Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]([CH3:16])=[C:3]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C1COCC1.C([Li])CCC.Cl[P:28]([CH:35]1[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1)[CH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1>O>[C:4]1([C:3]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[C:2]([P:28]([CH:35]2[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40]2)[CH:29]2[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]2)[CH3:16])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: ClP(C1CCCCC1)C1CCCCC1
Reactant: CC(Br)=C(c1ccccc1)c1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: CC(=C(c1ccccc1)c1ccccc1)P(C1CCCCC1)C1CCCCC1
Temperature: -70 °C
Reaction time: 1.25 h
Yield: 72.5 %

Procedure:
Into a reactor were introduced 8.50 g (31.1 mmol) of the 2-bromo-1,1-diphenylpropene obtained in Example 1 (2) and 85 ml of THF under a nitrogen atmosphere. The contents were cooled to −70° C. Thereto was gradually added dropwise 21.4 mL (34.2 mmol; 1.6 M hexane solution) of butyllithium. The resultant mixture was stirred for 30 minutes. Thereafter, 8.25 mL (37.3 mmol) of chlorodicyclohexylphosphine was added, and this mixture was stirred for 75 minutes, subsequently heated to room temperature, and then further stirred for 15.5 hours. Water was added to the reaction mixture. The organic layer was extracted with ethyl acetate, and the extract was dried with anhydrous magnesium sulfate. Thereafter, the solvent was removed under reduced pressure. The concentrate was recrystallized from ethanol to obtain 8.80 g (72%) of the target compound as white crystals.
Reaction SMILES: [CH2:1]([NH:8][CH2:9][CH:10]([C:12]1[CH:27]=[CH:26][C:15]([O:16][C:17]2[CH:25]=[CH:24][C:20]([C:21]([NH2:23])=[O:22])=[CH:19][N:18]=2)=[CH:14][CH:13]=1)[CH3:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]>>[CH2:1]([N:8]([CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[CH2:9][CH:10]([C:12]1[CH:27]=[CH:26][C:15]([O:16][C:17]2[CH:25]=[CH:24][C:20]([C:21]([NH2:23])=[O:22])=[CH:19][N:18]=2)=[CH:14][CH:13]=1)[CH3:11])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCCCBr
Reactant: CC(CNCc1ccccc1)c1ccc(Oc2ccc(C(N)=O)cn2)cc1
Product: CCCCCN(Cc1ccccc1)CC(C)c1ccc(Oc2ccc(C(N)=O)cn2)cc1

Procedure:
Using a method similar to example 3, using 6-[4-(2-benzylamino-1-methyl-ethyl)-phenoxy]-nicotinamide (example 190 step 2), and 1-bromopentane gives the title product: HPLC (30/70 to 90/10 ACN/(0.1% TFA in water) Zorbax SB-Phenyl Column 4.6 mm×15 cm×5 micron: Retention time: 8.52 minutes, Purity: 97.4%; mass spectrum (ion spray): m/z=432.3 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][C@H:12]([CH2:14]Cl)[N:11]([CH2:16][C:17]([N:19]2[C:27]3[C:22](=[N:23][CH:24]=[C:25]([CH2:28][C:29]4[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=4)[CH:26]=3)[C:21]([CH3:37])([CH3:36])[CH2:20]2)=[O:18])[CH2:10][C@H:9]1[CH3:38])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:39][C@@H:40]1[CH2:45][O:44][CH2:43][CH2:42][NH:41]1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][C@H:12]([CH2:14][N:41]2[CH2:42][CH2:43][O:44][CH2:45][C@H:40]2[CH3:39])[N:11]([CH2:16][C:17]([N:19]2[C:27]3[C:22](=[N:23][CH:24]=[C:25]([CH2:28][C:29]4[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=4)[CH:26]=3)[C:21]([CH3:37])([CH3:36])[CH2:20]2)=[O:18])[CH2:10][C@H:9]1[CH3:38])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C[C@@H]1COCCN1
Reactant: C[C@@H]1CN(CC(=O)N2CC(C)(C)c3ncc(Cc4ccc(F)cc4)cc32)[C@@H](CCl)CN1C(=O)OC(C)(C)C
Product: C[C@@H]1COCCN1C[C@H]1CN(C(=O)OC(C)(C)C)[C@H](C)CN1CC(=O)N1CC(C)(C)c2ncc(Cc3ccc(F)cc3)cc21

