Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[C@H:16]([N:18]1[C:22]2[CH:23]=[C:24]([N:27]3[CH2:32][CH2:31][N:30]([C:33]([C@H:35]4[CH2:39][CH2:38][CH2:37][N:36]4C(OC(C)(C)C)=O)=[O:34])[CH2:29][C@H:28]3[CH3:47])[CH:25]=[CH:26][C:21]=2[N:20]=[CH:19]1)[CH3:17]>ClCCl>[Cl:8][C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[C@H:16]([N:18]1[C:22]2[CH:23]=[C:24]([N:27]3[CH2:32][CH2:31][N:30]([C:33]([C@H:35]4[CH2:39][CH2:38][CH2:37][NH:36]4)=[O:34])[CH2:29][C@H:28]3[CH3:47])[CH:25]=[CH:26][C:21]=2[N:20]=[CH:19]1)[CH3:17]
Reactant: C[C@@H]1CN(C(=O)[C@H]2CCCN2C(=O)OC(C)(C)C)CCN1c1ccc2ncn([C@H](C)c3ccc(Cl)cc3Cl)c2c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@@H]1CN(C(=O)[C@H]2CCCN2)CCN1c1ccc2ncn([C@H](C)c3ccc(Cl)cc3Cl)c2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 21 %

Procedure:
Trifluoroacetic acid (0.5 mL) was added to a solution of the crude (R)-t-butyl 2-((R)-4-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-1H-benzo[d]imidazol-6-yl)-3-methylpiperazine-1-carbonyl)pyrrolidine-1-carboxylate in dichloromethane (2.0 mL) and the resulting solution was stirred at room temperature for 1 h. Excess solvent was removed in vacuo, and the residue was diluted with dichloromethane (5 mL). The organic layer was neutralized with saturated aqueous sodium bicarbonate, and the aqueous layer was further extracted with dichloromethane (2×10 mL). The combined organic layers were dried (Na2SO4), filtered, and concentrated in vacuo. The crude product was purified by flash chromatography (SiO2, 20% 7 N ammonia/methanol in dichloromethane) to give the title compound as a white solid (0.011 g, 0.023 mmol, 21% for 2 steps). 1H NMR (400 MHz, CDCl3) δ 8.07 (d, J=2.8 Hz, 1 H), 7.69 (dd, J=4.0, 8.8 Hz, 1 H), 7.45 (dd, J=2.0, 2.0 Hz, 1 H), 7.14 (dd, J=2.0, 8.4 Hz, 1 H), 6.99-6.95 (m, 1 H), 6.83 (dd, J=4.8, 8.4 Hz, 1 H), 6.59 (dd, J=2.0, 18.4 Hz, 1 H), 5.90 (q, J=6.8 Hz, 1 H), 4.45-4.35 (m, 1 H), 3.82-3.43 (m, 4 H), 3.32-3.17 (m, 2 H), 3.11-2.94 (m, 2 H), 2.39-2.28 (m, 2 H), 1.98 (dd, J=2.4, 6.8 Hz, 3 H), 1.94-1.80 (m, 3 H), 0.90 and 0.81 (d, J=6.4 and 6.0 Hz, 3 H); MS: (ES) m/z calculated for C25H30Cl2N5O [M+H]+ 486.2, found 485.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH2:5]O.[Cl:11]C(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl.N1C=CC=CC=1>O1CCCC1>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH2:5][Cl:11]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1ccccc1CO
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: COc1ccccc1CCl
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 290.5 %

