Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH2:5])[CH2:2][CH2:3][CH3:4].Br[CH2:7][C:8]([O:10][CH2:11][CH:12]([CH3:14])[CH3:13])=[O:9]>C(#N)C>[CH2:1]([NH:5][CH2:7][C:8]([O:10][CH2:11][CH:12]([CH3:14])[CH3:13])=[O:9])[CH2:2][CH2:3][CH3:4]
Reactant: CC(C)COC(=O)CBr
Reactant: CCCCN
Solvent: CC#N
Product: CCCCNCC(=O)OCC(C)C
Temperature: 20 °C
Reaction time: 2 h
Yield: 70.7 %

Procedure:
20 g (0.27 mol) of n-butylamine are dissolved in 100 ml of acetonitrile, and 7.8 g (0.04 mol) of 2-methylpropyl bromoacetate are added at 20° C. The mixture is stirred for 2 hours at 20° C. and subjected to rotary evaporation, the residue is taken up in methylene chloride/water, the organic phase is dried and subjected to rotary evaporation, and the residue is filtered over silica gel (eluent hexane:acetone=7:3). 5.3 g (71% of theory) of 2-methyl-propyl N-butylaminoacetate are obtained.
Reaction SMILES: C(O)(C(F)(F)F)=O.[C:8]([NH:16][C@@H:17]1[C:23](=[O:24])[N:22]2[C@H:25]([C:29]([O:31]C(C)(C)C)=[O:30])[CH2:26][CH2:27][CH2:28][N:21]2[C:20](=[O:36])[CH2:19][CH2:18]1)(=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C(Cl)Cl>[C:8]([NH:16][C@@H:17]1[C:23](=[O:24])[N:22]2[C@H:25]([C:29]([OH:31])=[O:30])[CH2:26][CH2:27][CH2:28][N:21]2[C:20](=[O:36])[CH2:19][CH2:18]1)(=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CC(C)(C)OC(=O)[C@@H]1CCCN2C(=O)CC[C@H](NC(=O)c3ccccc3)C(=O)N12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(N[C@H]1CCC(=O)N2CCC[C@@H](C(=O)O)N2C1=O)c1ccccc1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 85.4 %

Procedure:
TFA (20 ml) was added to an ice cold stirred solution of the t-butyl ester 211e (4.15 g, 10.34 mmol) in dry CH2Cl2 (20 ml). The mixture was kept cold for 1.5 h then left for 2.5 h at rt, concentrated. TFA was removed by repeated concentrations of CH2Cl2\ether and ether solutions of the residue. Finally trituration of the residue with ether afforded 212e 3.05 g (85%) of a white glassy solid: mp 118-126° C.; [α]D24 −70.5° (c 0.1, CH2Cl2). IR (KBr) 3361, 2943, 1737, 1659, 1537, 1426, 1220, 1174; 1H NMR (CDCl3) δ 7.80 (2H, m), 7.54-7.33 (4H, m), 8.83 (brs), 5.44 (1H, m), 5.26-5.13 (1H, m), 4.66 (1H, m), 3.59-3.41 (1H, m), 2.97, 2.76 (2H, 2m), 2.36 (2H, m), 1.98 (2H, m), 1.75 (2H, m). MS(ES−, m/z) 344 (M−1, 100%).
Reaction SMILES: [CH:1]([O:4][C:5](=[O:29])[NH:6][C@@H:7]1[CH2:28][C:10]2[N:11]([CH2:20][C:21]3[C:22]([NH2:27])=[N:23][CH:24]=[CH:25][CH:26]=3)[C:12]3[CH:13]=[CH:14][C:15]([C:18]#[N:19])=[CH:16][C:17]=3[C:9]=2[CH2:8]1)([CH3:3])[CH3:2].O.[C:31]([OH:35])(=[O:34])[CH:32]=O>CCO>[C:18]([C:15]1[CH:14]=[CH:13][C:12]2[N:11]([CH2:20][C:21]3[C:22]([NH:27][CH2:32][C:31]([OH:35])=[O:34])=[N:23][CH:24]=[CH:25][CH:26]=3)[C:10]3[CH2:28][C@@H:7]([NH:6][C:5]([O:4][CH:1]([CH3:3])[CH3:2])=[O:29])[CH2:8][C:9]=3[C:17]=2[CH:16]=1)#[N:19]
Reactant: CC(C)OC(=O)N[C@H]1Cc2c(n(Cc3cccnc3N)c3ccc(C#N)cc23)C1
Reactant: O=CC(=O)O
Solvent: CCO
Solvent: O
Product: CC(C)OC(=O)N[C@H]1Cc2c(n(Cc3cccnc3NCC(=O)O)c3ccc(C#N)cc23)C1
Temperature: 75 °C
Reaction time: 18 h
Yield: 65.3 %

