Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][C@H:6]([NH:14][C:15](=[O:34])[NH:16][C@@H:17]([CH2:25][CH2:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8].[C:35]([O:39][C:40](=[O:68])[CH2:41][N:42]1[CH:46]=[CH:45][N:44]=[C:43]1[CH2:47][N:48]([CH2:57][C:58]1[CH:63]=[CH:62][C:61]([O:64][CH2:65][C:66]#[CH:67])=[CH:60][CH:59]=1)[CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][C:54](O)=[O:55])([CH3:38])([CH3:37])[CH3:36].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>ClCCCl>[C:35]([O:39][C:40](=[O:68])[CH2:41][N:42]1[CH:46]=[CH:45][N:44]=[C:43]1[CH2:47][N:48]([CH2:57][C:58]1[CH:63]=[CH:62][C:61]([O:64][CH2:65][C:66]#[CH:67])=[CH:60][CH:59]=1)[CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][C:54](=[O:55])[NH:1][CH2:2][CH2:3][CH2:4][CH2:5][C@@H:6]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[NH:14][C:15](=[O:34])[NH:16][C@H:17]([C:18]([O:20][C:21]([CH3:22])([CH3:23])[CH3:24])=[O:19])[CH2:25][CH2:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])([CH3:36])([CH3:38])[CH3:37]
Reactant: CC(C)(C)OC(=O)CC[C@H](NC(=O)N[C@@H](CCCCN)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Reactant: C#CCOc1ccc(CN(CCCCCC(=O)O)Cc2nccn2CC(=O)OC(C)(C)C)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: C#CCOc1ccc(CN(CCCCCC(=O)NCCCC[C@H](NC(=O)N[C@@H](CCC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)Cc2nccn2CC(=O)OC(C)(C)C)cc1
Yield: 57.1 %

Procedure:
A solution of (S)-di-tert-butyl 2-(3-((S)-6-amino-1-(tert-butoxy)-1-oxohexan-2-yl)ureido)pentanedioate (0.480 g, 1.0 mmol), 6-(((1-(2-(tert-butoxy)-2-oxoethyl)-1H-imidazol-2-yl)methyl)(4-(prop-2-yn-1-yloxy)benzyl)amino)hexanoic acid (0.220 g, 0.468 mmol), EDCI (0.191 g, 1.0 mmol), HOBt (0.135 g, 1.0 mmol) and DIPEA (0.40 mL) in DCE (10.0 mL) was stirred at room temperature for 3 h. The solvent was evaporated to give a residue, which was purified by Biotage eluting with DCM/MeOH to give (14S,18S)-tri-tert-butyl 1-(1-(2-(tert-butoxy)-2-oxoethyl)-1H-imidazol-2-yl)-8,16-dioxo-2-(4-(prop-2-yn-1-yloxy)benzyl)-2,9,15,17-tetraazaicosane-14,18,20-tricarboxylate (0.251 g, 57%). MS (ESI), 939.5 (M+H)+.
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:15])=[C:10](F)[C:11]=2[F:13])[C:6](=[O:16])[C:5]([C:17]([OH:19])=[O:18])=[CH:4]1)[CH3:2].[CH:20]([NH:22][CH2:23][CH2:24][CH:25]1[O:30][CH2:29][CH2:28][NH:27][CH2:26]1)=[O:21]>>[CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:15])=[C:10]([N:27]3[CH2:28][CH2:29][O:30][CH:25]([CH2:24][CH2:23][NH:22][CH:20]=[O:21])[CH2:26]3)[C:11]=2[F:13])[C:6](=[O:16])[C:5]([C:17]([OH:19])=[O:18])=[CH:4]1)[CH3:2]
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(F)c(F)c21
Reactant: O=CNCCC1CNCCO1
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCOC(CCNC=O)C3)c(F)c21