Procedure:
2-Methoxybenzyl alcohol (1.01 g, 7.31 mmol) and triphosgene (757 mg, 2.55 mmol) were dissolved in tetrahydrofuran (5 ml). The solution was added with pyridine (1.18 ml, 14.6 mmol) under ice cooling, and then warmed to room temperature. After 20 minutes, insoluble solids were removed by filtration, and the solvent was evaporated under reduced pressure. The resulting oil was diluted with ethyl acetate and insoluble solids were further removed. The solvent was evaporated under reduced pressure to obtain the title compound as pale yellow oil (1.16 g, yield: 100%).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][N:13]([C:15]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[O:16])[CH2:12][CH:11]([C:23](O)=[O:24])[CH2:10]2)=[CH:5][CH:4]=1)[CH3:2].O[C:27]1([C:34](=[NH:36])[NH2:35])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]1[CH3:33]>>[CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([CH:9]2[CH2:10][CH:11]([C:23]3[O:24][N:36]=[C:34]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[CH3:33])[N:35]=3)[CH2:12][N:13]([C:15]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[O:16])[CH2:14]2)=[CH:7][CH:8]=1)[CH3:2]
Reactant: CC1C=CC=CC1(O)C(=N)N
Reactant: CCc1ccc(C2CC(C(=O)O)CN(C(=O)N3CCOCC3)C2)cc1
Product: CCc1ccc(C2CC(c3nc(-c4ccccc4C)no3)CN(C(=O)N3CCOCC3)C2)cc1

Procedure:
69 mg (0.20 mmol) of 5-(4-ethylphenyl)-1-(morpholin-4-ylcarbonyl)piperidine-3-carboxylic acid (Example 38A) and 33 mg (0.22 mmol, 1.1 eq.) of 1-hydroxy-2-methylbenzenecarboximidamide were reacted according to the General Method 1. Yield: 62 mg (68% of theory)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N:8]2[CH:12]=[C:11]([C@:13]([NH2:22])([CH3:21])[C:14]([F:20])([F:19])[CH2:15][O:16][C:17]#[N:18])[CH:10]=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[OH-].[NH4+].ClCCl>CO>[Br:1][C:2]1[CH:3]=[C:4]([N:8]2[CH:12]=[C:11]([C@:13]3([CH3:21])[C:14]([F:20])([F:19])[CH2:15][O:16][C:17]([NH2:18])=[N:22]3)[CH:10]=[N:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: C[C@@](N)(c1cnn(-c2cccc(Br)c2)c1)C(F)(F)COC#N
Agent: [NH4+]
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Product: C[C@]1(c2cnn(-c3cccc(Br)c3)c2)N=C(N)OCC1(F)F
Yield: 66.7 %

Procedure:
In a sealed tube a solution of (R)-1-[1-(3-bromo-phenyl)-1H-pyrazol-4-yl]-3-cyanato-2,2-difluoro-1-methylpropylamine (3.0 g, 8.08 mmol) and ammonium hydroxide (25% in water, 7 ml) in methanol (10 ml) was heated to 60° C. for 16 hours. For the workup, the solution was evaporated at reduced pressure. The crude material thus obtained was purified by column chromatography on silica gel using a 95:5-mixture of dichloromethane and methanol as the eluent to give the (R)-4-[1-(3-bromo-phenyl)-1H-pyrazol-4-yl]-5,5-difluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine (2.0 g, 54% yield) as a white solid. MS (ISP): m/z=371.2 [M+H]+.
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([NH:10][C:11](=[O:15])[CH:12](Cl)[CH3:13])=[CH:4][C:3]=2[O:2]1.[N:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([NH:10][C:11](=[O:15])[CH:12]([N:25]3[CH2:26][CH2:27][N:22]([C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][N:16]=4)[CH2:23][CH2:24]3)[CH3:13])=[CH:4][C:3]=2[O:2]1
Reactant: c1ccc(N2CCNCC2)nc1
Reactant: CC(Cl)C(=O)Nc1ccc2c(c1)OCO2
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC(C(=O)Nc1ccc2c(c1)OCO2)N1CCN(c2ccccn2)CC1