Procedure:
Prepared from (2R,5R)-5-chloromethyl-4-{2-[6-(4-fluoro-benzyl)-3,3-dimethyl-2,3-dihydro-pyrrolo[3,2-b]pyridin-1-yl]-2-oxo-ethyl}-2-methyl-piperazine-1-carboxylic acid tert-butyl ester (see Preparation 420) and (R)-3-methyl-morpholine in a similar manner to General Procedure 6. MS: [M+H]+=610.
Reaction SMILES: C([O:8][C:9](=[O:39])[CH2:10][O:11][C:12]1[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[CH:18]=[C:17]2[C:13]=1[C:14]([C:34](=[O:38])[C:35]([NH2:37])=[O:36])=[C:15]([CH2:32][CH3:33])[N:16]2[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)C1C=CC=CC=1.C1CC=CCC=1>O1CCCC1.[Pd]>[NH2:37][C:35](=[O:36])[C:34]([C:14]1[C:13]2[C:17](=[CH:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[C:12]=2[O:11][CH2:10][C:9]([OH:39])=[O:8])[N:16]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:15]=1[CH2:32][CH3:33])=[O:38]
Reactant: CCc1c(C(=O)C(N)=O)c2c(OCC(=O)OCc3ccccc3)c3ccccc3cc2n1Cc1ccccc1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: C1=CCC=CC1
Product: CCc1c(C(=O)C(N)=O)c2c(OCC(=O)O)c3ccccc3cc2n1Cc1ccccc1
Temperature: 50 °C
Reaction time: 3 h
Yield: 36.5 %

Procedure:
A mixture of 2-[[3-(2-amino-1,2-dioxoethyl)-1-benzyl-2-ethyl-1H-benz[f]indol-4-yl]oxy]acetic acid benzyl ester (29 mg, 0.056 mmol), 10% palladium-on-carbon (30 mg), and 1,4-cyclohexadiene (1 mL) in tetrahydrofuran (1 mL) was warmed to 50° C. with stirring for 3 h. The mixture was filtered and the resulting solution concentrated in vacuo. The filtered solids were washed with methanol and the resulting solution concentrated in vacuo. Both residues were dissolved methylene chloride and diluted with hexane. The resulting precipitate was collected via vacuum filtration to provide 8.8 mg (37%) of the title compound as a solid: mp 243-253° C. (dec). 1H NMR (DMSO-d6) δ8.26 (m, 1H), 8.11 (bs, 1H), 7.89 (m, 1H), 7.75 (s, 1H), 7.53 (s, 1H), 7.34 (m, 2H), 7.30 (m, 2H), 7.22 (t, J=7.0 Hz, 1H), 7.07 (d, J=7.3 Hz, 2H), 5.60 (s, 2H), 4.47 (s, 2H), 2.97 (q, J=7.7 Hz, 2H), 1.10 (t, J=7.3 Hz, 3H); TOF MS ES+ exact mass calculated for C25H23N2O5: m/z=431.1607 (p+1). Found: 431.1605.
Reaction SMILES: [CH3:1][N:2]([CH2:11][CH2:12][CH2:13][CH:14]1[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][CH2:15]1)[C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][N:4]=1.Cl[C:22]1[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[CH:24]N=1.CN[CH2:32][CH2:33]CC1CCN(C)CC1>CCO>[CH3:24][C:25]1[C:26]2[N:27]=[C:7]([C:6]3[CH:9]=[CH:10][C:3]([N:2]([CH3:1])[CH2:11][CH2:12][CH2:13][CH:14]4[CH2:15][CH2:16][N:17]([CH3:20])[CH2:18][CH2:19]4)=[N:4][CH:5]=3)[NH:8][C:33]=2[CH:32]=[C:29]([CH3:22])[CH:28]=1
Reactant: CNCCCC1CCN(C)CC1
Reactant: N#Cc1ccc(Cl)nc1
Reactant: CN1CCC(CCCN(C)c2ccc(C#N)cn2)CC1
Solvent: CCO
Product: Cc1cc(C)c2nc(-c3ccc(N(C)CCCC4CCN(C)CC4)nc3)[nH]c2c1
Temperature: 25 °C
Yield: 41 %

