: C[C@@H]1NCCN(CCCC(=O)N2CCC3(CC3)[C@H](O)C2)C1=O
Reactant: O=C=Nc1ccc(Cl)cc1
Product: C[C@H]1C(=O)N(CCCC(=O)N2CCC3(CC3)[C@H](O)C2)CCN1C(=O)Nc1ccc(Cl)cc1
Yield: 72 %

Procedure:
In analogy to the procedure described in Example 25, (S)-1-[4-((S)-4-hydroxy-6-aza-spiro[2.5]oct-6-yl)-4-oxo-butyl]-3-methyl-piperazin-2-one (intermediate 13) and 4-chlorophenyl isocyanate gave the titled compound in 72% yield as white foam. MS: 463.2 (MH+, Cl).
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([CH2:18][CH2:19][C:20]3[CH:21]=[C:22]([CH:29]=[CH:30][CH:31]=3)[O:23][CH2:24][C:25]([O:27]C)=[O:26])[NH:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+]>CO>[C:1]1([C:7]2[N:8]=[C:9]([CH2:18][CH2:19][C:20]3[CH:21]=[C:22]([CH:29]=[CH:30][CH:31]=3)[O:23][CH2:24][C:25]([OH:27])=[O:26])[NH:10][C:11]=2[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)COc1cccc(CCc2nc(-c3ccccc3)c(-c3ccccc3)[nH]2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)COc1cccc(CCc2nc(-c3ccccc3)c(-c3ccccc3)[nH]2)c1
Yield: 35.1 %

Procedure:
A mixture of methyl [3-(2-(4,5-diphenyl-1H-imidazol-2-yl)ethyl]phenoxy]acetate (l.20 g, 3 mmol), 5N NaOH solution (l.74 mL, 9 mmol) and methanol (30 mL) was heated to reflux on a steam bath for 20 minutes. The solvent was removed, the residue diluted with water and acidified to pH=1 with 2N HCl solution. A yellow solid was filtered off and subjected to chromatography on a column of silica gel using a mixture of chloroform and methanol (9:1) as eluent to give [3-[2-(4,5-diphenyl-1H-imidazol-2-yl)ethyl]phenoxy]-acetic acid (0.42 g, 36%), mp 244°-246° C.
Reaction SMILES: [N+:1](=[C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:12])=[N-:2].[C:13]([O:17][CH2:18][CH2:19][CH3:20])(=[O:16])[C:14]#[CH:15]>C1(C)C(C)=CC=CC=1>[O:12]=[C:4]1[N:1]2[N:2]=[C:14]([C:13]([O:17][CH2:18][CH2:19][CH3:20])=[O:16])[CH:15]=[C:3]2[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[NH:5]1
Reactant: [N-]=[N+]=C1C(=O)Nc2ccccc21
Reactant: C#CC(=O)OCCC
Solvent: Cc1ccccc1C
Product: CCCOC(=O)c1cc2c3ccccc3[nH]c(=O)n2n1
Yield: 43.86 %

Procedure:
2.0 g (0.0126 mole) of 3-diazo-oxindole and 1.7 g (1.2 equivalents) of n-propyl propiolate are dissolved in xylene (85 ml) and refluxed under nitrogen for 24 hours. The dark reddish-brown precipitates are filtered off, washed with ether and dried. Yield: 1.5 g, 43.86% yield.
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH2:16][CH:17]([CH3:19])[CH3:18])[CH3:15])[C:11]([C:20]([F:23])([F:22])[F:21])=[CH:10][C:9]=1[NH2:24])([CH3:4])([CH3:3])[CH3:2].C([O:30][C:31](=O)[CH2:32][C:33](=[O:45])[C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([N:40]2[CH:44]=[N:43][CH:42]=[N:41]2)[CH:35]=1)(C)(C)C>>[C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH2:16][CH:17]([CH3:19])[CH3:18])[CH3:15])[C:11]([C:20]([F:23])([F:22])[F:21])=[CH:10][C:9]=1[NH:24][C:31](=[O:30])[CH2:32][C:33](=[O:45])[C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([N:40]2[CH:44]=[N:43][CH:42]=[N:41]2)[CH:35]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)CN(C)c1cc(NC(=O)OC(C)(C)C)c(N)cc1C(F)(F)F
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-n2cncn2)c1
Product: CC(C)CN(C)c1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-n3cncn3)c2)cc1C(F)(F)F