Procedure:
The amide prepared in part (a) is condensed with 1-(2-pyridyl)-piperazine according to the method used in Example 1, using triethylamine as the base. The desired product is obtained with a melting point of 189°-191° C. (from toluene); Rf=0.44 (AcOEt); IR (nujol) νmax: 3280, 3250, 1680, 1660, 1595, 1540, 1520, 1490, 1450, 1440, 1250, 1165, 1035, 925, 775 cm-1.
Reaction SMILES: CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O.[OH:14][C@H:15]1[C@:19]2([CH3:33])[CH2:20][C@H:21]3[C@H:30]([CH2:31][C@H:18]2[CH2:17][CH2:16]1)[C@@H:29]1[C@@H:24]([CH2:25][C:26](=[O:32])[CH2:27][CH2:28]1)[CH2:23][CH2:22]3.CC(O)C>CC(C)=O>[CH3:33][C@:19]12[C:15](=[O:14])[CH2:16][CH2:17][C@@H:18]1[CH2:31][C@H:30]1[C@@H:21]([CH2:22][CH2:23][C@H:24]3[C@@H:29]1[CH2:28][CH2:27][C:26](=[O:32])[CH2:25]3)[CH2:20]2
Reactant: C[C@@]12C[C@@H]3CC[C@@H]4CC(=O)CC[C@@H]4[C@H]3C[C@H]1CC[C@H]2O
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CC(C)=O
Solvent: CC(C)O
Product: C[C@@]12C[C@@H]3CC[C@@H]4CC(=O)CC[C@@H]4[C@H]3C[C@H]1CCC2=O
Reaction time: 0.17 h
Yield: 95.4 %

Procedure:
Jones reagent was added to a solution of compound 53 (115 mg, 0.42 mmol) in acetone (20 mL) at 0° C. until a brown-yellowish color persisted. After 10 min, 2-propanol (1.0 mL) was added to consume excess oxidant and then brine (50 mL) was added. The product was extracted into EtOAc (50 mL×3), and the combined extracts were dried, filtered, and concentrated. The residue was purified by flash column chromatography (silica gel eluted with 25% EtOAc in hexanes) to give compound 54 (110 mg 4aR:4aS ratio 2.5:1) as a white solid: 1H NMR (CDCl3) δ 0.84 (s, 3H); 13C NMR (CDCl3) 4aR diastereomer δ 220.3, 212.2, 47.8, 45.6, 42.6, 39.8, 39.0, 38.5, 38.2, 38.1, 36.3, 35.4, 30.7, 28.5, 28.4, 27.1, 23.9, 13.5.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][OH:8].[C:9]1([CH2:15][CH2:16][CH2:17][C:18](O)=[O:19])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:18](=[O:19])[CH2:17][CH2:16][CH2:15][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: OCCCCCCBr
Reactant: O=C(O)CCCc1ccccc1
Product: O=C(CCCc1ccccc1)OCCCCCCBr
Yield: 72 %

Procedure:
From 6-bromo-1-hexanol and 4-phenylbutyric acid. Working up by means of distillation. Yield: 72%. Boiling point: 158° C. (0.01 mbar)
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[N:8]3[C:12](=[C:13]([C:15]([NH2:17])=[O:16])[CH:14]=2)[CH2:11][CH2:10][CH2:9]3)[CH:2]=1.[Cl:18]N1C(=O)CCC1=O>>[Cl:18][C:14]1[C:13]([C:15]([NH2:17])=[O:16])=[C:12]2[N:8]([CH2:9][CH2:10][CH2:11]2)[C:7]=1[C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1
Reactant: NC(=O)c1cc(-c2cccnc2)n2c1CCC2
Reactant: O=C1CCC(=O)N1Cl
Product: NC(=O)c1c(Cl)c(-c2cccnc2)n2c1CCC2

Procedure:
6-Chloro-5-(3-pyridyl)-2,3-dihydropyrolizine-7-carboxamide is prepared as described in Example 45, from 0.45 g of 5-(3-pyridyl)-2,3-dihydropyrrolizine-7-carboxamide and 0.29 g of N-chlorosuccinimide. 0.27 g of expected product are thus obtained in the form of cream powder which melts at 215° C.
Reaction SMILES: [C:1]([C:7]1[CH:16]=[CH:15][CH:14]=[CH:13][C:8]=1[C:9](OC)=[O:10])#[C:2][CH2:3][CH2:4][CH2:5][CH3:6].Cl.[CH3:18][NH:19][O:20][CH3:21].[Li]CCCC>>[C:1]([C:7]1[CH:16]=[CH:15][CH:14]=[CH:13][C:8]=1[C:9]([N:19]([CH3:18])[O:20][CH3:21])=[O:10])#[C:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCC#Cc1ccccc1C(=O)OC
Reactant: CNOC
Agent: Cl
Agent: [Li]CCCC
Product: CCCCC#Cc1ccccc1C(=O)N(C)OC
Yield: 77 %