Procedure:
Dissolve [(S)-4-(2-amino-pyridin-3-ylmethyl)-7-cyano-1,2,3,4-tetrahydro-cyclopenta[b]indol-2-yl]-carbamic acid isopropyl ester (253 mg, 0.650 mmol) in EtOH (25 mL). Add 3 Å molecular sieves and glyoxylic acid monohydrate (239 mg, 2.60 mmol), then stir at 40-110° C. for 18 h under hydrogen (60 psi, 4.08 bar). Filter the reaction through a pad of diatomaceous earth and wash the catalyst/sieves with THF (50 mL). Combine the filtrate and concentrate in vacuo to a yellow oil. Triturate with water (30 mL) and sonicate the resulting aqueous slurry for 5 min. Filter off a tan solid and dry in vacuo. Triturate the solid with Et2O (5 mL) and sonicate the slurry for 30 min. Filter to obtain 190 mg (65%) of the product as a tan solid. LCMS 100% @ 3.99 min m/z 448 (M+H), 446 (M−H).
Reaction SMILES: [CH:1]1[C:6]([CH2:7][N:8]2[CH2:9][CH2:10][NH:11]/[C:12]/2=[N:13]\[N+:14]([O-:16])=[O:15])=[CH:5][N:4]=[C:3]([Cl:17])[CH:2]=1.Br[CH2:19][CH:20]=[CH:21][CH2:22]Br.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Cl:17][C:3]1[CH:2]=[CH:1][C:6]([CH2:7][N:8]2[CH2:9][CH2:10][N:11]([CH2:19][CH:20]=[CH:21][CH2:22][N:11]3[CH2:10][CH2:9][N:8]([CH2:7][C:6]4[CH:1]=[CH:2][C:3]([Cl:17])=[N:4][CH:5]=4)[C:12]3=[N:13][N+:14]([O-:16])=[O:15])[C:12]2=[N:13][N+:14]([O-:16])=[O:15])=[CH:5][N:4]=1
Reactant: BrCC=CCBr
Reactant: O=[N+]([O-])/N=C1\NCCN1Cc1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=[N+]([O-])N=C1N(CC=CCN2CCN(Cc3ccc(Cl)nc3)C2=N[N+](=O)[O-])CCN1Cc1ccc(Cl)nc1

Procedure:
Imidacloprid (3.37 g, 12 mmol), 1,4-dibromo-2-butene (1.60 g, 6 mmol), and potassium carbonate (1.83 g, 12 mmol) were mixed in 30 ml of acetonitrile, and the mixture was refluxed for 19 hours. After distilling off the solvent under reduced pressure, the residue was extracted with chloroform, and the chloroform layer was dried over magnesium sulfate. After distilling off the solvent, the residue was then subjected to silica gel column chromatography with a mixed solvent of ethyl acetate and ethanol (15:1 (v/v)) as the eluate. The crude product was purified by recrystallizing from ethanol. The yield of crystalline product was 0.22 g (7%), and the melting point was 199 to 202° C. The results of elementary analysis and NMR analysis are shown below.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:13]([C:14]3[CH:19]=[CH:18][N:17]=[C:16]([Cl:20])[CH:15]=3)[N:12]=[C:11]([C:21](O)=[O:22])[CH:10]=2)[CH:5]=[C:6]([F:8])[CH:7]=1.ClC1C=C(C2N(C3C=NC=CC=3)N=C(C([N:45]3[CH2:50][CH2:49][NH:48][C:47](=[O:51])[CH2:46]3)=O)C=2)C=C(F)C=1.O=C1CNCCN1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:13]([C:14]3[CH:19]=[CH:18][N:17]=[C:16]([Cl:20])[CH:15]=3)[N:12]=[C:11]([C:21]([N:45]3[CH2:50][CH2:49][NH:48][C:47](=[O:51])[CH2:46]3)=[O:22])[CH:10]=2)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: O=C1CN(C(=O)c2cc(-c3cc(F)cc(Cl)c3)n(-c3cccnc3)n2)CCN1
Reactant: O=C(O)c1cc(-c2cc(F)cc(Cl)c2)n(-c2ccnc(Cl)c2)n1
Agent: O=C1CNCCN1
Product: O=C1CN(C(=O)c2cc(-c3cc(F)cc(Cl)c3)n(-c3ccnc(Cl)c3)n2)CCN1

