Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:5][CH:4]=1.Br.Br[CH2:25][CH2:26][CH2:27][NH2:28].C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2([C:15]3[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=3)[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:7][CH:8]=1.[NH2:28][CH2:27][CH2:26][CH2:25][N:12]1[CH2:13][CH2:14][C:9]([C:15]2[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=2)([C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)[CH2:10][CH2:11]1
Reactant: NCCCBr
Agent: Br
Agent: COc1ccc(C2(c3ccc(OC)cc3)CCNCC2)cc1
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: COc1ccc(C2(c3ccc(OC)cc3)CCN(CCCN)CC2)cc1

Procedure:
4,4-bis-(4-Methoxyphenyl)piperidine (9.01 g, 30.3 mmol, 1.00 equiv), 3-bromopropylamine hydrobromide (6.66 g, 30.3 mmol, 1.00 equiv) and potassium carbonate (5.02 g, 36.3 mmol, 1.20 equiv) were stirred in refluxing anhydrous 1,4-dioxane (200 mL) for 12 hours. After removal of dioxane, water (200 mL) was added and the pH was adjusted to 11-12 by addition of 1 N aqueous NaOH. The mixture was extracted with CH2Cl2 (4×200 mL). The combined organic solutions were dried over MgSO4 and concentrated. The residue was purified by flash chromatography (SiO2, CHCl3-MeOH-NH3 (2 M in MeOH) 100:20:10) to give 6.50 g of 4,4-bis-(4-methoxyphenyl)piperidine and 2.70 g (25%, 90% after correction for recovered starting material) of 1-(3-aminopropyl)-4,4-bis-(4-methoxyphenyl)piperidine (colorless oil), which was characterized spectroscopically.
Reaction SMILES: [OH:1][C:2]1([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.CCN(C(C)C)C(C)C.[Br:22][C:23]1[CH:24]=[N:25][C:26](Cl)=[N:27][CH:28]=1.O>CCO>[Br:22][C:23]1[CH:24]=[N:25][C:26]([N:5]2[CH2:4][CH2:3][C:2]([OH:1])([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:7][CH2:6]2)=[N:27][CH:28]=1
Reactant: Clc1ncc(Br)cn1
Reactant: CCOC(=O)C1(O)CCNCC1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: CCOC(=O)C1(O)CCN(c2ncc(Br)cn2)CC1
Temperature: 80 °C
Yield: 50.2 %

Procedure:
To an ice-cold solution of ethyl 4-hydroxypiperidine-4-carboxylate (0.60 g, 3.44 mmol) in EtOH (15 mL) was added DIPEA (2.95 mL, 17.24 mmol) followed by the addition of 5-bromo-2-chloropyrimidine (0.67 g, 3.44 mmol). The reaction was heated to 80° C. for 3 h then cooled to rt, water added and extracted with EtOAc (3×100 mL). The combined organics were washed with brine, dried over anhydrous Na2SO4, filtered and evaporated under reduced pressure. The crude residue was purified over 100-200 M silica-gel using 20% EtOAc:hexane to obtain the desired product as a yellow solid (0.57 g, 88%). 1H NMR (DMSO-d6): δ 8.44 (s, 2H), 5.58 (s, 1H), 4.27 (m, 2H), 4.10 (q, J=7.20 Hz, 2H), 3.28 (m, 2H), 1.81 (m, 2H), 1.66 (m, 2H), and 1.18 (t, J=7.20 Hz, 3H).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:8]([S:10]([N:13]1[CH2:18][CH2:17][CH:16]([C:19]2[C:27]3[C:22](=[C:23]([C:40]([NH2:42])=[O:41])[CH:24]=[C:25]([C:28]4[CH:32]=[C:31]([CH2:33][N:34]([C@@H:36]([CH3:39])[CH2:37]O)[CH3:35])[S:30][CH:29]=4)[CH:26]=3)[NH:21][CH:20]=2)[CH2:15][CH2:14]1)(=[O:12])=[O:11])[CH3:9].N[C@@H](C)CO>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[O:11]=[S:10]1(=[O:12])[CH2:8][CH2:39][CH:36]([N:34]([CH2:33][C:31]2[S:30][CH:29]=[C:28]([C:25]3[CH:26]=[C:27]4[C:22](=[C:23]([C:40]([NH2:42])=[O:41])[CH:24]=3)[NH:21][CH:20]=[C:19]4[CH:16]3[CH2:15][CH2:14][N:13]([S:10]([CH2:8][CH3:9])(=[O:11])=[O:12])[CH2:18][CH2:17]3)[CH:32]=2)[CH3:35])[CH2:37]1
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4csc(CN(C)[C@@H](C)CO)c4)cc23)CC1
Agent: C[C@H](N)CO
Solvent: O=C(O)C(F)(F)F
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4csc(CN(C)C5CCS(=O)(=O)C5)c4)cc23)CC1

