Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Li+].[BH4-].C(O[C:6](=O)[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([NH:14][CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[N:9]=1)C.C1C[O:27]CC1>>[C:19]([O:18][C:16]([CH2:15][NH:14][C:10]1[N:9]=[C:8]([CH:7]([OH:27])[CH3:6])[CH:13]=[CH:12][CH:11]=1)=[O:17])([CH3:22])([CH3:21])[CH3:20]
Reactant: CCOC(=O)Cc1cccc(NCC(=O)OC(C)(C)C)n1
Reactant: C1CCOC1
Agent: [BH4-]
Agent: [Li+]
Product: CC(O)c1cccc(NCC(=O)OC(C)(C)C)n1
Temperature: 0 °C
Yield: 88 %

Procedure:
A solution of 2 N LiBH4 in THF (7 mL, 14 mmole) was added via syringe to a stirred solution of ethyl-6-[(tert-butoxycarbonyl)methylamino]-2-pyridylacetate (6.97 g, 23.7 mmole) in anhydrous THF (30 mL) under argon. The reaction was then slowly heated to reflux (initial exotherm). After 16 h at reflux, the reaction was cooled to 0° C. and carefully quenched with water (50 mL). The mixture was extracted with EtOAc (150 mL), and the organic layer was washed with brine, dried (Na2SO4), and concentrated. Purification by flash chromatography on silica gel (35% EtOAc/hexane) gave the title compound (5.26 g, 88%) as a clear oil: 1H NMR (400 MHz, CDCl3) δ 7.57 (m, 2H), 6.88 (d, J=7.2 Hz, 1H), 4.01 (t, 2H), 3.39 (s, 3H), 3.00 (t, 2H), 1.53 (s, 9H); MS (ES) m/e 253.2 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](OB(O)O)=[CH:4][CH:3]=1.Br[C:13]1[CH:14]=[C:15]([N+:20]([O-:22])=[O:21])[C:16]([OH:19])=[N:17][CH:18]=1.C([O-])([O-])=O.[Na+].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CC(C)=O.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:13]2[CH:14]=[C:15]([N+:20]([O-:22])=[O:21])[C:16]([OH:19])=[N:17][CH:18]=2)=[CH:4][CH:3]=1
Reactant: OB(O)Oc1ccc(Cl)cc1
Reactant: O=[N+]([O-])c1cc(Br)cnc1O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: O
Solvent: CC(C)=O
Product: O=[N+]([O-])c1cc(-c2ccc(Cl)cc2)cnc1O
Temperature: 60 °C
Reaction time: 18 h

Procedure:
23.5 g (150 mmol) 4-chlorophenyl-boric acid are added under argon to a solution of 22.1 g (101 mmol) 5-bromo-3-nitro-pyridin-2-ol, 200 mL (400 mmol) of a 2 M Na2CO3 solution and 731 mg (1.00 mmol) Pd(dppf)Cl2 in 400 mL acetone and 80 mL water. The reaction mixture is stirred for 18 h at 60° C. Acetone is eliminated i.vac. and the residue is adjusted to pH 7 with 160 mL 1 M citric acid. The aqueous phase is extracted three times with EtOAc and once with MeOH. The organic phase is dried over MgSO4 and the solvent is eliminated i.vac. The residue is triturated with EtOAc.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:7]([O:11][C:12]([N:14]1[CH2:18][CH:17]([CH2:19][C:20](O)=[O:21])[CH2:16][C@@H:15]1[C@H:23]1[O:27][C:26]([CH3:29])([CH3:28])[N:25]([C:30](=[O:32])[CH3:31])[C@H:24]1[CH2:33][C:34]1[CH:39]=[C:38]([F:40])[CH:37]=[C:36]([F:41])[CH:35]=1)=[O:13])([CH3:10])([CH3:9])[CH3:8].F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1.CN(C1C=CC=CN=1)C.C(N(CC)CC)C>ClCCl>[C:7]([O:11][C:12]([N:14]1[CH2:18][CH:17]([CH2:19][C:20](=[O:21])[N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[CH2:16][C@@H:15]1[C@H:23]1[O:27][C:26]([CH3:29])([CH3:28])[N:25]([C:30](=[O:32])[CH3:31])[C@H:24]1[CH2:33][C:34]1[CH:35]=[C:36]([F:41])[CH:37]=[C:38]([F:40])[CH:39]=1)=[O:13])([CH3:8])([CH3:9])[CH3:10]
Reactant: C1CCNCC1
Reactant: CC(=O)N1[C@@H](Cc2cc(F)cc(F)c2)[C@@H]([C@H]2CC(CC(=O)O)CN2C(=O)OC(C)(C)C)OC1(C)C
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: CN(C)c1ccccn1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N1[C@@H](Cc2cc(F)cc(F)c2)[C@@H]([C@H]2CC(CC(=O)N3CCCCC3)CN2C(=O)OC(C)(C)C)OC1(C)C