Procedure:
Treatment of methyl 2-(1-hexyn-1-yl)benzoate (157) (2.29 g, 10.6 mmol) with a mixture of N,O-dimethylhydroxylamine hydrochloride and nBuLi gave 2.0 g (77%) of the title compound (158) as a yellow oil. 1H NMR (400 MHz, CDCl3): δ 0.92 (t, J=7.2 Hz, 3H), 1.40-1.60 (m, 4H), 2.39 (t, J=7.0 Hz, 2H), 3.32 (br s, 3H), 3.50 (br s, 3H), 7.26-7.35 (m, 3H), 7.37-7.45 (m, 1H). LCMS (APCI): m/z 246 (M+H)+.
Reaction SMILES: [CH:1]([NH:4][S:5]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=1)(=[O:7])=[O:6])([CH3:3])[CH3:2].[H-].[Na+].Cl[CH2:21][CH2:22][CH2:23][N:24]([CH2:26][CH2:27][C:28]1[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[C:30]([O:36][CH3:37])[CH:29]=1)[CH3:25]>CN(C)C=O>[CH3:37][O:36][C:30]1[CH:29]=[C:28]([CH2:27][CH2:26][N:24]([CH3:25])[CH2:23][CH2:22][CH2:21][N:4]([CH:1]([CH3:3])[CH3:2])[S:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:15])[F:16])[CH:9]=2)(=[O:7])=[O:6])[CH:33]=[CH:32][C:31]=1[O:34][CH3:35]
Reactant: COc1ccc(CCN(C)CCCCl)cc1OC
Reactant: CC(C)NS(=O)(=O)c1cccc(C(F)(F)F)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(CCN(C)CCCN(C(C)C)S(=O)(=O)c2cccc(C(F)(F)F)c2)cc1OC
Reaction time: 2 h
Yield: 43.3 %

Procedure:
N-isopropyl-3-trifluoromethylbenzenesulfonamide (5.362 g, 0.02 mol) in dimethylformamide (30 mL) was treated with sodium hydride (60% in mineral oil), (0.802 g) and stirred for 2 hours. Then N-(3-chloropropyl)-3,4-dimethoxy-N-methylphenethylamine (5.436 g, 0.02 mol) was added and the reaction heated overnight. Filtration and removal of solvent provided the crude product (6.95 g). Column chromatography and high pressure liquid chromatography provided the pure product (4.35 g) as a gum. 1H NMR (CDCl3) 1.15 (d, 6, J=3.5H, Me2) 2.25 (s, 3, N--Me) 3.84 (d, 6, (OMe)2) 6.76 (m, 3, Ar) 7.25 (m, 3, Ar).
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.C1(C)C=CC=CC=1.[Cl:18][C:19]1[CH:33]=[C:32]([Cl:34])[CH:31]=[CH:30][C:20]=1[O:21][C:22]1[CH:29]=[CH:28][CH:27]=[CH:26][C:23]=1[C:24]#N.[OH2:35]>C1COCC1>[Cl:18][C:19]1[CH:33]=[C:32]([Cl:34])[CH:31]=[CH:30][C:20]=1[O:21][C:22]1[CH:29]=[CH:28][CH:27]=[CH:26][C:23]=1[CH:24]=[O:35]
Reactant: N#Cc1ccccc1Oc1ccc(Cl)cc1Cl
Reactant: O
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: O=Cc1ccccc1Oc1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 16 h