Procedure:
30 mg (0.09 mmol) of the compound of Example 28A is reacted analogously to the synthesis of the compound of Example 4 with 9 mg (0.09 mmol) of 2-oxopiperazine. 32 mg (87% of theory) of the title compound is obtained.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10](=[O:17])[NH:9][N:8]=2)[CH2:3][CH2:2]1.CC([O-])(C)C.[K+].C1(P(O[NH2:39])(C2C=CC=CC=2)=O)C=CC=CC=1>C1COCC1.CCOC(C)=O>[NH2:39][N:9]1[N:8]=[C:7]([N:4]2[CH2:5][CH2:6][O:1][CH2:2][CH2:3]2)[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]1=[O:17]
Reactant: O=c1[nH]nc(N2CCOCC2)c2ccccc12
Reactant: NOP(=O)(c1ccccc1)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Nn1nc(N2CCOCC2)c2ccccc2c1=O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 39.5 %

Procedure:
To a mixture of the product from Example 1A (0.300 g, 1.30 mmol) in THF (3.5 mL) was added a 1 M solution of potassium 2-methylpropan-2-olate in THF (1.7 mL, 1.7 mmol). The mix was stirred at room temperature for 90 minutes, and O-(diphenylphosphoryl)hydroxylamine (0.395 g, 1.70 mmol) was added and stirred overnight. The mixture was diluted with EtOAc, washed with 0.5N NaOH and water, concentrated, and chromatographed (40% EtOAc/DCM) to give 126.4 mg of product as a white solid: 1H NMR (300 MHz, DMSO-d6) δ 8.31-8.25 (m, 1H), 8.03-7.98 (m, 1H), 7.94-7.80 (m, 2H), 6.20 (s, 2H), 3.87-3.78 (m, 4H), 3.15-3.07 (m, 4H).
Reaction SMILES: [Cl:1][C:2]1[C:10]([O:11][CH2:12][CH2:13][CH2:14]Cl)=[CH:9][C:8]([C:16]2[N:17]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[C:18]3[C:23]([CH:24]=2)=[CH:22][C:21]([CH2:25][N:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)=[CH:20][CH:19]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:39].[NH:40]1[CH2:45][CH2:44][CH:43]([CH2:46][OH:47])[CH2:42][CH2:41]1.O>CN(C)C(=O)C>[Cl:1][C:2]1[C:10]([O:11][CH2:12][CH2:13][CH2:14][N:40]2[CH2:45][CH2:44][CH:43]([CH2:46][OH:47])[CH2:42][CH2:41]2)=[CH:9][C:8]([C:16]2[N:17]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[C:18]3[C:23]([CH:24]=2)=[CH:22][C:21]([CH2:25][N:26]2[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]2)=[CH:20][CH:19]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:39]
Reactant: CC(C)(C)OC(=O)n1c(-c2cc(OCCCCl)c(Cl)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Reactant: OCC1CCNCC1
Solvent: CC(=O)N(C)C
Solvent: O
Product: CC(C)(C)OC(=O)n1c(-c2cc(OCCCN3CCC(CO)CC3)c(Cl)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Yield: 78.8 %