Procedure:
Add piperidine (0.013 g, 0.151 mmol) to a solution of (R)-2-[(4S,5S)-3-Acetyl-4-(3,5-difluoro-benzyl)-2,2-dimethyl-oxazolidin-5-yl]-4-carboxymethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (mixture of isomers) (0.05 g, 0.101 mmol), bromo tris-pyrrolidinophosphonium hexafluorophosphate (0.094 g, 0.201 mmol), dimethylamino-pyridine (0.001 g, 0.01 mmol) and triethylamine (0.021 mL, 0.151 mmol) in 2.2 mL of dichloromethane. Stir the reaction overnight. Concentrate under reduced pressure and subject the residue to silica gel chromatography, eluting with hexane/ethyl acetate (70% gradient to 100%) to provide both isomers of the desired compound. The 4(R) isomer is the slower eluting (0.033 g, 60%).
Reaction SMILES: [CH3:1][C:2]1([CH3:33])[C:6]2[C:7]([O:12][C:13]3[N:18]=[CH:17][C:16]([NH:19][C:20]([C@H:22]([NH:25][C:26](=[O:32])OC(C)(C)C)[CH2:23][CH3:24])=[O:21])=[CH:15][N:14]=3)=[CH:8][CH:9]=[C:10]([CH3:11])[C:5]=2[O:4][CH2:3]1.ClC(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl>Cl.C(O)(C)C.C(OCC)(=O)C>[CH2:23]([C@H:22]1[NH:25][C:26](=[O:32])[N:19]([C:16]2[CH:15]=[N:14][C:13]([O:12][C:7]3[C:6]4[C:2]([CH3:33])([CH3:1])[CH2:3][O:4][C:5]=4[C:10]([CH3:11])=[CH:9][CH:8]=3)=[N:18][CH:17]=2)[C:20]1=[O:21])[CH3:24]
Reactant: CC[C@@H](NC(=O)OC(C)(C)C)C(=O)Nc1cnc(Oc2ccc(C)c3c2C(C)(C)CO3)nc1
Agent: Cl
Agent: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Solvent: CC(C)O
Product: CC[C@H]1NC(=O)N(c2cnc(Oc3ccc(C)c4c3C(C)(C)CO4)nc2)C1=O
Temperature: 35 °C
Yield: 89.6 %