Procedure:
The title compound was prepared according to the general procedure of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-{[[(1S)-2-hydroxy-1-methylethyl](methyl)amino]methyl}-3-thienyl)-1H-indole-7-carboxamide trifluoroacetate, substituting (1,1-dioxidotetrahydro-3-thienyl)amine (1.20 mmol) for (2S)-2-amino-1-propanol to afford 9.3 mg of the title compound.
Reaction SMILES: [BH4-].[Na+].[O:3]1[CH:7]=[CH:6][CH:5]=[C:4]1[C:8]1[O:9][C:10]([CH3:25])=[C:11]([CH2:13][O:14][C:15]2[CH:22]=[CH:21][C:18]([CH:19]=[O:20])=[CH:17][C:16]=2[O:23][CH3:24])[N:12]=1.CO.O>O1CCCC1>[O:3]1[CH:7]=[CH:6][CH:5]=[C:4]1[C:8]1[O:9][C:10]([CH3:25])=[C:11]([CH2:13][O:14][C:15]2[CH:22]=[CH:21][C:18]([CH2:19][OH:20])=[CH:17][C:16]=2[O:23][CH3:24])[N:12]=1
Reactant: COc1cc(C=O)ccc1OCc1nc(-c2ccco2)oc1C
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: COc1cc(CO)ccc1OCc1nc(-c2ccco2)oc1C
Reaction time: 1 h
Yield: 101.4 %

Procedure:
Sodium borohydride (825 mg) was added to a solution of 4-[2-(2-furyl)-5-methyl-4-oxazolylmethoxy]-3-methoxybenzaldehyde (6.84 g) in tetrahydrofuran (50 ml)-methanol (50 ml) at 0° C. After stirring for 1 hour, the reaction mixture was poured into water to give 4-[2-(2-furyl)-5-methyl-4-oxazolylmethoxy]-3-methoxybenzyl alcohol (6.98 g, yield 92%) as crystals.
Reaction SMILES: Cl[CH2:2][C:3](=O)[C:4](=[N:35][O:36][CH2:37][C:38]([O:40][CH3:41])=[O:39])[C:5]([NH:7][CH:8]1[C:33](=[O:34])[N:10]2[C:11]([C:17]([O:19][CH:20]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:18])=[C:12]([CH:15]=[CH2:16])[CH2:13][S:14][C@H:9]12)=[O:6].[NH2:43][C:44]([NH2:46])=[S:45].C([O-])(=O)C.[Na+]>O1CCCC1.O>[NH2:46][C:44]1[S:45][CH:2]=[C:3]([C:4](=[N:35][O:36][CH2:37][C:38]([O:40][CH3:41])=[O:39])[C:5]([NH:7][CH:8]2[C:33](=[O:34])[N:10]3[C:11]([C:17]([O:19][CH:20]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=4)=[O:18])=[C:12]([CH:15]=[CH2:16])[CH2:13][S:14][C@H:9]23)=[O:6])[N:43]=1
Reactant: C=CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)C(=NOCC(=O)OC)C(=O)CCl)[C@H]2SC1
Reactant: NC(N)=S
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: C=CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)C(=NOCC(=O)OC)c3csc(N)n3)[C@H]2SC1
Temperature: 40 °C
Reaction time: 4 h
Yield: 96.6 %