Procedure:
In a similar manner to Step 2 of Example 440, 4-chloro-5-(3-chloropropoxy)-7-[1-(tert-butoxycarbonyl)-5-(piperidin-1-ylmethyl)indol-2-yl]isoindolinone (97.6 mg, 0.170 mmol) was dissolved in N,N-dimethylacetoamide (1.0 mL), and the solution was treated with 4-piperidine methanol (0.196 mL, 1.70 mmol). The reaction mixture was added with water. The obtained solid was collected by filtration and washed with water, followed by drying under reduced pressure to obtain 4-chloro-5-[3-(4-hydroxymethylpiperidin-1-yl)propoxy]-7-[1-(tert-butoxycarbonyl)-5-(piperidin-1-ylmethyl)indol-2-yl]isoindolinone (87.2 mg, yield 79%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[N:10]=[N:11][C:12](Cl)=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][CH:25]([NH:27][C:28](=[O:30])[CH3:29])[CH3:26])=[CH:19][CH:18]=1>>[CH2:1]([O:8][C:9]1[N:10]=[N:11][C:12]([O:16][C:17]2[CH:18]=[CH:19][C:20]([CH2:23][CH2:24][CH:25]([NH:27][C:28](=[O:30])[CH3:29])[CH3:26])=[CH:21][CH:22]=2)=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)NC(C)CCc1ccc(O)cc1
Reactant: Clc1ccc(OCc2ccccc2)nn1
Product: CC(=O)NC(C)CCc1ccc(Oc2ccc(OCc3ccccc3)nn2)cc1

Procedure:
3-Benzyloxy-6-chloropyridazine (411 mg, 1.86 mmol) was reacted with N-[3-(4-hydroxyphenyl)-1-methylpropyl]acetamide in analogy to example 1b.
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH2:4][N:3]1[CH2:13][C:14]([O:16]C)=O.[CH:18]([N:21]([CH:26]([CH3:28])[CH3:27])[CH2:22][CH2:23][CH2:24][NH2:25])([CH3:20])[CH3:19]>>[CH3:20][CH:18]([N:21]([CH:26]([CH3:28])[CH3:27])[CH2:22][CH2:23][CH2:24][NH:25][C:14](=[O:16])[CH2:13][N:3]1[CH2:4][CH:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:6][C:2]1=[O:1])[CH3:19]
Reactant: COC(=O)CN1CC(c2ccccc2)CC1=O
Reactant: CC(C)N(CCCN)C(C)C
Product: CC(C)N(CCCNC(=O)CN1CC(c2ccccc2)CC1=O)C(C)C

Procedure:
From 6.2 g. of methyl 2-oxo-4-phenylpyrrolidineacetate and 8.0 g. of 3-(diisopropylamino)propylamine [J.A.C.S. 65, 2012 (1943)], following the procedure of Example 1, there is obtained N-[3-[bis(1-methylethyl)amino]propyl]-2-oxo-4-phenyl-1-pyrrolidineacetamide in pure form as an oil, without need for distillation.
Reaction SMILES: [C:1]([OH:13])(=O)/[CH:2]=[CH:3]/[C:4]1[CH:11]=[CH:10][C:8]([OH:9])=[C:6]([OH:7])[CH:5]=1.C(N(CC)CC)C.[NH2:21][CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=1>CN(C=O)C.ClCCl>[CH:25]1[C:24]([CH2:23][CH2:22][NH:21][C:1](/[CH:2]=[CH:3]/[C:4]2[CH:11]=[CH:10][C:8]([OH:9])=[C:6]([OH:7])[CH:5]=2)=[O:13])=[CH:29][CH:28]=[C:27]([OH:30])[CH:26]=1
Reactant: NCCc1ccc(O)cc1
Reactant: O=C(O)/C=C/c1ccc(O)c(O)c1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(/C=C/c1ccc(O)c(O)c1)NCCc1ccc(O)cc1
Temperature: 0 °C
Reaction time: 20 h