Procedure:
By the use of 1-ethyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid and 2-(2-formylaminoethyl)morpholine, the reaction is similarly carried out as Example 1 to give 1-ethyl-6,8-difluoro-7-[2-(2-formylaminoethyl)morpholino]-1,4-dihydro-4-oxoquinoline-3-carboxylic acid.
Reaction SMILES: [C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24](/[C:26](=[N:71]/[O:72][CH3:73])/[C:27]([NH:29][CH:30]2[C:69](=[O:70])[N:32]3[C:33]([C:57]([O:59][CH2:60][C:61]4[CH:66]=[CH:65][C:64]([O:67][CH3:68])=[CH:63][CH:62]=4)=[O:58])=[C:34]([CH:37]=P(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[CH2:35][S:36][C@H:31]23)=[O:28])[N:25]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Si:74]([O:81][CH2:82][CH:83]=O)([C:77]([CH3:80])([CH3:79])[CH3:78])([CH3:76])[CH3:75]>ClCCl.CCCCCC.C(OCC)(=O)C>[C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24](/[C:26](=[N:71]/[O:72][CH3:73])/[C:27]([NH:29][CH:30]2[C:69](=[O:70])[N:32]3[C:33]([C:57]([O:59][CH2:60][C:61]4[CH:66]=[CH:65][C:64]([O:67][CH3:68])=[CH:63][CH:62]=4)=[O:58])=[C:34](/[CH:37]=[CH:83]\[CH2:82][O:81][Si:74]([C:77]([CH3:78])([CH3:79])[CH3:80])([CH3:75])[CH3:76])[CH2:35][S:36][C@H:31]23)=[O:28])[N:25]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CO/N=C(\C(=O)NC1C(=O)N2C(C(=O)OCc3ccc(OC)cc3)=C(C=P(c3ccccc3)(c3ccccc3)c3ccccc3)CS[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reactant: CC(C)(C)[Si](C)(C)OCC=O
Solvent: CCCCCC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CO/N=C(\C(=O)NC1C(=O)N2C(C(=O)OCc3ccc(OC)cc3)=C(/C=C\CO[Si](C)(C)C(C)(C)C)CS[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Yield: 45.8 %

Procedure:
A solution of 4-methoxyphenylmethyl 7-[(Z)-2-(2-tritylaminothiazol-4-yl)-2-methoxyiminoacetamido]-3-(triphenylphosphoranylidene)methyl- 3-cephem-4-carboxylate (10.5 g; 10.30 mmol) and t-butyldimethylsilyloxyacetaldehyde (2.58 g; 14.83 mmol) in dichloromethane (100 ml) was stirred at room temperature for 16 hours. After the solvent was distilled off under reduced pressure, the residue was purified by chromatography on a silica gel column (n-hexane:ethyl acetate=2.5:1) whereby the title compound (4.30 g; 4.72 mmol; 45.8%) was obtained.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:24])[CH2:22]Cl)=[CH:16][CH:15]=1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O.O>[Cl:13][C:14]1[CH:15]=[CH:16][C:17]([NH:20][C:21](=[O:24])[CH2:22][N:10]2[CH2:9][CH2:8][N:7]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=3)[CH2:12][CH2:11]2)=[CH:18][CH:19]=1
Reactant: O=C(CCl)Nc1ccc(Cl)cc1
Reactant: c1ccc(N2CCNCC2)nc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(CN1CCN(c2ccccn2)CC1)Nc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 84.6 %