Procedure:
6-{Methyl-[3-(1-methyl-piperidin-4-yl)-propyl]-amino}-nicotinonitrile. A solution of 6-chloro-nicotinonitrile (322 mg, 2.33 mmol) and methyl-[3-(1-methyl-piperidin-4-yl)-propyl]-amine (0.400 g, 2.56 mmol) in EtOH (10 mL) was heated at 100° C. in a sealed tube for 4 h. The mixture was cooled to rt and concentrated to give a crude product which was purified by FCC to give 260 mg (41%) of the title compound as a yellow oil. 1H NMR (CDCl3): 8.40 (d, J=2.3 Hz, 1H), 7.52 (dd, J=9.0, 2.3 Hz, 1H), 6.39 (d, J=9.0 Hz, 1H), 3.56 (t, J=7.6 Hz, 2H), 3.17 (s, 3H), 2.93-2.73 (m, 2H), 2.33 (s, 3H), 1.97-1.77 (m, 4H), 1.33-1.16 (m, 8H), 0.93-0.77 (m, 1H).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:8][OH:9])[CH:3]=1.[CH3:10][NH:11][CH2:12][CH2:13][CH2:14][OH:15].[Cl:16]N1C(=O)CCC1=O>>[Cl:16][C:3]1[C:4]([CH2:8][OH:9])=[N:5][CH:6]=[CH:7][C:2]=1[N:11]([CH3:10])[CH2:12][CH2:13][CH2:14][OH:15]
Reactant: CNCCCO
Reactant: OCc1cc(Cl)ccn1
Reactant: O=C1CCC(=O)N1Cl
Product: CN(CCCO)c1ccnc(CO)c1Cl

Procedure:
As described in example D3., the title compound is prepared in two steps starting from (4-chloro-pyridin-2-yl)-methanol (15.3 g, 106 mmol) and 3-methylamino-propanol (10.0 g, 112 mmol) and subsequent chlorination of the crude product with N-chlorosuccinimide (19 g, 143 mmol). Yield: 6.4 g (26%), colourless oil.
Reaction SMILES: [OH:1][CH:2]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=1)[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:12]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[CH:14]=[CH:15][CH:16]=2)[CH2:7][CH2:6]1.[CH3:31][O:32][C:33]1[CH:38]=[CH:37][C:36](O)=[CH:35][CH:34]=1>>[CH3:31][O:32][C:33]1[CH:38]=[CH:37][C:36]([O:1][CH:2]([C:23]2[CH:24]=[CH:25][C:26]([O:29][CH3:30])=[CH:27][CH:28]=2)[CH2:3][CH2:4][N:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:12]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[CH:14]=[CH:15][CH:16]=3)[CH2:7][CH2:6]2)=[CH:35][CH:34]=1
Reactant: COc1ccc(O)cc1
Reactant: COc1ccc(C(O)CCN2CCC(c3cccc(NC(=O)C(C)C)c3)CC2)cc1
Product: COc1ccc(OC(CCN2CCC(c3cccc(NC(=O)C(C)C)c3)CC2)c2ccc(OC)cc2)cc1

Procedure:
Prepared by Procedure A and Scheme AN using N-(3-{1-[3-hydroxy-3-(4-methoxyphenyl)propyl]-4-piperidinyl}phenyl)-2-methylpropanamide and 4-methoxyphenol: ESMS m/e: 517.4 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[O:17][C@H:16]([C:18]([NH:20][CH2:21][CH3:22])=[O:19])[C@@H:14]([OH:15])[C@H:12]2[OH:13])=[C:4]([NH:23][CH2:24][CH:25]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:3]=1.[NH2:38][CH2:39][CH2:40][CH2:41][NH2:42].Cl.[N:44]1(C(N)=N)[CH:48]=CC=[N:45]1.N1C=CN=C1>CS(C)=O.CO>[NH2:45][N:44]=[CH:48][NH:38][CH2:39][CH2:40][CH2:41][NH:42][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[O:17][C@H:16]([C:18]([NH:20][CH2:21][CH3:22])=[O:19])[C@@H:14]([OH:15])[C@H:12]2[OH:13])=[C:4]([NH:23][CH2:24][CH:25]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:3]=1
Reactant: CCNC(=O)[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(Cl)nc32)[C@H](O)[C@@H]1O
Reactant: NCCCN
Reactant: N=C(N)n1cccn1
Agent: Cl
Agent: c1c[nH]cn1
Solvent: CS(C)=O
Solvent: CO
Product: CCNC(=O)[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(NCCCNC=NN)nc32)[C@H](O)[C@@H]1O
Reaction time: 24 h
Yield: 56.6 %