Procedure:
1,1-dimethylethyl {(1R)-1-[({2-[(3,3,7-trimethyl-2,3-dihydro-1-benzofuran-4-yl)oxy]-5-pyrimidinyl}amino)carbonyl]propyl}carbamate (Intermediate 191, 213 mg, 0.47 mmol) was dissolved in HCl 5-6 N in isopropanol (1 mL) and the resulting solution was heated to 35° C. for 30 minutes. The reaction mixture was then concentrated under vacuum, the residue diluted with ethyl acetate (50 mL) and an aqueous 5% solution of K2CO3 (30 mL). Two phases were separated and the organic layer was washed with an aqueous saturated solution of ammonium chloride (30 mL), dried over Na2SO4 and concentrated under vacuum. The resulting crude was dissolved in ethyl acetate (10 mL) and triethylamine was added (0.23 mL, 1.64 mmol). The reaction mixture was cooled to 0-5° C. and a solution of triphosgene (55 mg, 0.185 mmol) in ethyl acetate (5 mL) was added drop wise in 10 minutes. The reaction was quenched with water (50 mL) and extracted with ethyl acetate (50 mL). The organic layer was washed with brine dried over Na2SO4 and concentrated under vacuum. The residue was purified purified by flash chromatography on silica gel using cyclohexane/ethyl acetate 50:50 as eluent affording the title compound (161 mg) as a white solid.
Reaction SMILES: [O:1]=[C:2]1[N:6]([CH2:7][C:8]2[CH:17]=[CH:16][C:11]3[NH:12][C:13](=[O:15])[NH:14][C:10]=3[CH:9]=2)[C:5]2[CH:18]=[C:19]([C:22]([OH:24])=O)[CH:20]=[CH:21][C:4]=2[O:3]1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1.[CH3:53][N:54]([CH3:58])[CH2:55][CH2:56][NH2:57]>CN(C=O)C.O>[CH3:53][N:54]([CH3:58])[CH2:55][CH2:56][NH:57][C:22]([C:19]1[CH:20]=[CH:21][C:4]2[O:3][C:2](=[O:1])[N:6]([CH2:7][C:8]3[CH:17]=[CH:16][C:11]4[NH:12][C:13](=[O:15])[NH:14][C:10]=4[CH:9]=3)[C:5]=2[CH:18]=1)=[O:24]
Reactant: CN(C)CCN
Reactant: O=C(O)c1ccc2oc(=O)n(Cc3ccc4[nH]c(=O)[nH]c4c3)c2c1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CN(C)CCNC(=O)c1ccc2oc(=O)n(Cc3ccc4[nH]c(=O)[nH]c4c3)c2c1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
330 mg (0.76 mmol) of 2-oxo-3-(2-oxo-2,3-dihydro-1H-benzimidazol-5-yl-methyl)-2,3-dihydrobenzoxazole-5-carboxylic acid are dissolved in 3 ml of DMF, and 294 mg (1.52 mmol) of EDCI, 106 mg (0.76 mmol) of HOBt and 157 μl (1.52 mmol) of N-methylmorpholine are added. 81 mg (0.91 mmol) of 2-dimethylaminoethylamine are subsequently added, and the reaction solution is stirred at room temperature for 3 days. The reaction mixture is subsequently added to water and extracted with dichloromethane. The organic phase is dried over sodium sulfate, evaporated to dryness and purified by column chromatography on silica gel. The product is purified again by preparative HPLC; 100 mg of “A35” trifluoromethylacetate; ESI 397 (M+H), HPLC: Rt=3.89 min (method A).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:10](=O)[CH3:11])[CH:5]=[CH:6][CH:7]=1.[NH2:19]/[C:20](/[CH3:26])=[CH:21]\[C:22]([O:24][CH3:25])=[O:23].C(O)(=O)C>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:9]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[C:10]([CH3:11])[NH:19][C:20]([CH3:26])=[C:21]2[C:22]([O:24][CH3:25])=[O:23])[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)/C=C(/C)N
Reactant: CC(=O)C(=Cc1cccc(Cl)c1)c1ccccc1
Solvent: CCO
Solvent: CC(=O)O
Product: COC(=O)C1=C(C)NC(C)=C(c2ccccc2)C1c1cccc(Cl)c1

Procedure:
12.82 g (50 mmol) of 1-(3-chlorophenyl)-2-phenyl-3-oxo-1-butene in 80 ml of ethanol are heated to reflux with 11.5 g (100 mmol) of methyl β-aminocrotonate and 6 ml (100 mmol) of acetic acid overnight. 11.5 g of methyl β-aminocrotonate and 6 ml of acetic acid are added once more, and the mixture is heated under reflux for 24 hours. On cooling, crystals are produced, and these are filtered off with suction and washed with ethanol. For complete purification, they are passed through a silica gel column using toluene/ethyl acetate 20:1. 5.3 g of a colorless substance, of melting point 191° C., are obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C@@H:11]([CH3:22])[CH2:10]2)=[C:4]([CH3:23])[CH:3]=1.[Br:24][C:25]1[CH:26]=[N:27][CH:28]=[C:29]([S:31](Cl)(=[O:33])=[O:32])[CH:30]=1>>[Br:24][C:25]1[CH:30]=[C:29]([S:31]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([CH2:8][N:9]3[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:19])([CH3:21])[CH3:20])=[O:16])[C@@H:11]([CH3:22])[CH2:10]3)=[C:4]([CH3:23])[CH:3]=2)(=[O:33])=[O:32])[CH:28]=[N:27][CH:26]=1
Reactant: O=S(=O)(Cl)c1cncc(Br)c1
Reactant: Cc1cc(N)ccc1CN1CCN(C(=O)OC(C)(C)C)[C@@H](C)C1
Product: Cc1cc(NS(=O)(=O)c2cncc(Br)c2)ccc1CN1CCN(C(=O)OC(C)(C)C)[C@@H](C)C1
Reaction time: 8 h