Procedure:
A mixture of 1-pyridin-2-ylpiperazine (24 mg, 0.15 mmol, Aldrich), N-(4-chlorophenyl)-2-chloroacetamide (41 mg, 0.20 mmol, Maybridge) and sodium carbonate (50 mg) in N,N-dimethylformamide/water (2:1, 2 mL) was shaken at room temperature for 18 hours. The resulting mixture was decanted, concentrated under reduced pressure and the residue purified by preparative HPLC to provide 42 mg (85%) of the desired product. 1H NMR (500 MHz, DMSO-d6) δ b2.60 (t, J=4 Hz, 4H), 3.21 (s, 2H), 3.58 (t, J=4 Hz, 4H), 6.63 (t, J=5 Hz, 1H), 6.83 (d, J=6 Hz, 1H), 7.38 (d, J=6 Hz, 2H), 7.54 (t, J=6 Hz, 1H), 7.70 (d, J=6 Hz, 2H), 8.12 (d, J=5 Hz, 1H), 9.90 (s, 1H); MS (ESI/APCI+) m/e 331 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[N:9]=[CH:8][N:7]([CH2:11][C:12](=[O:14])[CH3:13])[C:6]=2[C:5](=[O:15])[NH:4][C:3]1=[O:16].Cl[CH2:18][CH2:19][CH2:20][CH2:21][C:22]([OH:25])([CH3:24])[CH3:23].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[OH:25][C:22]([CH3:24])([CH3:23])[CH2:21][CH2:20][CH2:19][CH2:18][N:4]1[C:5](=[O:15])[C:6]2[N:7]([CH2:11][C:12](=[O:14])[CH3:13])[CH:8]=[N:9][C:10]=2[N:2]([CH3:1])[C:3]1=[O:16]
Reactant: CC(=O)Cn1cnc2c1c(=O)[nH]c(=O)n2C
Reactant: CC(C)(O)CCCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)Cn1cnc2c1c(=O)n(CCCCC(C)(C)O)c(=O)n2C

Procedure:
22.2 g (0.1 mol) of the xanthine from stage (a) are reacted with 16.6 g (0.11 mol) of 1-chloro-5-hydroxy-5-methylhexane (Example 1a) and 15.2 g (0.11 mol) of potassium carbonate in 500 ml of dimethylformamide and the mixture is worked up, under the experimental conditions described in Example 2. The reaction product is purified by column chromatography and finally recrystallized from diisopropyl ether, with the addition of ethyl acetate, at the boiling point.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([Cl:14])=[CH:9][C:8]=2[Cl:15])[N:5]=[C:4]([CH:16]([CH3:18])[CH3:17])[C:3]=1[C:19]([NH2:21])=[O:20].[NH2:22][C:23]1[C:31]2[C:26](=[CH:27][CH:28]=[C:29]([CH2:32][C:33](OCC)=O)[CH:30]=2)[NH:25][N:24]=1.[O-]CC.[Na+]>C(O)C>[Cl:13][C:12]1[CH:11]=[C:10]([Cl:14])[CH:9]=[C:8]([Cl:15])[C:7]=1[N:6]1[C:2]2=[N:1][C:33]([CH2:32][C:29]3[CH:30]=[C:31]4[C:26](=[CH:27][CH:28]=3)[NH:25][N:24]=[C:23]4[NH2:22])=[N:21][C:19](=[O:20])[C:3]2=[C:4]([CH:16]([CH3:18])[CH3:17])[NH:5]1
Reactant: CC(C)c1nn(-c2c(Cl)cc(Cl)cc2Cl)c(N)c1C(N)=O
Reactant: CCOC(=O)Cc1ccc2[nH]nc(N)c2c1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CC(C)c1[nH]n(-c2c(Cl)cc(Cl)cc2Cl)c2nc(Cc3ccc4[nH]nc(N)c4c3)nc(=O)c1-2
Reaction time: 16 h