Procedure:
A solution of caffeic acid (300 mg; 1.66 mmol) and of triethylamine (1.5 eq; 2.49 mmol) in DMF (3.5 mL) is cooled to 4° C. using an ice bath. An amine, tyramine (1 eq; 1.66 mmol) is added to the medium, followed by addition of a solution of BOP (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate; 1 eq; 1.66 mmol) in dichloromethane (3.5 mL); the mixture is stirred for about thirty minutes in the ice bath and then for 20 hours at room temperature. Stirring is then stopped and the dichloromethane is evaporated off under vacuum. 30 mL of water are added to the remaining solution and the mixture obtained is extracted with ethyl acetate (3×75 mL). The organic phase is successively washed with 100 mL of 1N HCl solution, 100 mL of water and 100 mL of 1M sodium bicarbonate (NaHCO3) solution. It is then dried over sodium sulfate and evaporated to dryness. The product is obtained in the form of a white precipitate after purification by chromatography on a column of silica gel.
Reaction SMILES: [C:1]1(C2C=CC=CC=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([N:9]1[CH2:15][CH:14]2[CH:11]([CH2:12][NH:13]2)[CH2:10]1)=[O:8].C1(C2C=CC=CC=2)C([C:28](O)=[O:29])=CC=CC=1>>[CH:11]12[CH2:12][NH:13][CH:14]1[CH2:15][N:9]([C:7]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=1[O:29][CH3:28])=[O:8])[CH2:10]2
Reactant: O=C(c1ccccc1-c1ccccc1)N1CC2CNC2C1
Reactant: O=C(O)c1ccccc1-c1ccccc1
Product: COc1ccccc1C(=O)N1CC2CNC2C1

Procedure:
The title compound was prepared in a manner analogous to Intermediate 19, substituting 2-methoxybenzoic acid for biphenyl-2-carboxylic acid. MS (ESI) mass calcd. for C13H16N2O2, 232.28; m/z found, 233.2 [M+H]+.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[N:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([CH3:21])[CH:15]=3)[CH:11]=[C:10]([C:22]([F:25])([F:24])[F:23])[N:9]=2)[CH:5]=[CH:4][N:3]=1.[C:26]([NH:30][S:31]([C:34]1[CH:35]=[C:36](B(O)O)[CH:37]=[CH:38][CH:39]=1)(=[O:33])=[O:32])([CH3:29])([CH3:28])[CH3:27]>>[C:26]([NH:30][S:31]([C:34]1[CH:35]=[CH:36][CH:37]=[C:38]([C:2]2[CH:7]=[C:6]([C:8]3[N:13]=[C:12]([C:14]4[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([CH3:21])[CH:15]=4)[CH:11]=[C:10]([C:22]([F:24])([F:23])[F:25])[N:9]=3)[CH:5]=[CH:4][N:3]=2)[CH:39]=1)(=[O:33])=[O:32])([CH3:29])([CH3:27])[CH3:28]
Reactant: CC(C)(C)NS(=O)(=O)c1cccc(B(O)O)c1
Reactant: Cc1cc(-c2cc(C(F)(F)F)nc(-c3ccnc(Cl)c3)n2)ccc1Cl
Product: Cc1cc(-c2cc(C(F)(F)F)nc(-c3ccnc(-c4cccc(S(=O)(=O)NC(C)(C)C)c4)c3)n2)ccc1Cl

Procedure:
3-{4-[4-(4-Chloro-3-methyl-phenyl)-6-trifluoromethyl-pyrimidin-2-yl]-pyridin-2-yl}-benzenesulfonic acid tert-butylamide was prepared from 2-(2-chloro-pyridin-4-yl)-4-(4-chloro-3-methyl-phenyl)-6-trifluoromethyl-pyrimidine (example E.43) (0.14 g, 0.36 mmol) and commercially available 3-(tert.-butylsulfamoyl)-phenylboronic acid (0.11 g, 0.43 mmol) according to the general procedure VI. Obtained as light brown solid (0.17 g), which was subsequently deprotected.
Reaction SMILES: [N+:1]([C:4]1[C:5]([N+:18]([O-])=O)=[C:6]([CH:15]=[CH:16][CH:17]=1)[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:8])([O-])=O>O1CCCC1.[Ni]>[NH2:1][C:4]1[C:5]([NH2:18])=[C:6]([CH:15]=[CH:16][CH:17]=1)[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:8]
Reactant: O=C(c1ccccc1)c1cccc([N+](=O)[O-])c1[N+](=O)[O-]
Agent: [Ni]
Solvent: C1CCOC1
Product: Nc1cccc(C(=O)c2ccccc2)c1N
Yield: 103.1 %