Procedure:
The title compound was prepared from D7 and 3-bromopyridine-5-sulfonyl chloride using a method similar to that described for D15 except that the reaction time was overnight and column chromatography was carried out eluting with 0-100% Et2O/petroleum ether. δH (CDCl3, 400 MHz) 8.83 (1H, d), 8.80 (1H, d), 8.12 (1H, t), 7.16 (1H, d), 7.13 (1H, br.s), 6.92 (1H, d), 6.86 (1H, dd), 4.17 (1H, br.s), 3.77 (1H, d), 3.34 (2H, s), 2.99 (1H, m), 2.64 (1H, m), 2.51 (1H, d), 2.31 (3H, s), 2.14 (1H, m), 1.96 (1H, m), 1.46 (9H, s), 1.17 (3H, d). MS (ES+): MH+ 539/541.
Reaction SMILES: [Na+].[Cl-].CC1C[C@@H]2C3C=CC(O)=CC=3O[C@:14]3([C:26]4[CH:27]=[CH:28][C:29]([OH:33])=[CH:30][C:31]=4O)[CH:15]2[C@@H:6]([C:7]2[C:8]([OH:44])=[CH:9][C:10](C4OC5C=C(O)C=CC=5C=4)=[CH:11][C:12]=2O3)C=1.[CH3:45][OH:46]>>[CH3:45][O:46][C:10]1[CH:11]=[CH:12][C:7]([CH2:6][CH2:15][CH2:14][C:26]2[CH:27]=[CH:28][C:29]([OH:33])=[CH:30][CH:31]=2)=[C:8]([OH:44])[CH:9]=1
Reactant: CO
Reactant: CC1=C[C@@H]2c3c(O)cc(-c4cc5ccc(O)cc5o4)cc3O[C@]3(c4ccc(O)cc4O)Oc4cc(O)ccc4[C@@H](C1)C23
Agent: [Cl-]
Agent: [Na+]
Product: COc1ccc(CCCc2ccc(O)cc2)c(O)c1

Procedure:
Yellow powder; mp 95-96° C.; UV (MeOH) λmax (log ε) 279 (3.67), 231 (3.82) nm; IR (NaCl) γmax 3380, 1625, 1558, 1507 cm 1; 1H NMR (CD3OD, 500 MHz) δ 1.78 (2H, m, H-2), 2.51 (4H, m, H-1 and H-3), 3.71 (3H, s, OCH3), 6.31 (1H, dd, J=2.5 and 8.1 Hz, H-5′), 6.33 (1H, d, J=2.4 Hz, H-3′), 6.67 (2H, d, J=8.6 Hz, H-3″), 6.90 (1H, d, J=8.2 Hz, H-6′), 6.98 (2H, d, J=8.5 Hz, H-2″); 13C NMR (CD3OD, 125 MHz) δ 30.3 (C-1), 33.5 (C-2), 35.9 (C-3), 55.6 (OCH3), 102.3 (C-3′), 105.4 (C-5′), 116.0 (C-3″), 122.5 (C-1′), 130.3 (C-2″), 131.4 (C-6′), 134.9 (C-1″), 156.2 (C-4″), 157.0 (C-2′), 160.3 (C-4′); EIMS m/z 258 (M+, 62), 151 (21), 137 (100), 107 (26).
Reaction SMILES: CC([N:5]([C@H:9]([CH3:30])[C:10]([NH:12][C:13]1[CH:14]=[N:15][C:16]([O:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH:27]([CH3:29])[CH3:28])[CH:21]=2)=[CH:17][CH:18]=1)=[O:11])C(=O)[O-])(C)C.C(O)(C(F)(F)F)=O>ClCCl>[CH3:29][CH:27]([O:26][C:22]1[CH:21]=[C:20]([O:19][C:16]2[N:15]=[CH:14][C:13]([NH:12][C:10](=[O:11])[C@@H:9]([CH3:30])[NH2:5])=[CH:18][CH:17]=2)[CH:25]=[CH:24][CH:23]=1)[CH3:28]
Reactant: CC(C)Oc1cccc(Oc2ccc(NC(=O)[C@@H](C)N(C(=O)[O-])C(C)(C)C)cn2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)Oc1cccc(Oc2ccc(NC(=O)[C@@H](C)N)cn2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.9 %