Procedure:
At 0° C., a 1.2 M solution of diisobutylaluminum hydride in toluene (12.3 ml, 14.8 mmol) was added dropwise to a solution of 2-(2,4-dichlorophenoxy)benzonitrile (3.0 g, 11.3 mmol) in THF (30 ml). The reaction mixture was warmed to room temperature and stirred for 16 hours. It was cooled to 0° C. Water (10 ml) was added dropwise. It was warmed to room temperature. The solid was removed by filtration through a plug of celite. The solvent was removed from the filtrate in vacuo. The crude product was purified by flash chromatography on silica (130 g), using ethyl acetate/heptane 1:3 as eluent, to give 800 mg of 2-(2,4-dichlorophenoxy)benzaldehyde.
Reaction SMILES: Br[CH:2]([CH2:25][CH3:26])[C:3]([N:5]1[C:9]([CH3:16])([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:8][C:7]([C:17]2[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=2[F:24])=[N:6]1)=[O:4].[CH3:27][N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>CCCCO>[F:24][C:18]1[CH:19]=[CH:20][C:21]([F:23])=[CH:22][C:17]=1[C:7]1[CH2:8][C:9]([CH3:16])([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:5]([C:3]([CH:2]([N:31]2[CH2:32][CH2:33][N:28]([CH3:27])[CH2:29][CH2:30]2)[CH2:25][CH3:26])=[O:4])[N:6]=1
Reactant: CN1CCNCC1
Reactant: CCC(Br)C(=O)N1N=C(c2cc(F)ccc2F)CC1(C)c1ccccc1
Solvent: CCCCO
Product: CCC(C(=O)N1N=C(c2cc(F)ccc2F)CC1(C)c1ccccc1)N1CCN(C)CC1

Procedure:
A solution of the more polar (lower Rf on silica gel TLC plate) diastereomeric 1-(2-bromobutanoyl)-3-(2,5-difluorophenyl)-5-methyl-5-phenyl-4,5-dihydro-1H-pyrazole (1-1, 370 mg, 0.878 mmol, 1 equiv) and 1-methylpiperazine (0.500 mL, 0.536 mmol, 6.11 equiv) in n-BuOH (3 mL) was heated at 100° C. for 20 h. The reaction mixture was cooled and purified by reverse-phase LC (H2O/CH3CN gradient w/0.1% TFA present). The desired fractions were partitioned between a 1:1 saturated aqueous sodium bicarbonate solution and brine and ethyl acetate (2×100 mL). The combined organic layers were dried over sodium sulfate and concentrated to give 1-(1-{[3-(2,5-difluorophenyl)-5-methyl-5-phenyl-4,5-dihydro-1H-pyrazol-1-yl]carbonyl}propyl)-4-methylpiperazine as a diastereomerically pure racemic mixture. The racemic mixture was separated by normal-phase chiral chromatography (ChiralPak AD column: 95% Hex and 5% i-PrOH with 0.1% diethylamine as a modifier) to provide 1-((1S)-1-{[(5S)-3-(2,5-difluorophenyl)-5-methyl-5-phenyl-4,5-dihydro-1H-pyrazol-1-yl]carbonyl}propyl)-4-methylpiperazine (1-2, more polar enantiomer) as a white foam. 1H NMR (300MHz, CDCl3) δ 7.63 (m, 1H), 7.35-7.19 (m, 5H), 7.07 (m, 2H), 4.37 (dd, 1H, J=9.2, 5.5 Hz), 3.54 (dd, 1H, J=18.6, 3.0 Hz), 3.46 (dd, 1H, J=18.6, 3.0 Hz), 2.73 (m, 4H), 2.41 (m, 4H), 2.26 (s, 3H), 2.07 (s, 3H), 1.80 (m, 1H), 1.58 (m, 1H), 0.86 (t, 3H, J=7.3 Hz). LRMS m/z (M+H) 441.5 found, 441.2 required.
Reaction SMILES: Cl[C:2]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[O:19][CH3:20])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([Cl:11])[CH:9]=2)[NH:4][C:3]1=[O:12].FC(F)(F)C(O)=O.[NH2:28][CH2:29][C:30]([N:32]([CH3:34])[CH3:33])=[O:31]>>[Cl:11][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[NH:4][C:3](=[O:12])[C:2]2([NH:28][CH2:29][C:30]([N:32]([CH3:34])[CH3:33])=[O:31])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[O:19][CH3:20]
Reactant: CN(C)C(=O)CN
Reactant: COc1ccccc1C1(Cl)C(=O)Nc2ccc(Cl)cc21
Solvent: O=C(O)C(F)(F)F
Product: COc1ccccc1C1(NCC(=O)N(C)C)C(=O)Nc2ccc(Cl)cc21