Procedure:
A total of 50 grams of dinitrobenzophenone, assay 96.5 weight percent of which 94 percent was m,m'-dinitrobenzophenone and six weight percent was the m,p'-isomer, dissolved in 400 milliliters of tetrahydrofuran was subjected to hydrogenation in a one-liter autoclave in contact with eight grams of nickel catalyst at a temperature of 150° C. and a hydrogenation pressure of 500 psig (3.5 MPa) until the reaction stopped. On workup, as before, 40.2 grams of diaminobenzophenone were obtained containing nine weight percent of tetrahydrofuran of crystallization.
Reaction SMILES: [CH:1]1([NH2:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=1)[C:12](Cl)=[O:13]>>[Cl:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=1)[C:12]([NH:7][CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)=[O:13]
Reactant: NC1CCCCC1
Reactant: O=C(Cl)c1cccc(Cl)c1
Product: O=C(NC1CCCCC1)c1cccc(Cl)c1
Yield: 70 %

Procedure:
Employing 0.19 g (1.9 mmol) of cyclohexylamine and 0.51 g, (2.9 mmol) of 3-chloro-benzoyl chloride in the procedure described above and elution with CHCl3/MeOH/Et3N (9.8:0.1:0.1) gave white crystals in 70% yield.
Reaction SMILES: Cl.[CH2:2]1[CH2:6][O:5][CH2:4][CH2:3]1>>[OH:5][CH2:4][C:3]1[CH:2]=[CH:6][C:3]([CH:4]=[O:5])=[CH:2][CH:6]=1
Reactant: C1CCOC1
Agent: Cl
Product: O=Cc1ccc(CO)cc1

Procedure:
7.9 g (44 mmol) of the above alcohol and 100 ml of THF are introduced into a round-bottomed flask, 20 ml of hydrochloric acid (1N) are added and the mixture is heated to reflux for 4 h. The reaction medium is evaporated to dryness, the residue is taken up with ethyl ether and saturated sodium bicarbonate solution and the organic phase is separated after settling has taken place, dried over magnesium sulphate and evaporated.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([CH2:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH:6]=[CH:7][C:8]=1[O:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17](=[O:26])[C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([Cl:25])[CH:19]=2)=[CH:12][CH:11]=1.N1C=CC=CC=1.[C:41](Cl)(=[O:48])[C:42]1[CH:47]=[CH:46][CH:45]=[N:44][CH:43]=1>C(Cl)Cl.O>[Cl:25][C:20]1[CH:19]=[C:18]([CH:23]=[CH:22][C:21]=1[Cl:24])[C:17]([NH:16][C:13]1[CH:12]=[CH:11][C:10]([O:9][C:8]2[CH:7]=[CH:6][C:5]([CH2:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])=[CH:4][C:3]=2[CH2:2][NH:1][C:41](=[O:48])[C:42]2[CH:47]=[CH:46][CH:45]=[N:44][CH:43]=2)=[CH:15][CH:14]=1)=[O:26]
Reactant: CC(C)(C)OC(=O)Cc1ccc(Oc2ccc(NC(=O)c3ccc(Cl)c(Cl)c3)cc2)c(CN)c1
Reactant: O=C(Cl)c1cccnc1
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: O
Product: CC(C)(C)OC(=O)Cc1ccc(Oc2ccc(NC(=O)c3ccc(Cl)c(Cl)c3)cc2)c(CNC(=O)c2cccnc2)c1
Reaction time: 12 h
Yield: 66 %