Procedure:
To a solution of 1,1-dimethylethyl((1R)-1-methyl-2-{[6-({3-[(1-methylethyl)oxy]phenyl}oxy)-3-pyridinyl]amino}-2-oxoethyl)carbamate (Intermediate 31, 400 mg, 0.96 mmol) in dichloromethane (14 mL) was added TFA (6 mL) portionwise during 15 minutes at 0° C. The resulting mixture was stirred at room temperature for 2 hours. The solvent was distilled off to afford the title compound (260 mg, 85%) as a grey oil.
Reaction SMILES: [C:1]([C:4]1[C:8]([CH3:9])=[C:7]([Cl:10])[S:6][C:5]=1Cl)(=[O:3])[CH3:2].[C:12]1(B(O)O)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(=O)(O)[O-].[Na+]>COCCOC.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[C:1]([C:4]1[C:8]([CH3:9])=[C:7]([Cl:10])[S:6][C:5]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)(=[O:3])[CH3:2]
Reactant: OB(O)c1ccccc1
Reactant: CC(=O)c1c(Cl)sc(Cl)c1C
Agent: Cl[Pd]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Product: CC(=O)c1c(-c2ccccc2)sc(Cl)c1C
Yield: 77.9 %

Procedure:
To a stirred solution of 3-acetyl-2,5-dichloro-4-methylthiophene (0.98 g, 4.69 mmol) in DME (15 mL) were added benzeneboronic acid (0.69 g, 7.09 mmol), a saturated aqueous solution of sodium bicarbonate (5 mL) and bis(triphenylphosphine)palladium(II)chloride (0.39 g, 0.56 mmol) at room temperature under nitrogen. The mixture was heated at reflex temperature for 3 hours. The whole was extracted with diethyl ether (50 mL×2), and the combined organic layers were washed with brine, dried over MgSO4, and concentrated in vacuo. The residue was purified by flash chromatography eluting with hexane-ethyl acetate (10:1) to provide the title product (916 mg, 78% yield ).
Reaction SMILES: Cl.Cl.Cl.[CH3:4][C:5]1[C:6]2[O:28][CH:27]=[CH:26][C:7]=2[C:8]([N:11]2[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C@H:19]3[CH2:24][CH2:23][C@H:22]([NH2:25])[CH2:21][CH2:20]3)[CH2:13][CH2:12]2)=[N:9][CH:10]=1.[O:29]1[CH2:34][CH2:33][CH:32]([CH2:35][C:36](O)=[O:37])[CH2:31][CH2:30]1>>[CH3:4][C:5]1[C:6]2[O:28][CH:27]=[CH:26][C:7]=2[C:8]([N:11]2[CH2:12][CH2:13][N:14]([CH2:17][CH2:18][C@H:19]3[CH2:20][CH2:21][C@H:22]([NH:25][C:36](=[O:37])[CH2:35][CH:32]4[CH2:33][CH2:34][O:29][CH2:30][CH2:31]4)[CH2:23][CH2:24]3)[CH2:15][CH2:16]2)=[N:9][CH:10]=1
Reactant: O=C(O)CC1CCOCC1
Reactant: Cc1cnc(N2CCN(CC[C@H]3CC[C@H](N)CC3)CC2)c2ccoc12
Agent: Cl
Product: Cc1cnc(N2CCN(CC[C@H]3CC[C@H](NC(=O)CC4CCOCC4)CC3)CC2)c2ccoc12