Procedure:
A solution of 1-[2-chloro6-[(2,2-diphenylethyl)amino]-9H-purin-9-yl]-1-deoxy-N-ethyl-β-D-ribofuranuronamide (0.310, 0.592 mmol) in dimethylsulphoxide (2 ml) was heated with 1,3-diaminopropane (0.542 g, 7.31 mmol) at 120° for 24h. The cooled mixture was partitioned between ethyl acetate (50 ml) and water (50 ml) and the aqueous phase was separated and extracted with ethyl acetate (20 ml). The combined ethyl acetate solution was washed with water (20 ml), dried (MgSO4) and evaporated to leave a froth (0.302 g). This froth (0.3 g) was dissolved in 50% aqueous methanol (20 ml) and the solution was heated at reflux with pyrazole-1-carboxamidine hydrochloride (0.099 g, 0.675 mmol) and imidazole (0.05 g, 0.734 mmol) for 18h. More pyrazole-1-carboxamidine hydrochloride (0.099 g, 0.675 mmol) was added and heating was continued for a further 24h. The mixture was evaporated to leave a solid which was purified by preparative HPLC (20-60% acetonitrile) to give the title compound (0.202 g) as a solid from ether. The product had MH+ =603, nmr(δ,DMSO-d6) includes 1.02(t,3H), 1.7-1.9(m,2H), 3.05-3.25(m,4H), 3.3-3.5(m,2H), 4.15-4.25(m,1H), 4.8(s,1H), 4.5-4.7(m,2H), 5.85(d,1H), 7.15-7.4(m,10H), 7.5-7.65(m,1H), 8.12(s,1H), 8.1-8.25(m,1H).
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][C:7]1[CH:12]=[C:11]([CH3:13])[CH:10]=[C:9]([Cl:14])[CH:8]=1)(=[O:3])[CH3:2].[Br:15]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[C:1]([O:4][CH2:5][CH2:6][C:7]1[CH:8]=[C:9]([Cl:14])[CH:10]=[C:11]([CH2:13][Br:15])[CH:12]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OCCc1cc(C)cc(Cl)c1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: CC(=O)OCCc1cc(Cl)cc(CBr)c1

Procedure:
A mixture of 3-chloro-5-methylphenylethyl acetate (0.20 g; 0.958 mol), N-bromosuccinimide (0.21 g; 1.21 mmol) and 2,2-azobis(isobutyronitrile) (0.01 g; 0.037 mmol) in carbon tetrachloride (2 ml) were refluxed for 2 hours. After cooling and filtration of the precipitate, the filtrate was condensed under reduced pressure. The residue was purified by column chromatograph on silica gel (hexane:ethyl acetate=20:1) to give 3-bromomethyl-5-chlorophenylethyl acetate as colorless oil (0.16 g; 57%).
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([C@@H:7]([NH2:11])[C:8]([OH:10])=[O:9])=[CH:3][CH:2]=1.S(Cl)([Cl:14])=O.[CH3:16]O>>[CH3:16][O:9][C:8]([C@@H:7]([NH2:11])[C:4]1[CH:3]=[CH:2][CH:1]=[CH:6][CH:5]=1)=[O:10].[ClH:14]
Reactant: N[C@@H](C(=O)O)c1ccccc1
Reactant: O=S(Cl)Cl
Reactant: CO
Product: COC(=O)[C@@H](N)c1ccccc1
Product: Cl
Yield: 100 %