Procedure:
The product of step C (0.050 g, 0.997 mmol) was dissolved into 1 mL of DCM in a small test tube. Pyridine (0.017 g, 0.219 mmol) and nicotinoyl chloride (0.0195 g, 0.110 mmol) were added, and the reaction mixture was stirred for 12 hours. The reaction mixture was then diluted with methylene chloride and water. The methylene chloride layer was separated and loaded directly onto a biotage 12i column eluting with methylene chloride:MeOH (95:5) to yield tert-butyl 2-(4-(4-(3,4-dichlorobenzamido)phenoxy)-3-(nicotinamidomethyl)phenyl)-acetate (44 mg, 73% yield) as a clear oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5](Cl)=[CH:4][C:3]=1[Br:12].C([O-])(O)=O.[Na+:17].[NH2:18][CH2:19][C:20]([OH:22])=[O:21]>CN(C=O)C.O>[Na+:17].[Br:12][C:3]1[C:2]([Cl:1])=[CH:7][C:6]([N+:8]([O-:10])=[O:9])=[C:5]([NH:18][CH2:19][C:20]([O-:22])=[O:21])[CH:4]=1
Reactant: O=[N+]([O-])c1cc(Cl)c(Br)cc1Cl
Reactant: NCC(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C([O-])CNc1cc(Br)c(Cl)cc1[N+](=O)[O-]
Temperature: 65 °C
Reaction time: 65 h

Procedure:
To a stirred solution of 2,5-dichloro-4-nitrobromobenzene (1.000 g, 3.691 mmol, as prepared above) in DMF (10.0 mL) at 65° C., was added, dropwise, a solution of NaHCO3 (0.316 g, 3.76 mmol) and glycine (0.280 g, 3.73 mmol, Aldrich, used as received) in water (3.8 mL). The resulting suspension was stirred at 65° C. for 65 h. The bright orange suspension was then cooled to room temperature, filtered, washed with water (1.0 mL), and dried under vacuum to afford 0.284 g (98%, based on recovered starting material) of the pure (1H NMR) title compound as an orange powder; m.p. 264-265° C. (decomposed); 1H NMR (DMSO-d6): δ 3.451 (d, 2H, J=3.9 Hz), 7.199 (s, 1H), 8.130 (s, 1H), 8.793 (t, 1H, J=3.6 Hz). It was used as such for the next reaction.
Reaction SMILES: [CH3:1][C:2]1[CH2:3][C:4]2[C:9]([CH:10]=1)=[C:8]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH:7]=[CH:6][CH:5]=2.[CH3:17][SiH:18]([N:20](Cl)[C:21]([CH3:24])([CH3:23])[CH3:22])[CH3:19]>C1COCC1>[CH3:1][C:2]1[CH:3]([Si:18]([NH:20][C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:19])[CH3:17])[C:4]2[C:9]([CH:10]=1)=[C:8]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH:7]=[CH:6][CH:5]=2
Reactant: CC1=Cc2c(cccc2-c2ccccc2)C1
Reactant: C[SiH](C)N(Cl)C(C)(C)C
Solvent: C1CCOC1
Product: CC1=Cc2c(-c3ccccc3)cccc2C1[Si](C)(C)NC(C)(C)C
Reaction time: 16 h
Yield: 82 %

Procedure:
2-methyl-4-phenylindene (synthesized substantially according to the technique reported in U.S. Pat. No. 5,329.033) (3.00 g, 0.014 moles) in THF (10 mL) was added dropwise to a stirring solution of KH (0.601 g, 0.0150 moles) in THF (50 mL). This mixture was allowed to stir for 16 hours. The solution was then filtered and added dropwise to a solution of dimethylsilyl(t-butylamino)chloride (2.41 g, 0.0145 moles) in THF (75 mL). This mixture was allowed to stir for 16 hours. After the reaction period the volatiles were removed and the residue extracted and filtered using hexane. Removal of the volatiles resulted in the isolation of the desired product as a light yellow oil (4.00 g, 82.0 percent).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([C:15]([C:17]2[CH:22]=[CH:21][C:20](I)=[CH:19][CH:18]=2)=[O:16])[CH2:11][CH2:10]1.[NH:24]1[CH2:28][CH2:27][CH2:26][C:25]1=[O:29]>>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([C:15]([C:17]2[CH:22]=[CH:21][C:20]([N:24]3[CH2:28][CH2:27][CH2:26][C:25]3=[O:29])=[CH:19][CH:18]=2)=[O:16])[CH2:11][CH2:10]1
Reactant: O=C1CCCN1
Reactant: Cc1ccc(N2CCN(C(=O)c3ccc(I)cc3)CC2)c(C)c1
Product: Cc1ccc(N2CCN(C(=O)c3ccc(N4CCCC4=O)cc3)CC2)c(C)c1