Procedure:
The title compound, white solid (115 mg, 82%), MS (ISP) m/z=469.5 [(M+H)+], mp 205.5° C., was prepared in accordance with the general method of example 32 from trans-4-{2-[4-(7-methyl-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexylamine trihydrochloride (intermediate F) (136 mg, 0.3 mmol) and tetrahydropyran-4-yl-acetic acid.
Reaction SMILES: O.[Br:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]=[CH:10][C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)=[CH:5][CH:4]=1.C1OC1C.II>C1COCC1.C1CCCCC1>[Br:2][C:3]1[CH:4]=[CH:5][C:6]2[CH:9]=[CH:10][C:11]3[C:12]([C:7]=2[CH:8]=1)=[CH:13][C:14]([Cl:17])=[CH:15][CH:16]=3
Reactant: Clc1ccc(C=Cc2ccc(Br)cc2)cc1
Agent: CC1CO1
Agent: II
Solvent: C1CCOC1
Solvent: O
Solvent: C1CCCCC1
Product: Clc1ccc2ccc3ccc(Br)cc3c2c1
Reaction time: 24 h
Yield: 100.9 %

Procedure:
A 2 L vessel equipped with a pyrex inner water-cooled jacket was charged with 5.16 g (17 mmol) of 1-bromo-4-[2-(4-chlorophenyl)vinyl]benzene from Step 1, 2 L of cyclohexane, 25 mL of THF, 25 mL of propylene oxide and 6.7 g (26 mmol) of iodine. The stirring solution was degassed by bubbling nitrogen and was exposed to UV light for 24 hrs by inserting a 450 W medium pressure mercury lamp in the inner. The reaction was quenched with 10% Na2S2O3 and aqueous layer was extracted with ethyl acetate. Combined organic layers were washed with brine, dried over Na2SO4 and volatiles were removed under reduced pressure. The residue was swished in a minimal amount of ethyl acetate to afford approx. 5 g of 3-bromo-6-chlorophenanthrene as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:12][C:11](=[O:13])[CH2:10][CH2:9]S(=O)(=O)[CH:7]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[F:22])[C:6]=2[CH:23]=1.C(O)(C)(C)C.O>C(Cl)(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:12][C:11](=[O:13])[CH2:10][CH:9]=[C:7]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[F:22])[C:6]=2[CH:23]=1
Reactant: O=C1CCS(=O)(=O)C(c2ccccc2F)c2cc(Cl)ccc2N1
Solvent: CC(C)(C)O
Solvent: ClC(Cl)(Cl)Cl
Solvent: O
Product: O=C1CC=C(c2ccccc2F)c2cc(Cl)ccc2N1
Temperature: 35 °C
Reaction time: 0.58 h

Procedure:
67.0 g of 8-chloro-6-(2-fluorophenyl)-1,3,4,6-tetrahydro-2-oxo-2H-5,1-benzothiazocine 5,5-dioxide are suspended in a mixture of 670 ml of carbon tetrachloride, 670 ml of t-butanol and 31.5 ml of water. The suspension is pre-warmed to 35° C. There are then rapidly added thereto while cooling four 51.5 g portions of potassium t-butylate (the temperature amounts to 45°-50°). The mixture is stirred for a further 35 minutes, the temperature dropping to about 35°. The mixture is poured on to ice, whereupon it is extracted with methylene chloride. The organic phase is evaporated and the residue is triturated with ether. The crystalline product is filtered off. There is obtained 7-chloro-5-(2-fluorophenyl)-1,3-dihydro-2H-1-benzazepin-2-one of melting point 214°-215°.
Reaction SMILES: [CH2:1]([N:8]([CH2:21][C:22]1[CH:51]=[CH:50][C:25]([O:26][C:27]2[CH:28]=[C:29]([CH:47]=[CH:48][CH:49]=2)[O:30][CH2:31][CH2:32][CH2:33][C:34]([N:36]2[CH2:41][CH2:40][CH2:39][CH:38]([C:42]([O:44]CC)=[O:43])[CH2:37]2)=[O:35])=[CH:24][CH:23]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])[C:10]=1[CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].C(O)C.Cl>C(OCC)(=O)C.O1CCCC1>[CH2:1]([N:8]([CH2:21][C:22]1[CH:51]=[CH:50][C:25]([O:26][C:27]2[CH:28]=[C:29]([CH:47]=[CH:48][CH:49]=2)[O:30][CH2:31][CH2:32][CH2:33][C:34]([N:36]2[CH2:41][CH2:40][CH2:39][CH:38]([C:42]([OH:44])=[O:43])[CH2:37]2)=[O:35])=[CH:24][CH:23]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][S:16]([CH3:19])(=[O:17])=[O:18])[C:10]=1[CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C1CCCN(C(=O)CCCOc2cccc(Oc3ccc(CN(Cc4ccccc4)c4cccc(NS(C)(=O)=O)c4C)cc3)c2)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1c(NS(C)(=O)=O)cccc1N(Cc1ccccc1)Cc1ccc(Oc2cccc(OCCCC(=O)N3CCCC(C(=O)O)C3)c2)cc1