Procedure:
To a stirred solution of 139 mg (0.40 mmol) of 5-amino-3-isopropyl-1-(2,4,6-trichlorophenyl)pyrazole-4-carboxamide in 3 mL of absolute ethanol was added 329 mg (1.50 mmol) of ethyl 3-aminoindazol-5-ylacetate followed by 1.13 mL (3.0 mmol) of 2.66 M sodium ethoxide in ethanol. The solution was stirred 16 h at reflux, and the heating mantle was then removed. The reaction was treated with 8 mL of 10% aq. HOAc, poured into water, and extracted with EtOAc. The organic extract was washed with brine, dried (MgSO4), concentrated under reduced pressure, and chromatographed on silica gel (gradient elution with 5% to 10% MeOH—CH2Cl2) to give, after removal of solvent, 123 mg (61%) of 1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(3-aminoindazol-5-ylmethyl)pyrazolo[3,4-d]pyrimidin-4-one as a white, amorphous solid. Mass spec.: 502.0712 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[C:11]([C:13]([O:15]CC)=[O:14])[C:10]([C:18]([F:21])([F:20])[F:19])=[N:9]2)=[CH:4][CH:3]=1.[OH-].[Na+]>C(O)C.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[C:11]([C:13]([OH:15])=[O:14])[C:10]([C:18]([F:20])([F:19])[F:21])=[N:9]2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cn(-c2ccc(F)cc2)nc1C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)c1cn(-c2ccc(F)cc2)nc1C(F)(F)F
Reaction time: 8 h
Yield: 73.2 %

Procedure:
To a solution of ethyl 1-(4-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-4-carboxylate (140 mg, 0.463 mmol) in ethanol (4 mL) was added a solution of NaOH (4 mL, 4.00 mmol) in water (2 mL). The reaction mixture was stirred overnight. The next day, LCMS showed complete reaction so the reaction was concentrated in vacuo and then extracted using dilute HCl and EtOAc. Obtained 1-(4-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid (93 mg, 0.339 mmol, 73.2% yield) as a white powder. MS (M+1)=275; HPLC RT=0.82 minutes.
Reaction SMILES: COC[O:4][C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[C:7](B(O)O)[CH:6]=1.I[C:16]1[CH:26]=[CH:25][C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+]>C(O)C.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:4][C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[C:7]([C:16]2[CH:26]=[CH:25][C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:18][CH:17]=2)[CH:6]=1
Reactant: COCOc1ccc(C)c(B(O)O)c1
Reactant: CCOC(=O)c1ccc(I)cc1
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: [K+]
Solvent: CCO
Product: CCOC(=O)c1ccc(-c2cc(O)ccc2C)cc1

Procedure:
In a manner similar to that of Example 11(d), by reaction of 3.7 g (18.8 mmol) of 4-methoxymethoxy-1-methylbenzene-2-boronic acid described in Example 16(c) with 4.7 g (17 mmol) of ethyl 4-iodobenzoate, 17 mL of 2.0M potassium carbonate solution and 1 g (0.8 mmol) of tetrakis(triphenylphosphine)palladium, followed by deprotection in ethanol, the desired product is obtained in the form of a colourless oil (m=3.07 g; Y=71%).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[Br:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[NH:12][C:13](=[O:22])[CH:14]=[CH:15]C1C=CC=CC=1>ClC1C=CC=CC=1>[Br:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:7]=1[NH:12][C:13](=[O:22])[CH:14]=[CH:15]2
Reactant: O=C(C=Cc1ccccc1)Nc1ccccc1Br
Agent: [Al+3]
Agent: [Cl-]
Solvent: Clc1ccccc1
Product: O=c1ccc2cccc(Br)c2[nH]1
Temperature: 125 °C
Yield: 67.2 %

Procedure:
Aluminum chloride (2.6 g, 19.92 mmol) was added to a solution of N-(2-bromophenyl)cinnamamide (1.0 g, 3.32 mmol) in chlorobenzene, and the resulting mixture was heated at 125° C. for 2 h. The reaction mixture was then cooled to 50° C. and treated with ice-cold water (25 mL) to provide a brown precipitate. The precipitate was collected by vacuum filtration and dried in vacuo, then triturated with EtOH to provide 8-bromoquinolin-2(1H)-one (0.5 g, 67% yield) as an off-white solid. m/z (ESI, +ve) 226.2 (M+H)+
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([NH:9][C:10]([C:12]2[O:13][CH:14]=[CH:15][C:16]=2[CH3:17])=[O:11])[CH:6]=[CH:7][CH:8]=1)#[CH:2].Br[C:19]1[CH:20]=[N:21][CH:22]=[C:23]([CH:27]=1)[C:24]([OH:26])=[O:25]>>[CH3:17][C:16]1[CH:15]=[CH:14][O:13][C:12]=1[C:10]([NH:9][C:5]1[CH:4]=[C:3]([C:1]#[C:2][C:19]2[CH:20]=[N:21][CH:22]=[C:23]([CH:27]=2)[C:24]([OH:26])=[O:25])[CH:8]=[CH:7][CH:6]=1)=[O:11]
Reactant: O=C(O)c1cncc(Br)c1
Reactant: C#Cc1cccc(NC(=O)c2occc2C)c1
Product: Cc1ccoc1C(=O)Nc1cccc(C#Cc2cncc(C(=O)O)c2)c1