Procedure:
To a solution of benzhydryl 7-(4-chloro-2-methoxycarbonylmethoxyimino-3-oxobutyramido)-3-vinyl-3-cephem-4-carboxylate (syn isomer) (2.0 g) in a mixture of tetrahydrofuran (10 ml) and water (10 ml) were added thiourea (0.5 g) and sodium acetate (1.34 g). The mixture was stirred at 40° C. for 4 hours. The resultant solution was extracted with ethyl acetate (100 ml), and the extract was washed with a saturated aqueous sodium chloride twice. After the resultant solution was dried over magnesium sulfate, the solvent was removed by distillation under reduced pressure to give benzhydryl 7-[2-(2-aminothiazol-4-yl)-2-methoxycarbonylmethoxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylate (syn isomer) (2.0 g).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]2[C:20]([NH:21][C:22]3[CH:23]=[CH:24][CH:25]=[C:26]([C:28]#[CH:29])[CH:27]=3)=[N:19][CH:18]=[N:17][C:9]2=[CH:10][C:11]=1[O:12][CH2:13][CH2:14][O:15][CH3:16].N#N.C(Cl)[Cl:33]>C(#N)C>[C:28]([C:26]1[CH:27]=[C:22]([NH:21][C:20]2[C:8]3[C:9](=[CH:10][C:11]([O:12][CH2:13][CH2:14][O:15][CH3:16])=[C:6]([O:5][CH2:4][CH2:3][O:2][CH3:1])[C:7]=3[Cl:33])[N:17]=[CH:18][N:19]=2)[CH:23]=[CH:24][CH:25]=1)#[CH:29]
Reactant: C#Cc1cccc(Nc2ncnc3cc(OCCOC)c(OCCOC)cc23)c1
Reactant: ClCCl
Agent: N#N
Solvent: CC#N
Product: C#Cc1cccc(Nc2ncnc3cc(OCCOC)c(OCCOC)c(Cl)c23)c1
Reaction time: 0.5 h