Procedure:
To a stirred solution of D-phenylglycine (11) (20 g, 132 mmol) in methanol (100 ml) at -10° C. was added thionyl chloride (10.62 ml, 146 mmol) and the solution was refluxed for 2 hours. After concentration in vacuo the product was recrystallised from methanol-diethyl ether mixture to give the title compound (12) (26.6 g, 100%); δH (D2O; 200 MHz) 2.95-3.18 (2H, m, CH2CH), 3.62 (3H, s, CH3), 4.21 (1H, dd, J=6.1 and 7.4, CH2CH), 4.59 (2H, s, NH2), 7.06-7.27 (5H, m, ArCH).
Reaction SMILES: [CH:1]1([N:5]2[CH2:10][CH2:9][N:8]([C:11]([C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[NH:18][C:17]([C:22]([N:24]3[CH2:29][CH2:28][C:27]([F:31])([F:30])[CH2:26][CH2:25]3)=[O:23])=[CH:16]4)=[O:12])[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.[CH3:32][S:33]([NH:36][C:37]1[CH:42]=[CH:41][C:40](B(O)O)=[CH:39][CH:38]=1)(=[O:35])=[O:34].N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH:1]1([N:5]2[CH2:6][CH2:7][N:8]([C:11]([C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[N:18]([C:40]3[CH:39]=[CH:38][C:37]([NH:36][S:33]([CH3:32])(=[O:34])=[O:35])=[CH:42][CH:41]=3)[C:17]([C:22]([N:24]3[CH2:25][CH2:26][C:27]([F:30])([F:31])[CH2:28][CH2:29]3)=[O:23])=[CH:16]4)=[O:12])[CH2:9][CH2:10]2)[CH2:2][CH2:3][CH2:4]1
Reactant: CS(=O)(=O)Nc1ccc(B(O)O)cc1
Reactant: O=C(c1ccc2[nH]c(C(=O)N3CCC(F)(F)CC3)cc2c1)N1CCN(C2CCC2)CC1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CS(=O)(=O)Nc1ccc(-n2c(C(=O)N3CCC(F)(F)CC3)cc3cc(C(=O)N4CCN(C5CCC5)CC4)ccc32)cc1
Yield: 19 %

Procedure:
The title compound was synthesized in analogy to example 66, from [5-(4-cyclobutyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(4,4-difluoro-piperidin-1-yl)-methanone (example 41), 4-(methanesulfonylamino)phenylboronic acid, copper(II) acetate and pyridine in dichloromethane, to give the desired product as a colorless foam (19%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[C:4]([F:9])[C:3]=1[OH:10].[F:11][C:12]1[CH:20]=[C:19]([S:21]([CH3:24])(=[O:23])=[O:22])[CH:18]=[CH:17][C:13]=1[C:14](O)=O.[OH-].[Na+]>CCOC(C)=O.O>[Br:8][C:6]1[CH:5]=[C:4]([F:9])[C:3]2[O:10][C:14]([C:13]3[CH:17]=[CH:18][C:19]([S:21]([CH3:24])(=[O:22])=[O:23])=[CH:20][C:12]=3[F:11])=[N:1][C:2]=2[CH:7]=1
Reactant: Nc1cc(Br)cc(F)c1O
Reactant: CS(=O)(=O)c1ccc(C(=O)O)c(F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Product: CS(=O)(=O)c1ccc(-c2nc3cc(Br)cc(F)c3o2)c(F)c1
Temperature: 195 °C

Procedure:
2-Amino-4-bromo-6-fluorophenol (2.6 g, 9.7 mmol) and 2-fluoro-4-(methylsulfonyl)benzoic acid (2.1 g, 9.7 mmol) were dissolved in polyposphoric acid (63.5 g). This mixture was heated at 195° C. for three and half hours. Reaction mixture cooled to rt and diluted with ice water (100 ml). Aqueous layer basified with sodium hydroxide pellets to pH 9. Work up (EtOAc/H2O) followed by evaporation of EtOAc afforded the crude. Crude (3.1 g) was used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:10][C:9](=[O:11])[O:8][C:7]([CH2:16][CH2:17][NH:18][C:19](=[O:27])[C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)([C:12]([F:15])([F:14])[F:13])[C:6]=2[CH:28]=1.CCCCCC>CC(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:10][C:9](=[O:11])[O:8][C@@:7]([CH2:16][CH2:17][NH:18][C:19](=[O:27])[C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)([C:12]([F:15])([F:14])[F:13])[C:6]=2[CH:28]=1
Reactant: O=C1Nc2ccc(Cl)cc2C(CCNC(=O)c2ccc(F)cc2)(C(F)(F)F)O1
Solvent: CCCCCC
Solvent: CC(C)O
Product: O=C1Nc2ccc(Cl)cc2[C@](CCNC(=O)c2ccc(F)cc2)(C(F)(F)F)O1