Procedure:
With 2.01 g of 3,5-dichloro-3-(2-methoxyphenyl)-1,3-dihydro-2H-indol-2-one and the compound obtained in Step 62-2 (7.81 mmol, crude form) as starting material, 1.91 g of the title compound (colorless powder) was obtained by a similar method to Step 4-2.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5](F)=[C:6]([CH:19]=1)[C:7]([C:9](=[CH:15][N:16]([CH3:18])C)[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[O:8].N[C@H:22]1[CH2:27]C[CH2:25][N:24]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:23]1.C(=O)([O-])[O-].[K+].[K+].Cl>CN(C=O)C>[Br:1][C:2]1[CH:19]=[C:6]2[C:5](=[N:4][CH:3]=1)[N:16]([C@H:18]1[CH2:27][CH2:22][CH2:23][N:24]([C:28]([O:30][C:31]([CH3:32])([CH3:34])[CH3:33])=[O:29])[CH2:25]1)[CH:15]=[C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:7]2=[O:8]
Reactant: CCOC(=O)C(=CN(C)C)C(=O)c1cc(Br)cnc1F
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](N)C1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn([C@H]2CCCN(C(=O)OC(C)(C)C)C2)c2ncc(Br)cc2c1=O
Temperature: 90 °C
Yield: 75.5 %

Procedure:
Ethyl 2-(5-bromo-2-fluoronicotinoyl)-3-(dimethylamino)acrylate (Intermediate 3, 2.0 g, 5.79 mmol), (S)-tert-butyl 3-aminopiperidine-1-carboxylate (1.160 g, 5.79 mmol), and potassium carbonate (2.042 g, 7.38 mmol) were combined in DMF (10.0 mL). The reaction mixture was heated at 90° C. for 2 h. The reaction mixture was cooled to 0° C. and 1N HCl was slowly added until pH was 5. The resulting precipitate was collected by filtration, washed with water and dried overnight to yield a light yellow solid (2.10 g, 75%).
Reaction SMILES: Br.Br[CH2:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][N:16]([CH2:19][CH3:20])[CH2:17][CH3:18])=[C:9]([Cl:21])[CH:8]=1)=[O:5].[Cl:22][C:23]1[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[CH:25][C:24]=1[NH2:33]>CN(C=O)C.O>[Cl:21][C:9]1[CH:8]=[C:7]([NH:6][C:4](=[O:5])[CH2:3][NH:33][C:24]2[CH:25]=[CH:26][C:27]([C:29]([F:30])([F:31])[F:32])=[CH:28][C:23]=2[Cl:22])[CH:12]=[CH:11][C:10]=1[O:13][CH2:14][CH2:15][N:16]([CH2:19][CH3:20])[CH2:17][CH3:18]
Reactant: CCN(CC)CCOc1ccc(NC(=O)CBr)cc1Cl
Reactant: Nc1ccc(C(F)(F)F)cc1Cl
Agent: Br
Solvent: O
Solvent: CN(C)C=O
Product: CCN(CC)CCOc1ccc(NC(=O)CNc2ccc(C(F)(F)F)cc2Cl)cc1Cl
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of 0.228 g (0.511 mmol) of 2-bromo-N-[3-chloro-4-(2-diethylamino-ethoxy)-phenyl]-acetamide-hydrobromide (intermediate product Z1c) and 0.200 g (1.023 mmol) of 2-chloro-4-trifluoromethyl-phenylamine in 5 mL DMF was stirred for 16 hours at 90° C. and then for 24 hours at 120° C. The reaction mixture was cooled to RT, diluted with water and exhaustively extracted with EtOAc. The combined org. extracts were dried over magnesium sulphate and evaporated down i. vac. The residue was dissolved in DMF and purified by HPLC-MS (Stable Bond C18; 3.5 μm; water:acetonitrile:formic acid 9:1:0.01→1:9:0.01 over 9 min).
Reaction SMILES: [C:1]1([N:7]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[C:28]4[C:24](=[N:25][NH:26][N:27]=4)[C:23]([C:29]4[CH:34]=[CH:33][C:32]([N:35]([C:42]5[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=5)[C:36]5[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=5)=[CH:31][CH:30]=4)=[CH:22][CH:21]=3)=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:49]1[CH:50]=[CH:51][C:52]2[C:53](=[O:69])[N:54]([CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH3:68])[C:55](=[O:62])[C:56]3[C:61]=2[C:60]=1[CH:59]=[CH:58][CH:57]=3.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>C(OCC)(=O)C.[Cu]I>[C:8]1([N:7]([C:14]2[CH:15]=[CH:16][C:17]([C:20]3[C:28]4[C:24](=[N:25][N:26]([C:59]5[CH:58]=[CH:57][C:56]6[C:55](=[O:62])[N:54]([CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH3:68])[C:53](=[O:69])[C:52]7[C:61]=6[C:60]=5[CH:49]=[CH:50][CH:51]=7)[N:27]=4)[C:23]([C:29]4[CH:34]=[CH:33][C:32]([N:35]([C:36]5[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=5)[C:42]5[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=5)=[CH:31][CH:30]=4)=[CH:22][CH:21]=3)=[CH:18][CH:19]=2)[C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CCCCCCN1C(=O)c2cccc3c(Br)ccc(c23)C1=O
Reactant: c1ccc(N(c2ccccc2)c2ccc(-c3ccc(-c4ccc(N(c5ccccc5)c5ccccc5)cc4)c4n[nH]nc34)cc2)cc1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCCCCN1C(=O)c2cccc3c(-n4nc5c(-c6ccc(N(c7ccccc7)c7ccccc7)cc6)ccc(-c6ccc(N(c7ccccc7)c7ccccc7)cc6)c5n4)ccc(c23)C1=O
Temperature: 160 °C