Procedure:
300 mg erlotinib was dissolved in 200 mL CH2Cl2 at −78° C. cooled by dry-ice/acetone bath. A mixture of F2 and N2 gas containing 20% F2/80% N2 was passed through the reaction vessel continuously at a flow rate of 2 L/min. Reaction was stopped after 30 min and the solvent was removed under vacuum. Dried reaction products were dissolved in 3 mL acetonitrile and was separated on an Agilent Zorbax C8 250×4.6 mm column, gradient elution from 30% MeOH/70% 0.1% formic acid in dd-H2O to 90% MeOH/10% 0.1% formic acid in dd-H2O, 1 ml/min total flow rate. Each fraction was analyzed by mass spectrometry. Fractions containing reaction products without excess amount of the starting material erlotinib, were mixed to form the modified erlotinib mixture compound library for drug property screening to identify components with improved properties over erlotinib. A component with m/z value corresponding to mono-chlorinated erlotinib was isolated and purified by successive preparative HPLC separations. The purified compound was analyzed by LC-MS/MS and NMR to provide the structure of the title compound. The observed m/z value 428.1370 (Thermo Finnigan LTQ Orbitrap, positive ion mode), is consistent with calculated m/z of protonated mono-chlorinated erlotinib (m/z(calc)=428.1372), molecular formula: C22H23ClN3O4+. High resolution MSn (n=2-4) experiments on LTQ orbitrap indicate the fluorine substitution is on the quinazoline ring of erlotinib (fragment at m/z 118.0649, calc: 118.0651 for C8H8N+ indicates the 3-ethynylphenyl ring is not substituted) and are not on the side chain of the quinazoline ring (elimination of two C3H6O groups from the side chains). 1H-NMR spectra data indicate the chlorine substitution is at the 5-position of the quinazoline ring of erlotinib. 1H-NMR (400 MHz, DMSO-d6) δ ppm 3.42 (s, 3H), 3.46 (s, 3H), 3.83 (m, 4H), 4.27 (s, 1H), 4.36 (m, 4H), 7.39 (s, 1H), 7.49 (dd, J=8.5, 8.3, 1H), 7.66 (ddd, J=8.5, 2.5, 2.2, 1H), 7.87 (dd, J=2.5, 1.8, 1H), 7.91 (ddd, J=8.3, 2.2, 1.8), 8.93 (s, 1H).
Reaction SMILES: C([O-])(=O)C.[Na+].BrN1C(C)(C)C(=O)N(Br)C1=O.[F:17][C@H:18]1[CH2:35][C@@:33]2([CH3:34])[C@@H:29]([CH2:30][CH2:31][C:32]2=[O:36])[C@H:28]2[C@H:19]1[C@@H:20]1[C:25](=[CH:26][CH2:27]2)[CH:24]=[C:23]([O:37]C)[CH2:22][CH2:21]1.S([O-])([O-])=O.[Na+].[Na+].[Br-].[Li+].C(=O)([O-])[O-].[Li+].[Li+]>CN(C=O)C.C(OCC)(=O)C>[F:17][C@H:18]1[CH2:35][C@@:33]2([CH3:34])[C@@H:29]([CH2:30][CH2:31][C:32]2=[O:36])[C@H:28]2[C@H:19]1[C@@H:20]1[C:25]([CH:26]=[CH:27]2)=[CH:24][C:23](=[O:37])[CH2:22][CH2:21]1
Reactant: COC1=CC2=CC[C@@H]3[C@H]([C@@H](F)C[C@]4(C)C(=O)CC[C@@H]34)[C@H]2CC1
Agent: CC(=O)[O-]
Agent: CC1(C)C(=O)N(Br)C(=O)N1Br
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C[C@]12C[C@H](F)[C@H]3[C@@H](C=CC4=CC(=O)CC[C@@H]43)[C@@H]1CCC2=O
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
5 ml of a 10% by weight sodium acetate solution and, in portions, 2.5 g of 1,3-dibromo-5,5-dimethylhydantoin were added in succession at 0° C. to 5.0 g of 11β-fluoro-3-methoxy-estra-3,5-dien-17-one (A″) in 50 ml of DMF. After 30 minutes, 2.3 g of sodium sulfite and then 2.5 g of lithium bromide and 2.0 g of lithium carbonate were added and stirred for 2 hours at 100° C. The reaction mixture was stirred into ice water. The precipitated product was suctioned off, dissolved in ethyl acetate, washed with water, dried and concentrated by evaporation in a vacuum. After recrystallization from ethyl acetate, 3.6 g of 11β-fluoro-estra-4,6-diene-3,17-dione (B) with a melting point of 198° C. was obtained.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)[C:6](OC)=[O:7])#[N:2].[BH4-].[Li+].O1CCCC1>O1CCOCC1>[CH:13]1([C:12]2[CH:11]=[CH:10][C:5]([CH2:6][OH:7])=[CH:4][C:3]=2[C:1]#[N:2])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]1
Reactant: COC(=O)c1ccc(C2CCCCC2)c(C#N)c1
Agent: [BH4-]
Agent: [Li+]
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: N#Cc1cc(CO)ccc1C1CCCCC1
Temperature: 0 °C
Yield: 72 %

Procedure:
To a solution of methyl 3-cyano-4-cyclohexylbenzoate (299.0 mg, 1.229 mmol) in 1,4-dioxane (30 mL) was added 2 M lithium borohydride solution in tetrahydrofuran (1.23 mL, 2.46 mmol). The mixture was heated under reflux for 2.5 h. The mixture was cooled to 0° C. and quenched with 1 N aqueous HCl solution slowly to pH 5. After the addition of brine solution, the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure and purified by silica gel column chromatography to provide the title compound as a white solid (190.5 mg). LCMS m/z=216.5 [M+H]+; 1H NMR (400 MHz, CDCl3) δ ppm 1.23-1.33 (m, 1H), 1.41-1.52 (m, 4H), 1.76-1.83 (m, 1H), 1.84-1.92 (m, 4H), 2.90-3.05 (m, 1H), 4.70 (d, J=5.81 Hz, 2H), 7.36 (d, J=8.21 Hz, 1H), 7.53 (dd, J=8.27, 1.71 Hz, 1H), 7.61 (d, J=1.39 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:13])=[C:4]([S:9](Cl)(=[O:11])=[O:10])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[NH2:14][CH2:15][C:16]1[CH:17]=[C:18]([CH:41]=[C:42]([O:44][C:45]2[CH:50]=[CH:49][C:48]([F:51])=[CH:47][CH:46]=2)[CH:43]=1)[CH2:19][N:20]([CH2:33][C:34]1[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=1)[S:21]([C:24]1[CH:29]=[C:28]([Cl:30])[CH:27]=[C:26]([Cl:31])[C:25]=1[OH:32])(=[O:23])=[O:22].CCN(CC)CC>C(Cl)Cl>[Cl:31][C:26]1[C:25]([OH:32])=[C:24]([S:21]([N:20]([CH2:19][C:18]2[CH:41]=[C:42]([O:44][C:45]3[CH:46]=[CH:47][C:48]([F:51])=[CH:49][CH:50]=3)[CH:43]=[C:16]([CH2:15][NH:14][S:9]([C:4]3[CH:5]=[C:6]([Cl:8])[CH:7]=[C:2]([Cl:1])[C:3]=3[OH:13])(=[O:10])=[O:11])[CH:17]=2)[CH2:33][C:34]2[CH:35]=[CH:36][C:37]([F:40])=[CH:38][CH:39]=2)(=[O:23])=[O:22])[CH:29]=[C:28]([Cl:30])[CH:27]=1
Reactant: O=S(=O)(Cl)c1cc(Cl)cc(Cl)c1O
Reactant: NCc1cc(CN(Cc2ccc(F)cc2)S(=O)(=O)c2cc(Cl)cc(Cl)c2O)cc(Oc2ccc(F)cc2)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=S(=O)(NCc1cc(CN(Cc2ccc(F)cc2)S(=O)(=O)c2cc(Cl)cc(Cl)c2O)cc(Oc2ccc(F)cc2)c1)c1cc(Cl)cc(Cl)c1O
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 84.9 %