Procedure:
In a manner similar to that described for Example 480 (step 1), 3-methyl-furan-2-carboxylic acid (3-ethynyl-phenyl)-amide and 5-bromo nicotinic acid were reacted to provide the title compound.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([OH:19])=O)=[CH:13][CH:12]=2)=[C:7]([CH3:20])[CH:6]=1)(=[O:3])[CH3:2].[CH3:21][N:22]1[CH2:27][CH2:26][C:25]2([C:38]3[C:30](=[CH:31][C:32]4[CH2:33][CH2:34][NH:35][C:36]=4[CH:37]=3)[O:29][CH2:28]2)[CH2:24][CH2:23]1.C(Cl)(=O)C(Cl)=O>>[C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]=[CH:13][C:14]([C:17]([N:35]3[C:36]4[CH:37]=[C:38]5[C:25]6([CH2:28][O:29][C:30]5=[CH:31][C:32]=4[CH2:33][CH2:34]3)[CH2:26][CH2:27][N:22]([CH3:21])[CH2:23][CH2:24]6)=[O:19])=[CH:15][CH:16]=2)=[C:7]([CH3:20])[CH:6]=1)(=[O:3])[CH3:2]
Reactant: CN1CCC2(CC1)COc1cc3c(cc12)NCC3
Reactant: CC(=O)Nc1ccc(-c2ccc(C(=O)O)cc2)c(C)c1
Agent: O=C(Cl)C(=O)Cl
Product: CC(=O)Nc1ccc(-c2ccc(C(=O)N3CCc4cc5c(cc43)C3(CCN(C)CC3)CO5)cc2)c(C)c1

Procedure:
The title compound was prepared from 4'-acetamido-2'-methylbiphenyl-4-carboxylic acid (D47) and 1'-methyl-2,3,6,7-tetrahydrospiro[furo[2,3-f]indole-3,4'-piperidine] (D8) following a similar procedure to Example 1 using oxalyl chloride in place of thionyl chloride, as a yellow oil (43%). This was converted to its oxalate salt which crystallised as a white solid from acetone.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([N+:16]([O-])=O)[C:11]=1[O:19][CH2:20][CH3:21])=[O:7])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+].Cl.C(=O)([O-])O.[Na+]>O.O.O.O.O.O.[Ni](Cl)Cl.CO>[C:25]([O:24][C:22]([N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:7])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([NH2:16])[C:11]=1[O:19][CH2:20][CH3:21])=[O:23])([CH3:28])([CH3:26])[CH3:27]
Reactant: CCOc1c(CN(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)cccc1[N+](=O)[O-]
Agent: Cl[Ni]Cl
Agent: Cl
Agent: O=C([O-])O
Solvent: O
Solvent: CO
Product: CCOc1c(N)cccc1CN(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 85 %