Procedure:
The title compound was prepared from [2-amino-5-(isobutyl-methyl-amino)-4-trifluoromethyl-phenyl]-carbamic acid tert-butyl ester (Example J36) (361 mg, 1.0 mmol) and 3-oxo-3-(3-[1,2,4]triazol-1-yl-phenyl)-propionic acid tert-butyl ester (Example K25) (287 mg, 1.0 mmol) according to the general procedure M. Obtained as a light red foam (490 mg, 85%).
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:8]2[CH:12]=[C:11]([CH:13]3[CH2:16][O:15][CH2:14]3)[N:10](COCC[Si](C)(C)C)[N:9]=2)[C:4]([CH3:7])=[CH:5][CH:6]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[CH3:1][C:2]1[N:3]([C:8]2[CH:12]=[C:11]([CH:13]3[CH2:16][O:15][CH2:14]3)[NH:10][N:9]=2)[C:4]([CH3:7])=[CH:5][CH:6]=1
Reactant: Cc1ccc(C)n1-c1cc(C2COC2)n(COCC[Si](C)(C)C)n1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: Cc1ccc(C)n1-c1cc(C2COC2)[nH]n1
Temperature: 88 °C
Reaction time: 8 h
Yield: 53.4 %

Procedure:
Into a 250-mL round-bottom flask under nitrogen was placed 3-(2,5-dimethyl-1H-pyrrol-1-yl)-5-(oxetan-3-yl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-pyrazole (12.0 g, 34.5 mmol, 1.0 equiv.), followed by the addition of a solution of TBAF (120 g, 5.0 equiv) in THF (120 mL). The resulting solution was stirred at 88° C. for 8 h, cooled to 30° C., concentrated in vacuo and diluted with 200 mL of EtOAc. The resulting mixture was washed with 2×300 mL of water and 2×100 mL of brine, dried (Na2SO4) and concentrated in vacuo. The residue was purified by SiO2 chromatography eluting with EtOAc/PE (1:100-1:3) to afford 3-(2,5-dimethyl-1H-pyrrol-1-yl)-5-(oxetan-3-yl)-1H-pyrazole (4.0 g, 48% yield) as a white solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:8]([O:10][C:11](=[O:16])[C:12](Br)([F:14])[F:13])[CH3:9].C(OC(C)C)(=O)C>CN(C=O)C>[CH2:8]([O:10][C:11](=[O:16])[C:12]([F:14])([F:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1)[CH3:9]
Reactant: CCOC(=O)C(F)(F)Br
Reactant: Brc1ccccn1
Solvent: CC(=O)OC(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)C(F)(F)c1ccccn1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 75 %

Procedure:
2-Bromopyridine (4.5 g, 28.5 mmol) and 2-bromo-2,2-difluoroacetic acid ethyl ester (6 g, 29.6 mmol) were dissolved in DMF (25 ml) and Cu (4.5 g, 71.2 mmol) was added. The reaction mixture was heated at 50° C. for 18 h and after adding isopropyl acetate (30 ml) the reaction mixture was quenched with a solution of potassium dihydrogen phosphate (8 g) in water (50 ml). The resultant solution was stirred for 30 min, filtered and washed with isopropyl acetate. The organic layer was separated, washed with water and brine. After drying the organic layer was dried over MgSO4, it was filtered and concentrated to give 2,2-difluoro-2-pyridin-2-ylacetic acid ethyl ester (4.3 g) as a brown liquid.