Procedure:
To a solution of 3,5-dichloro-2-hydroxybenzene-1-sulfonyl chloride (27.1 mg, 0.104 mmol) in 4 mL of CH2Cl2 was added solid N-(3-(aminomethyl)-5-(4-fluorophenoxy)benzyl)-3,5-dichloro-N-(4-fluorobenzyl)-2-hydroxybenzenesulfonamide (60 mg, 0.104 mmol) followed by Et3N (110 μL) at rt. The mixture was stirred at rt for 45 min. Direct purification of the reaction mixture by prep HPLC provided the desired product (71 mg, 85%). 1H NMR (CD3OD): δ 7.68 (s, 1H), 7.60 (s, 1H), 7.49 (s, 2H), 7.13˜6.90 (m, 8H), 6.67 (s, 1H), 6.61 (s, 1H), 6.45 (s, 1H), 4.44 (s, 2H), 4.30 (s, 2H), 4.08 (s, 2H); MS (ESI): (M+H)+=805.
Reaction SMILES: [Cl:1][C:2]1[C:3](F)=[CH:4][C:5]([F:29])=[C:6]([S:8]([N:11]([C:23]2[S:24][C:25]([Cl:28])=[CH:26][N:27]=2)CC2C=CC(OC)=CC=2OC)(=[O:10])=[O:9])[CH:7]=1.[Cl:31][C:32]1[CH:33]=[CH:34][C:35]([OH:49])=[C:36]([CH:38]2[CH2:41][N:40](C(OC(C)(C)C)=O)[CH2:39]2)[CH:37]=1.FC(F)(F)C(O)=O>ClCCl>[NH:40]1[CH2:41][CH:38]([C:36]2[CH:37]=[C:32]([Cl:31])[CH:33]=[CH:34][C:35]=2[O:49][C:3]2[C:2]([Cl:1])=[CH:7][C:6]([S:8]([NH:11][C:23]3[S:24][C:25]([Cl:28])=[CH:26][N:27]=3)(=[O:9])=[O:10])=[C:5]([F:29])[CH:4]=2)[CH2:39]1
Reactant: CC(C)(C)OC(=O)N1CC(c2cc(Cl)ccc2O)C1
Reactant: COc1ccc(CN(c2ncc(Cl)s2)S(=O)(=O)c2cc(Cl)c(F)cc2F)c(OC)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=S(=O)(Nc1ncc(Cl)s1)c1cc(Cl)c(Oc2ccc(Cl)cc2C2CNC2)cc1F