Procedure:
The product from Example 279A was treated with 2N NaOH aqueous solution (1 mL), ethyl alcohol (0.5 mL) and tetrahydrofuran (0.5 mL) at room temperature overnight. 1N hydrochloric acid was dropped to the reaction mixture until pH=2˜3. Ethyl acetate (3 mL) was used to extract the product. The organic layer was separated, dried (Na2SO4), concentrated in vaccuo, and purified by HPLC to provide the titled compound. 1H NMR (500 MHz, DMSO-d6) δ12.03-12.70 (br.s, 1 H), 8.95 (s, 1 H), 7.24 (m, 8 H), 7.04 (m, 1 H), 6.94 (m, 4 H), 6.69 (m, 1 H), 6.49 (m, 2 H), 4.06 (s, 2 H), 4.03 (s, 2 H), 3.94 (t, J=6.4 Hz, 2 H), 3.82 (m, 1 H), 3.72 (m, 1 H), 3.31 (dd, J=13.6, 9.2 Hz, 1 H), 2.98 (t, J=11.1 Hz, 1 H), 2.91 (s, 3 H), 2.38 (m, 5 H), 2.24 (m, 1 H), 1.90 (m, 3 H), 1.65 (m, 1 H), 1.52 (m, 1 H), 1.34 (m, 1 H); MS (APCI+) m/z 686.1 (M+H)+.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([N:11]=O)[C:8]([CH3:13])=[CH:7][C:6]=1[OH:14])([CH3:4])([CH3:3])[CH3:2].O.NN>C(O)C>[NH2:11][C:9]1[C:8]([CH3:13])=[CH:7][C:6]([OH:14])=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH:10]=1
Reactant: Cc1cc(O)c(C(C)(C)C)cc1N=O
Agent: NN
Solvent: CCO
Solvent: O
Product: Cc1cc(O)c(C(C)(C)C)cc1N
Temperature: 25 °C
Reaction time: 16 h
Yield: 90.2 %

Procedure:
To a solution of 2-(tert-butyl)4-nitroso-5-methylphenol (47.0 g, 243 mmol) in ethanol (500 ml) was slowly added dropwise hydrazine hydrate (29.5 ml, 608 mmol) at 0° C. After completing the dropwise addition, the mixture was stirred at room temperature for 16 hours, and the solvent was removed under reduced pressure. The residue was combined with water (500 ml), and the crystals were filtered. The crystals were dissolved in ethyl acetate, washed with saturated brine, dried over sodium sulfate and purified by silica gel column chromatography on a small amount of silica gel which was eluted with ethyl acetate. After the solvent was removed under reduced pressure, the residue was suspended in hexane and the crystals were collected by filtration to obtain 39.3 g of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([O:11][CH:12]([CH3:14])[CH3:13])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.C(OC([NH:22][CH2:23][C:24]1[CH:25]=[C:26]([CH2:32][CH:33]([O:37][CH:38]([CH3:40])[CH3:39])[C:34]([O-:36])=[O:35])[CH:27]=[CH:28][C:29]=1[O:30][CH3:31])=O)(C)(C)C>>[Cl:1][C:2]1[CH:10]=[C:9]([O:11][CH:12]([CH3:14])[CH3:13])[CH:8]=[CH:7][C:3]=1[C:4]([NH:22][CH2:23][C:24]1[CH:25]=[C:26]([CH2:32][CH:33]([O:37][CH:38]([CH3:40])[CH3:39])[C:34]([OH:36])=[O:35])[CH:27]=[CH:28][C:29]=1[O:30][CH3:31])=[O:6]
Reactant: COc1ccc(CC(OC(C)C)C(=O)[O-])cc1CNC(=O)OC(C)(C)C
Reactant: CC(C)Oc1ccc(C(=O)O)c(Cl)c1
Product: COc1ccc(CC(OC(C)C)C(=O)O)cc1CNC(=O)c1ccc(OC(C)C)cc1Cl