Procedure:
A mixture of Intermediate D (1.00 g, 1.65 mmol), 6-bromo-2-hexyl-1H-benzo[de]isoquinoline-1,3(2H)-dione (720 mg, 2.0 mmol), potassium carbonate (276 mg, 2.0 mmol), CuI (382 mg, 2.0 mmol), and dimethylformamide (12 mL) was stirred under argon and heated at 160° C. for 3 days. After cooling, the reaction mixture was diluted with ethyl acetate (100 mL), washed with water (3×50 mL), dried over magnesium sulfate, and the solvent was removed under reduced pressure. The crude product was purified by column chromatography (silica gel, hexane/dichloromethane 1:1) and washing with ethanol to give 6-(4,7-bis(4-(N,N-diphenylamino)phenyl)-2H-benzo[d][1,2,3]triazol-2-yl)-2-hexyl-1H-benzo[de]isoquinoline-1,3(2H)-dione (Example 18), brown-violet crystals, 445 mg (30%). 1H NMR (400 MHz, CDCl3): δ 9.08 (dd, J=8.4 and 1.1 Hz, 1H, naphthalene), 8.74 (d, J=7.6 Hz, 1H, naphthalene), 7.69 (dd, J=7.3 and 1.1 Hz, 1H, naphthalene), 8.43 (d, J=8.1 Hz, 1H, naphthalene), 8.07 (d, J=8.8 Hz, 4H, p-phenylene), 7.85 (dd, J=8.4 and 7.3 Hz, 1H, naphthalene), 7.74 (s, 2H, benzotriazole), 7.28 (m, 8H, Ph), 7.21 (d, J=8.4 Hz, 4H, p-phenylene), 7.18 (m, 8H, Ph), 7.05 (tt, J=7.3 and 1.1 Hz, 4H, Ph). UV-vis spectrum (dichloromethane): λmax=381 nm. Fluorimetry (dichloromethane): λmax=481 nm.
Reaction SMILES: [BH4-].[Na+].[CH3:3][C:4]([C:6]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:7]=1[OH:13])=[O:5].C(O)(=O)C>CO>[Cl:12][C:10]1[CH:9]=[CH:8][C:7]([OH:13])=[C:6]([CH:4]([OH:5])[CH3:3])[CH:11]=1
Reactant: CC(=O)c1cc(Cl)ccc1O
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CC(O)c1cc(Cl)ccc1O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 94.9 %