Procedure:
5-Chloro-N-(5-chloro-1,3-thiazol-2-yl)-N-(2,4-dimethoxybenzyl)-2,4-difluorobenzenesulfonamide (Preparation 655) and tert-butyl 3-(5-chloro-2-hydroxyphenyl)azetidine-1-carboxylate (Preparation 237) were stirred in dichloromethane (2 ml) and trifluoroacetic acid (1 ml) to prepare the title compound using Method F above but where the N,N-dimethylformamide was replaced with dimethyl sulphoxide. The crude product was concentrated in vacuo and purified by preparative HPLC to afford the title compound.
Reaction SMILES: [C:1](#[N:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]#[N:13].O>C1(C)C=CC=CC=1>[CH2:12]([NH2:13])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH2:1][NH2:14]
Reactant: N#CCCCCCCCCCCC#N
Solvent: Cc1ccccc1
Solvent: O
Product: NCCCCCCCCCCCCN
Temperature: 80 °C
Reaction time: 22 h
Yield: 85 %

Procedure:
A mixture of 0.059 mmol RuHCl(H2)(PCy3)2, 2.87 mmol dodecanedinitrile, 5 mL water and 35 mL toluene was stirred in a Fisher-Porter tube at 80° C. under 860 kPa H2. After 22 hours, gc analysis showed that the dinitrile was completely converted and the product, 1,12-dodecanediamine, formed in 85% yield.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C@H:9]([NH:11][CH:12]([C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)[C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-])=O)[CH:14]=2)[CH3:10])[CH:6]=[CH:7][CH:8]=1.[Sn](Cl)(Cl)(Cl)Cl>C(O)C>[CH3:29][O:28][C:25]1[CH:26]=[CH:27][C:22]([CH:12]([NH:11][C@@H:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=2)[CH3:10])[C:13]2[CH:14]=[C:15]([NH2:19])[CH:16]=[CH:17][CH:18]=2)=[CH:23][CH:24]=1
Reactant: COc1ccc(C(N[C@H](C)c2cccc(OC)c2)c2cccc([N+](=O)[O-])c2)cc1
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: CCO
Product: COc1ccc(C(N[C@H](C)c2cccc(OC)c2)c2cccc(N)c2)cc1

Procedure:
Following a similar reaction, separation and purification procedure to that described in Example (94b), 9.04 g of N-[(R)-1-(3-methoxyphenyl)ethyl]-N-[(4-methoxyphenyl)-(3-nitrophenyl)methyl]amine [prepared as described in step (a) above], 17.5 g of anhydrous tin chloride and 150 ml of ethanol were reacted, to obtain 1.48 g of isomer A and 1.28 g of isomer B of the title compound as a pale yellow oil.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:35])[NH:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:18]=[C:19]4[C:23](=[CH:24][CH:25]=3)[C:22](=[O:26])[N:21]([C@@H:27]([CH:32]([CH3:34])[CH3:33])[C:28]([O:30][CH3:31])=[O:29])[CH2:20]4)=[CH:13][CH:12]=2)=[CH:4][CH:3]=1.NC1C=CC(C2C=C3C(=CC=2)[C:48](=[O:52])N([C@@H](C(C)C)C(OC)=O)C3)=CC=1.COC1C=C(N=C=O)C=CC=1>>[CH3:48][O:52][C:3]1[CH:4]=[C:5]([NH:8][C:9](=[O:35])[NH:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:18]=[C:19]4[C:23](=[CH:24][CH:25]=3)[C:22](=[O:26])[N:21]([C@@H:27]([CH:32]([CH3:34])[CH3:33])[C:28]([O:30][CH3:31])=[O:29])[CH2:20]4)=[CH:13][CH:12]=2)[CH:6]=[CH:7][CH:2]=1
Reactant: COC(=O)[C@H](C(C)C)N1Cc2cc(-c3ccc(N)cc3)ccc2C1=O
Reactant: COC(=O)[C@H](C(C)C)N1Cc2cc(-c3ccc(NC(=O)Nc4ccc(F)cc4)cc3)ccc2C1=O
Agent: COc1cccc(N=C=O)c1
Product: COC(=O)[C@H](C(C)C)N1Cc2cc(-c3ccc(NC(=O)Nc4cccc(OC)c4)cc3)ccc2C1=O