Procedure:
To a mixture of the compound (5.09 g) obtained in Example 417d, nickel (II) chloride hexahydrate (61 mg) and methanol (130 ml), sodium borohydride (1.46 g) was added. The reaction mixture was stirred at room temperature for 20 min and, after addition of 2 N HCl, adjusted to pH 8 with a saturated aqueous sodium hydrogencarbonate solution and then concentrated under reduced pressure. To the resulting residue, water was added and the mixture was subjected to extraction with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried with anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent, ethyl acetate:n-hexane=1:4) to give the titled compound (yield, 85%).
Reaction SMILES: Br[C:2]1[C:3]([F:10])=[C:4]([NH2:9])[CH:5]=[CH:6][C:7]=1[F:8].[F:11][C:12]1[CH:13]=[CH:14][C:15](B2OC(C)(C)C(C)(C)O2)=[C:16]([CH:19]=1)[C:17]#[N:18].[F-].[K+].C(P(C(C)(C)C)C(C)(C)C)(C)(C)C>O1CCCC1.O.O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[NH2:9][C:4]1[C:3]([F:10])=[C:2]([C:15]2[C:16]([C:17]#[N:18])=[CH:19][C:12]([F:11])=[CH:13][CH:14]=2)[C:7]([F:8])=[CH:6][CH:5]=1
Reactant: CC1(C)OB(c2ccc(F)cc2C#N)OC1(C)C
Reactant: Nc1ccc(F)c(Br)c1F
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: O
Solvent: C1CCOC1
Product: N#Cc1cc(F)ccc1-c1c(F)ccc(N)c1F
Temperature: 50 °C
Reaction time: 0.17 h
Yield: 106.4 %

Procedure:
A solution of 3-bromo-2,4-difluorophenylamine (5.2 g, 25 mmol) and 5-fluoro-2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)benzonitrile (7.10 g, 28.8 mmol) in tetrahydrofuran (95 ml) and water (5 ml) was treated with potassium fluoride (4.8 g, 82.5 mmol) and this mixture was degassed with nitrogen for 10 min before adding tris(dibenzylideneacetone)dipalladium(0) (460 mg, 0.5 mmol) and tri-tert-butylphosphine (2.5 ml of a 0.2M solution in 1,4-dioxane, 0.5 mmol). The reaction was then heated at 50° C. for 2 h then cooled to ambient temperature. The mixture was poured into ice-cold 0.5N sodium hydroxide (750 ml), stirred for 10 min and the solid collected by filtration. This was triturated with water and dried to afford 3′-amino-4,2′,6′-trifluorobiphenyl-2-carbonitrile as a grey powder (6.6 g). Used without further purification: δH (360 MHz, CDCl3) 3.74 (2H, br), 6.79-6.89 (2H, m), 7.36-7.42 (1H, m), 7.45-7.51 (2H, m).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[C:4]=1[CH2:5][C:6]1[CH:16]=[CH:15][CH:14]=[C:8]2[C:9]([NH:11][C:12](=[O:13])[C:7]=12)=[O:10].[Br:22]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl.C(OCC)C>[Br:22][CH2:21][C:17]1[C:4]([CH2:5][C:6]2[CH:16]=[CH:15][CH:14]=[C:8]3[C:9]([NH:11][C:12](=[O:13])[C:7]=23)=[O:10])=[C:3]([O:2][CH3:1])[CH:20]=[CH:19][CH:18]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1cccc(C)c1Cc1cccc2c1C(=O)NC2=O
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: CCOCC
Solvent: ClC(Cl)(Cl)Cl
Product: COc1cccc(CBr)c1Cc1cccc2c1C(=O)NC2=O
Temperature: 25 °C
Yield: 86.9 %