Procedure:
N-{2-[6-chloro-2-oxo-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-4-yl]ethyl}-4-fluorobenzamide was subjected to optical resolution by HPLC (Chiralpack AD-H, n-hexane:2-propanol=3:1), and a fraction eluted at a later time was concentrated, whereby the objective compound was obtained.
Reaction SMILES: [CH3:1][N:2]([CH3:24])[C:3]1[CH:20]=[C:19]([N:21]([CH3:23])[CH3:22])[CH:18]=[CH:17][C:4]=1[C:5]([C:7]1[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][C:8]=1[C:9](O)=[O:10])=[O:6].CN(C)C1C=CC=C(N(C)C)C=1>>[CH3:24][N:2]([CH3:1])[C:3]1[CH:20]=[C:19]([N:21]([CH3:22])[CH3:23])[CH:18]=[CH:17][C:4]=1[CH:5]1[C:7]2[C:8](=[CH:12][C:13]([NH2:16])=[CH:14][CH:15]=2)[C:9](=[O:10])[O:6]1
Reactant: CN(C)c1ccc(C(=O)c2ccc(N)cc2C(=O)O)c(N(C)C)c1
Agent: CN(C)c1cccc(N(C)C)c1
Product: CN(C)c1ccc(C2OC(=O)c3cc(N)ccc32)c(N(C)C)c1

Procedure:
Condensation of 2-(2,4-bis(dimethylamino)benzoyl)-5-aminobenzoic acid and N,N,N',N'-tetramethyl-m-phenylenediamine by the method of part B of Example 3 and deacetylation of the resulting product affords 3,3-(2,4-bis(dimethylamino)phenyl-6-aminophthalide (I: X = Y2 = Y4 = (CH3)2N, Z4 = Z5 = Z7 = H, Z6 = H2N).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[C:7]([CH:8]=O)[C:6]([OH:11])=[CH:5][CH:4]=1.[Br:12][C:13]1[CH:26]=[CH:25][C:16]([NH:17][S:18]([CH2:21][C:22](O)=[O:23])(=[O:20])=[O:19])=[CH:15][CH:14]=1>C(O)(=O)C>[Br:12][C:13]1[CH:14]=[CH:15][C:16]([NH:17][S:18]([C:21]2[C:22](=[O:23])[O:11][C:6]3[C:7]([CH:8]=2)=[CH:10][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)(=[O:20])=[O:19])=[CH:25][CH:26]=1
Reactant: O=C(O)CS(=O)(=O)Nc1ccc(Br)cc1
Reactant: COc1ccc(O)c(C=O)c1
Solvent: CC(=O)O
Product: COc1ccc2oc(=O)c(S(=O)(=O)Nc3ccc(Br)cc3)cc2c1

Procedure:
A solution of 5-methoxysalicylaldehyde (1 mmol) and 4-bromoanilinosulfonyl acetic acid (1 mmol) in acetic acid (10 mL) was subjected to the General Procedure 1, Method A to yield the title compound; m.p. 166-168° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[CH2:15][CH2:14][CH2:13][CH2:12][C:11]=3[NH:10][N:9]=2)=[CH:4][CH:3]=1>C1[C@H]2[C@@H](CCCC2)CCC1.[Pd]>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[NH:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: Cc1ccc(-c2n[nH]c3c2CCCC3)cc1
Agent: [Pd]
Agent: C1CC[C@H]2CCCC[C@@H]2C1
Product: Cc1ccc(-c2n[nH]c3ccccc23)cc1
Yield: 81.5 %