Procedure:
Using [4-(2,4-dimethylphenyl)piperazin-1-yl](4-iodophenyl)methanone (6.0 g) described in Preparation Example 109 and pyrrolidin-2-one (1.3 mL) and by the reaction and treatment in the same manner as in Example 1, the title compound (1.80 g) was obtained.
Reaction SMILES: [B-](F)(F)(F)[C:2]([CH3:4])=[CH2:3].[K+].Br[C:10]1[CH:11]=[C:12]([O:27][CH3:28])[C:13]([NH:16][S:17]([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)(=[O:19])=[O:18])=[N:14][CH:15]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCCC1.O.ClCCl.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[F:26][C:23]1[CH:24]=[CH:25][C:20]([S:17]([NH:16][C:13]2[C:12]([O:27][CH3:28])=[CH:11][C:10]([C:2]([CH3:4])=[CH2:3])=[CH:15][N:14]=2)(=[O:19])=[O:18])=[CH:21][CH:22]=1
Reactant: COc1cc(Br)cnc1NS(=O)(=O)c1ccc(F)cc1
Reactant: C=C(C)[B-](F)(F)F
Agent: Cl[Pd]Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: ClCCl
Solvent: C1CCOC1
Product: C=C(C)c1cnc(NS(=O)(=O)c2ccc(F)cc2)c(OC)c1
Temperature: 140 °C
Yield: 64.6 %

Procedure:
Potassium trifluoro(prop-1-en-2-yl)borate (53.3 mg, 0.360 mmol), N-(5-bromo-3-methoxypyridin-2-yl)-4-fluorobenzenesulfonamide (130 mg, 0.360 mmol), caesium carbonate (352 mg, 1.080 mmol), palladium(II) chloride (1.276 mg, 7.20 μmol) and triphenylphosphine (5.66 mg, 0.022 mmol) were added to a microwave vial and suspended in tetrahydrofuran (THF) (2 mL) and water (0.2 mL). The reaction vessel was sealed and heated by microwaves to 140° C. for 30 minutes. After cooling, the mixture was diluted with dichloromethane (DCM) (5 mL) and water (5 mL), then passed through a celite column. The aqueous phase was washed with further DCM (5 mL) then the organics separated using a hydrophobic frit and concentrated in vacuo to give the crude product. This was purified by flash silica (Si) chromatography (0-50% ethyl acetate-cyclohexane gradient) to give the title product (75 mg). LCMS (2 min, formic) Rt 1.0 min, m/z (ES+) 323 (M+H).
Reaction SMILES: [N:1]1([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.F[C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][C:16]=1[CH3:24].C(N(CC)C(C)C)(C)C>CS(C)=O>[CH3:24][C:16]1[CH:17]=[C:18]([N+:21]([O-:23])=[O:22])[CH:19]=[CH:20][C:15]=1[N:4]1[CH2:5][CH2:6][N:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:2][CH2:3]1
Reactant: Cc1cc([N+](=O)[O-])ccc1F
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc([N+](=O)[O-])ccc1N1CCN(C(=O)OC(C)(C)C)CC1

Procedure:
In the same manner as in Production Example 5-1, but using tert-butyl piperazine-1-carboxylate in place of N-ethylpiperazine used in Production Example 5-1, using 2-fluoro-5-nitrotoluene in place of 2-fluoro-5-nitrobenzyl alcohol, using N,N-diisopropylethylamine in place of potassium carbonate, and using dimethylsulfoxide in place of N-methylpyrrolidone, 4.91 g of crude tert-butyl 4-[2-methyl-4-nitrophenyl]piperazine-1-carboxylate was obtained as a yellow solid.