Procedure:
To a solution of (2-methoxy-6-methylbenzyl)phthalimide (0.286 g, 1.02 mmol) in CCl4 (25 mL) was added recrystallized N-bromosuccinimide (0.177 g, 0.99 mmol) followed by benzoyl peroxide (28 mg, 0.11 mmol). The resultant mixture was heated to reflux for 90 minutes then cooled to room temperature. The mixture was diluted with diethyl ether (25 mL), filtered through filter paper, and the filtrate was concentrated. Purification of the crude material by column chromatography (3:1 hexanes-EtOAc) provided 0.31 g (86%) of (6-(bromomethyl)-2-methoxybenzyl)phthalimide as a white solid. 1H NMR (CDCl3) δ3.78 (s, 3H), 4.90 (s, 2H), 5.00 (s, 2H), 6.83 (d, 1H, J=8.4 Hz), 6.98 (d, 1H, J=7.2 Hz), 7.25 (dd, 1H, J=7.2, 8.4 Hz), 7.67-7.69 (m, 2H), 7.78-7.81 (m, 2H). ES-MS m/z 382 (M+Na), 384 (M+Na).
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([N:8]([CH2:17][CH2:18][CH2:19][C:20](O)=[O:21])[C:9]2[C:14]([CH3:15])=[CH:13][CH:12]=[CH:11][C:10]=2[CH3:16])=[O:7])=[CH:4][CH:3]=1.[NH2:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28]>>[Cl:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([N:8]([CH2:17][CH2:18][CH2:19][C:20]([NH:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])=[O:21])[C:9]2[C:10]([CH3:16])=[CH:11][CH:12]=[CH:13][C:14]=2[CH3:15])=[O:7])=[CH:4][CH:3]=1
Reactant: CCOC(=O)CN
Reactant: Cc1cccc(C)c1N(CCCC(=O)O)C(=O)c1ccc(Cl)cc1
Product: CCOC(=O)CNC(=O)CCCN(C(=O)c1ccc(Cl)cc1)c1c(C)cccc1C

Procedure:
Analogously to Example 1, by using equivalent quantities, reacting N-(p-chlorobenzoyl)-4-(2,6-dimethylanilino)butyric acid and ethyl glycinate and suitable processing produces ethyl N-[N-(p-chlorobenzoyl)-4-(2,6-dimethylanilino)butyryl]glycinate (oil), saponification of which and processing of the reaction product yields N-[N-(p-chlorobenzoyl)-4-(2,6-dimethylanilino)butyryl]glycine (M.P. 141° to 142°).
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[C:12]2[C:7](=[N:8][CH:9]=[C:10]([Cl:13])[CH:11]=2)[NH:6][CH:5]=1.[S:14](Cl)([C:17]1[CH:23]=[CH:22][C:20]([CH3:21])=[CH:19][CH:18]=1)(=[O:16])=[O:15].O>CN(C)C=O>[Br:3][C:4]1[C:12]2[C:7](=[N:8][CH:9]=[C:10]([Cl:13])[CH:11]=2)[N:6]([S:14]([C:17]2[CH:23]=[CH:22][C:20]([CH3:21])=[CH:19][CH:18]=2)(=[O:16])=[O:15])[CH:5]=1
Reactant: Clc1cnc2[nH]cc(Br)c2c1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)n2cc(Br)c3cc(Cl)cnc32)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 85.3 %