Procedure:
Into the solution of compound 8 (12.3 g, 0.058 mol) in trans-decahydronaphthalene (trans-decalin) was added 10% Pd/C (2.7 g), and the mixture was heated under reflux for 4 h, and then concentrated in vacuo in oil bath until there were about 20 mL solution left. Petroleum ether (80 mL) was added into the residue while hot, and the mixture was well mixed by shaking. The mixture was allowed to precipitate upon cooling to afford 3-(4-methylphenyl)-1H-indazole (10, 9.85 g, 82% yield).
Reaction SMILES: [CH3:1][N:2]([CH3:21])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].[CH2:22]([Cl:25])[CH:23]=[CH2:24].C(Br)C=C.C(=O)(O)[O-].[Na+]>C(O)(C)C>[Cl-:25].[CH2:22]([N+:2]([CH3:1])([CH3:21])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH:23]=[CH2:24]
Reactant: CCCCCCCCCCCCCCCCCCN(C)C
Reactant: C=CCCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Solvent: C=CCBr
Product: C=CC[N+](C)(C)CCCCCCCCCCCCCCCCCC
Product: [Cl-]

Procedure:
A 2-liter reaction vessel equipped with a mechanical stirrer and a reflux condenser was charged with 660.0 gm. dimethyl octadecyl amine, 199.0 gm. (2.19 mol) allyl chloride, 13.3 (0.11 mol) gm. allyl bromide, 20 gm. sodium bicarbonate, and 350 ml. isopropyl alcohol. This mixture was heated under reflux overnight. Analyses of a filtered aliquot indicated the reaction was complete. The mixture was filtered and upon analysis had an Effective gram MW of 496.74.
Reaction SMILES: ClC1C=C2C(C([CH:17]([CH2:21][C:22]([C:24]3[C:32]4[C:27](=[CH:28][C:29](Cl)=[CH:30][CH:31]=4)[NH:26][C:25]=3[C:34]3C=CC=CC=3)=O)[C:18]([OH:20])=[O:19])=C(C3C=CC=CC=3)N2)=CC=1.[CH2:40]([C:43]1[NH:44][C:45]2[C:50]([CH:51]=1)=[CH:49][CH:48]=[CH:47][CH:46]=2)CC.[CH2:52]([N:54]1[C:62]2[C:57](=[CH:58][CH:59]=[CH:60][CH:61]=2)[CH:56]=[C:55]1[CH3:63])[CH3:53]>>[CH2:18]([N:44]1[C:45]2[C:50](=[CH:49][CH:48]=[CH:47][CH:46]=2)[C:51]([C:17]2[C:18](=[O:19])[O:20][C:22]([C:24]3[C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[N:26]([CH2:22][CH2:24][CH3:25])[C:25]=3[CH3:34])([C:56]3[C:57]4[C:62](=[CH:61][CH:60]=[CH:59][CH:58]=4)[N:54]([CH2:52][CH3:53])[C:55]=3[CH3:63])[CH:21]=2)=[C:43]1[CH3:40])[CH2:17][CH3:21]
Reactant: O=C(CC(C(=O)O)c1c(-c2ccccc2)[nH]c2cc(Cl)ccc12)c1c(-c2ccccc2)[nH]c2cc(Cl)ccc12
Reactant: CCCc1cc2ccccc2[nH]1
Reactant: CCn1c(C)cc2ccccc21
Product: CCCn1c(C)c(C2=CC(c3c(C)n(CC)c4ccccc34)(c3c(C)n(CCC)c4ccccc34)OC2=O)c2ccccc21