Procedure:
Using 2-chloro-4-isopropoxybenzoic acid and 3-(3-([(tert-butoxycarbonyl)amino]methyl)-4-methoxyphenyl]-2-isopropoxypropanoate, 3-(3-[(2-chloro-4-isopropoxybenzoyl)amino]methyl-4-methoxyphenyl)-2-isopropoxypropanoic acid was obtained in the same method as in Example 38).
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([CH2:21][CH3:22])[C:5]([NH:10][C@@H]2C3C(=CC=CC=3)C[C@@H]2O)=[N:6][C:7]=1[CH2:8][CH3:9].C(C1C(N[CH:34]2[C:43]3[C:38](=[CH:39][C:40]([O:44][CH3:45])=[CH:41][CH:42]=3)[CH2:37][CH2:36][CH2:35]2)=NC(CC)=CN=1)C>>[Br:1][C:2]1[N:3]=[C:4]([CH2:21][CH3:22])[C:5]([NH:10][CH:34]2[C:43]3[C:38](=[CH:39][C:40]([O:44][CH3:45])=[CH:41][CH:42]=3)[CH2:37][CH2:36][CH2:35]2)=[N:6][C:7]=1[CH2:8][CH3:9]
Reactant: CCc1cnc(CC)c(NC2CCCc3cc(OC)ccc32)n1
Reactant: CCc1nc(N[C@@H]2c3ccccc3C[C@@H]2O)c(CC)nc1Br
Product: CCc1nc(NC2CCCc3cc(OC)ccc32)c(CC)nc1Br

Procedure:
Following the procedure for the preparation of (1R,2S)-1-[(5-bromo-3,6-diethylpyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-ol but substituting 3,6-diethyl-N-(6-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)pyrazin-2-amine and making non-critical variations provided the title compound as a oil: 1H NMR (400 MHz, CDCl3) δ) 7.26, 6.78, 6.69, 5.33, 4.49, 3.82, 2.89-2.78, 2.55, 2.05-1.84, 1.33-1.26; HRMS (FAB) calcd for C19H24BrN3O+H 390.1181, found 390.1180.
Reaction SMILES: [CH3:1][O:2][C@H:3]1[C@@H:8]([N:9]([CH3:11])[CH3:10])[CH2:7][CH2:6][N:5](CC2C=CC=CC=2)[CH2:4]1.[H][H]>[Pd]>[CH3:1][O:2][C@H:3]1[C@@H:8]([N:9]([CH3:10])[CH3:11])[CH2:7][CH2:6][NH:5][CH2:4]1
Reactant: [H][H]
Reactant: CO[C@@H]1CN(Cc2ccccc2)CC[C@@H]1N(C)C
Agent: [Pd]
Product: CO[C@@H]1CNCC[C@@H]1N(C)C
Yield: 100 %

Procedure:
A mixture of cis-3-methoxy-N,N-dimethyl-1-(phenylmethyl)-4-piperidinamine was hydrogenated at normal pressure and at room temperature with 5 parts of palladium-on-charcoal catalyst 10%. After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was evaporated, yielding 17 parts (100%) of cis-3-methoxy-N,N-dimethyl-4-piperidinamine (int. 28).