Procedure:
Sodium hydride (2.2 g, 54 mmol) was added portionwise to an ice-cold solution of 3-bromo-5-chloro-1H-pyrrolo[2,3-b]pyridine (4) (10.5 g, 45 mmol) in dimethylformamide (70 ml) under nitrogen. Thirty minutes later, tosyl chloride (8.7 g, 46 mmol) was added to the reaction mixture and the reaction mixture was stirred at room temperature for 18 h. The reaction mixture was hydrolysed with water (˜150 ml) and a brown solid was obtained by filtration and dried in vacuo to afford the title compound (14.8 g, 85%). 1H NMR (CDCl3) 2.4 (3H, s), 7.3-7.4 (2H, d), 7.8-7.9 (2H. 2 s), 8.1-8.2 (2H, d), 8.4 (1H, s); MS (ES+) 387
Reaction SMILES: [O:1]=[C:2]1[C:6]2[CH:7]=[CH:8][C:9]([CH2:11][CH2:12][N:13]([CH2:21][CH:22]=O)[C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[CH:10][C:5]=2[CH2:4][O:3]1.Cl.[NH2:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28].C([BH3-])#N.[Na+].C(O)(=O)C>CO>[CH2:30]([O:29][C:27](=[O:28])[CH2:26][NH:25][CH2:22][CH2:21][N:13]([C:14]([O:15][C:16]([CH3:17])([CH3:19])[CH3:18])=[O:20])[CH2:12][CH2:11][C:9]1[CH:8]=[CH:7][C:6]2[C:2](=[O:1])[O:3][CH2:4][C:5]=2[CH:10]=1)[CH3:31]
Reactant: CCOC(=O)CN
Reactant: CC(C)(C)OC(=O)N(CC=O)CCc1ccc2c(c1)COC2=O
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CCOC(=O)CNCCN(CCc1ccc2c(c1)COC2=O)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of tert-Butyl [2-(1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl](2-oxoethyl)carbamate (580 mg, 1.8 mmol) in MeOH (50 mL) was added ethyl aminoacetate hydrochloride (380 mg, 2.7 mmol), sodium cyanoborohydride (340 mg, 5.4 mmol) and a drop of acetic acid. The reaction was allowed to stir at RT for 16 hours. LC showed the desired product, which was purified by silica gel chromatography. LC-MS (IE, m/z): 407 [M+1]+.
Reaction SMILES: [CH2:1]([CH:8]1[C:31](=O)[N:30]([CH3:33])[CH:29]([CH2:34][CH:35]([CH3:37])[CH3:36])[C:28](=[O:38])[O:27][CH:26]([CH3:39])[C:25](=O)[N:24]([CH3:41])[CH:23]([CH2:42][CH:43]([CH3:45])[CH3:44])[C:22](=[O:46])[O:21][CH:20]([CH2:47][C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[C:19](=O)[N:18]([CH3:55])[CH:17]([CH2:56][CH:57]([CH3:59])[CH3:58])[C:16](=[O:60])[O:15][CH:14]([CH3:61])[C:13](=O)[N:12]([CH3:63])[CH:11]([CH2:64][CH:65]([CH3:67])[CH3:66])[C:10](=[O:68])[O:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B>C1COCC1>[CH2:47]([CH:20]1[CH2:19][N:18]([CH3:55])[CH:17]([CH2:56][CH:57]([CH3:59])[CH3:58])[C:16](=[O:60])[O:15][CH:14]([CH3:61])[CH2:13][N:12]([CH3:63])[CH:11]([CH2:64][CH:65]([CH3:67])[CH3:66])[C:10](=[O:68])[O:9][CH:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:31][N:30]([CH3:33])[CH:29]([CH2:34][CH:35]([CH3:37])[CH3:36])[C:28](=[O:38])[O:27][CH:26]([CH3:39])[CH2:25][N:24]([CH3:41])[CH:23]([CH2:42][CH:43]([CH3:45])[CH3:44])[C:22](=[O:46])[O:21]1)[C:48]1[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=1
Reactant: CC(C)CC1C(=O)OC(Cc2ccccc2)C(=O)N(C)C(CC(C)C)C(=O)OC(C)C(=O)N(C)C(CC(C)C)C(=O)OC(Cc2ccccc2)C(=O)N(C)C(CC(C)C)C(=O)OC(C)C(=O)N1C
Agent: B
Solvent: C1CCOC1
Product: CC(C)CC1C(=O)OC(C)CN(C)C(CC(C)C)C(=O)OC(Cc2ccccc2)CN(C)C(CC(C)C)C(=O)OC(C)CN(C)C(CC(C)C)C(=O)OC(Cc2ccccc2)CN1C

Procedure:
Similar to Example 1, 4.75 g (5 mmol) of PF 1022 in 10 ml of THF were reacted with 100 ml of a 1 M solution of borane and worked-up. Chromatography gave 0.75 g (17% of theory) of tetrareduction product 8,20-dibenzyl-5,11,17,23-tetraisobutyl-2,4,10,14,16,22-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-6,12,18,24-tetraone as a light-yellow viscous oil.