Procedure:
Following a procedure similar to that described above in part B of this example by using 2,4-bis(6-chloro-2-phenyl-3-indolyl)-4-oxobutanoic acid instead of 2,4-bis(1-n-propyl-2-methyl-3-indolyl)-4-oxobutanoic acid, and 2-propylindole is substituted for 1-ethyl-2-methylindole, there is obtained 3,5-bis-(6-chloro-2-phenyl-3-indolyl)-5-(2-propyl-3-indolyl-2(5H)-furanone (Formula III: R=R2 =Y1 =H; R1 =C6H5 ; R3 =CH3CH2CH2 ; Y=6-Cl).
Reaction SMILES: [CH3:1][N:2]([CH3:14])[C:3]([C:5]1[CH:9]=[N:8][N:7]([CH3:10])[C:6]=1[C:11]([OH:13])=O)=[O:4].[NH2:15][C:16]1[CH:21]=[CH:20][N:19]2[CH:22]=[C:23]([C:25]3[CH:26]=[C:27]([O:31][C:32](=[O:34])[CH3:33])[CH:28]=[CH:29][CH:30]=3)[N:24]=[C:18]2[N:17]=1>>[C:32]([O:31][C:27]1[CH:28]=[CH:29][CH:30]=[C:25]([C:23]2[N:24]=[C:18]3[N:17]=[C:16]([NH:15][C:11]([C:6]4[N:7]([CH3:10])[N:8]=[CH:9][C:5]=4[C:3](=[O:4])[N:2]([CH3:1])[CH3:14])=[O:13])[CH:21]=[CH:20][N:19]3[CH:22]=2)[CH:26]=1)(=[O:34])[CH3:33]
Reactant: CN(C)C(=O)c1cnn(C)c1C(=O)O
Reactant: CC(=O)Oc1cccc(-c2cn3ccc(N)nc3n2)c1
Product: CC(=O)Oc1cccc(-c2cn3ccc(NC(=O)c4c(C(=O)N(C)C)cnn4C)nc3n2)c1

Procedure:
The title compound was prepared in analogy to example 82, step 3, from 4-dimethylcarbamoyl-2-methyl-2H-pyrazole-3-carboxylic acid (step 2, example 85; 44.1 mg, 224 μmol) and acetic acid 3-(7-amino-imidazo[1,2-a]pyrimidin-2-yl)-phenyl ester (50 mg, 186 μmol). Yield: 53 mg (60%). Yellow solid. MS (m/z)=448.2 [M+H+].
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([CH3:18])[CH2:14][O:13][CH2:12][C:11]3=[CH:15][N:16]=[CH:17][N:10]23)=[CH:5][CH:4]=1.C[Si](I)(C)C.CO>C(#N)C>[CH3:18][C:9]1([C:6]2[CH:7]=[CH:8][C:3]([OH:2])=[CH:4][CH:5]=2)[CH2:14][O:13][CH2:12][C:11]2=[CH:15][N:16]=[CH:17][N:10]12
Reactant: COc1ccc(C2(C)COCc3cncn32)cc1
Agent: C[Si](C)(C)I
Solvent: CC#N
Solvent: CO
Product: CC1(c2ccc(O)cc2)COCc2cncn21
Reaction time: 0.5 h

Procedure:
A mixture of 3.6 mmol of 5-(4-methoxyphenyl)-5-methyl-5,6-dihydro-8H-imidazo[5,1-c][1,4]-oxazine and 10 ml of trimethylsilyl iodide in 40 ml of acetonitrile is heated to reflux for 24 hours. 10 ml of methanol are cautiously added and heating to reflux is continued for 30 minutes. The reaction mixture is evaporated. The title compound is identified from the residue on the basis of the Rf by flash chromatography (SiO2 60F).
Reaction SMILES: [C:1]([O:18][CH2:19][CH:20]([CH2:22][O:23][C:24](=[O:40])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[OH:21])(=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].Cl[C:42]([O:44][CH:45]([Cl:47])[CH3:46])=[O:43].N1C=CC=CC=1>C(Cl)(Cl)Cl.ClCCl>[Cl:47][CH:45]([O:44][C:42]([O:21][CH:20]([CH2:22][O:23][C:24](=[O:40])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[CH2:19][O:18][C:1](=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[O:43])[CH3:46]
Reactant: CCCCCCCCCCCCCCCC(=O)OCC(O)COC(=O)CCCCCCCCCCCCCCC
Reactant: CC(Cl)OC(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCCCCCCC(=O)OCC(COC(=O)CCCCCCCCCCCCCCC)OC(=O)OC(C)Cl
Temperature: 25 °C
Reaction time: 120 h

Procedure:
1,3-Dipalmitoylglycerol (2.5 g, 4.39 mmol) and 1-chloroethyl chloroformate (1.26 g, 8.79 mmol) were dissolved in chloroform (50 ml). To this was added anhydrous pyridine dropwise. The reaction mixture was stirred at ambient temperature for 5 days, diluted with dichloromethane and extracted with 0.5N HCl solution. The organic layer was washed with a saturated sodium bicarbonate solution, washed again with water, dried over sodium sulphate and concentrated to dryness. The waxy residue was dried under reduced pressure and used without further purification.