Procedure:
Sodium borohydride (0.5 g) was added in small portions to a cooled solution of 5-chloro-2-hydroxyacetophenone (5 g) in methanol (50 ml). The solution was stirred at room temperature for 0.5 hr and was then poured into ice-water and acidified with dilute acetic acid. The product was extracted with ether, the ethereal solution was washed with water and then 5% aqueous sodium bicarbonate solution. The ethereal solution was dried (Na2SO4) and the solvent removed under reduced pressure. The colourless oil crystallised from hexane/ethyl acetate to give 4-chloro-2-(1-hydroxyethyl)phenol (4.8 g); m.p. 98° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([NH2:13])[S:11][CH:12]=2)=[CH:4][CH:3]=1.[CH3:14][O:15][C:16](=[O:23])[C:17]([C:19]([F:22])([F:21])[F:20])=O.C([BH3-])#N.[Na+]>C(Cl)Cl.CO.[Ti](Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]([NH:13][C@H:17]([C:16]([O:15][CH3:14])=[O:23])[C:19]([F:22])([F:21])[F:20])[S:11][CH:12]=2)=[CH:6][CH:7]=1
Reactant: COC(=O)C(=O)C(F)(F)F
Reactant: Nc1nc(-c2ccc(Br)cc2)cs1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: COC(=O)[C@@H](Nc1nc(-c2ccc(Br)cc2)cs1)C(F)(F)F
Reaction time: 0.25 h
Yield: 43 %

Procedure:
4-(4-Bromophenyl)-1,3-thiazol-2-ylamine (510 mg, 2.0 mmol) and methyl-3,3,3-trifluoropyruvate (0.10 mL, 1.0 mmol) were dissolved in 50 mL methylene chloride. Titanium (IV) chloride (1M in toluene, 1.6 mL, 1.6 mmol) was added dropwise to give an orange-brown suspension. The mixture was stirred for 15 min and then added by cannula to a solution of sodium cyanoborohydride (0.26 g, 3.0 mmol) in 50 mL of methanol. The mixture was stirred for 15 min and then quenched by the addition of H2O and saturated aqueous sodium bicarbonate. The mixture was extracted three times with methylene chloride. The organics were combined, washed with water, brine, dried over anhydrous MgSO4, filtered and concentrated under reduced pressure. Flash chromatography (100% methylene chloride) afforded methyl N-[4-(4-bromophenyl)-1,3-thiazol-2-yl]-3,3,3-trifluoroalaninate (0.17 g, 44%) as a white solid. MS (ES) m/z 392.8.
Reaction SMILES: [CH3:1][C:2]([NH:5][S:6]([C:9]1[CH:13]=[CH:12][N:11]([Si](C(C)C)(C(C)C)C(C)C)[CH:10]=1)(=[O:8])=[O:7])([CH3:4])[CH3:3].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C1COCC1.C(O)(=O)C>C1COCC1>[CH3:4][C:2]([NH:5][S:6]([C:9]1[CH:13]=[CH:12][NH:11][CH:10]=1)(=[O:8])=[O:7])([CH3:1])[CH3:3]
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ccc(S(=O)(=O)NC(C)(C)C)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CC(C)(C)NS(=O)(=O)c1cc[nH]c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 81 %

Procedure:
A solution of N-(1,1-dimethylethyl)-1-[tris(1-methylethyl)sily]-1H-pyrrole-3-sulfonamide (1.7 g, 4.7 mmol) in 25 mL THF was treated with 5.2 mL of 1M tetrabutylammonium fluoride/THF solution, followed by 0.3 mL of acetic acid. After stirring 30 minutes at room temperature, the reaction mixture was filtered through silica with THF rinse, and the filtrate stripped. The solid residue was triturated with hexanes to afford 0.77 g of tan solids, m.p. 145°-147° C. dec.