Procedure:
The compound of example 250 was prepared analogous to compound of example 224 by reaction of compound of example 223 with 3-methoxy phenyl isocyanate. The compound of example 250 was used directly without isolation for the preparation of compound of example 251.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][C@@H:10]([NH:13][C:14]2[CH:19]=[CH:18][C:17](/[CH:20]=[CH:21]/[C:22]([NH:24][O:25]C3CCCCO3)=[O:23])=[CH:16][CH:15]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO.[ClH:34].CC#N>CO>[ClH:34].[CH2:1]([N:8]1[CH2:12][CH2:11][C@@H:10]([NH:13][C:14]2[CH:15]=[CH:16][C:17](/[CH:20]=[CH:21]/[C:22]([NH:24][OH:25])=[O:23])=[CH:18][CH:19]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(/C=C/c1ccc(N[C@@H]2CCN(Cc3ccccc3)C2)cc1)NOC1CCCCO1
Agent: Cl
Solvent: CO
Solvent: CC#N
Product: O=C(/C=C/c1ccc(N[C@@H]2CCN(Cc3ccccc3)C2)cc1)NO
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (2E)-3-(4-{[(3R)-1-benzyl-3-pyrrolidinyl]amino}phenyl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide (500 mg) in MeOH (5 mL) was added hydrogen chloride methanol reagent 10 (2.38 mL, Tokyo Kasei), and the mixture was stirred at ambient temperature for 1 hour. To the reaction mixture was added CH3CN and the solvent was removed in vacuo. Obtained colorless solid was triturated with CH3CN to give (2E)-3-(4-{[(3R)-1-benzyl-3-pyrrolidinyl]amino}phenyl)-N-hydroxyacrylamide hydrochloride (257.4 mg) as colorless powder.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([N+:11]([O-:13])=[O:12])[CH:10]=1)[NH:7]C(=O)[C:5]2=[O:15].[OH:16]O.Cl>[OH-].[Na+]>[NH2:7][C:8]1[C:9]([N+:11]([O-:13])=[O:12])=[CH:10][C:2]([Br:1])=[CH:3][C:4]=1[C:5]([OH:15])=[O:16]
Reactant: O=C1Nc2c(cc(Br)cc2[N+](=O)[O-])C1=O
Reactant: OO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Nc1c(C(=O)O)cc(Br)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 4 h
Yield: 94.5 %

Procedure:
To a slurry of 5-bromo-7-nitro-1H-indole-2,3-dione (5.5 g, 20.3 mmol) in aqueous 5N NaOH solution (23.2 mL) was added an aq. solution of 33% hydrogen peroxide solution (4.96 mL) slowly at 0° C. After completion of the addition, the reaction mixture was stirred at room temperature for 4 h. After completion of the reaction, the reaction mixture was acidified with 2N HCl and the solid the resulting precipitate was filtered, washed with water (2-3 times) and dried under vacuum to obtain the title compound as yellow solid (5 g, 94.5%).
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[C:4]([CH:9](C(OCC)=O)[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[N:5][CH:6]=[CH:7][CH:8]=1.CS(C)=O.[Cl-].[Na+]>O>[F:21][C:2]([F:1])([F:20])[C:3]1[C:4]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[N:5][CH:6]=[CH:7][CH:8]=1
Reactant: CCOC(=O)C(C(=O)OCC)c1ncccc1C(F)(F)F
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CCOC(=O)Cc1ncccc1C(F)(F)F
Temperature: 138.5 °C
Reaction time: 0.33 h
Yield: 99.6 %

Procedure:
6.10 g of diethyl (3-trifluoromethyl-2-pyridyl)malonate and 20 ml of dimethyl sulfoxide were mixed. To the mixture was added 1.40 g of sodium chloride and 0.72 g of water. The mixture was stirred for about 20 minutes at an inner temperature of 132 to 145° C. The reaction mixture was allowed to cool to room temperature, then, to the reaction mixture was added water, and extracted with ethyl acetate. The organic layer was washed with saturated brine twice, and dried over anhydrous magnesium sulfate, then, concentrated under reduced pressure, to obtain 4.64 g of ethyl (3-trifluoromethyl-2-pyridyl)acetate.
Reaction SMILES: Br.Br.[CH3:3][O:4][C:5](=[O:25])[C@H:6]([CH2:19][C:20]1[N:24]=[CH:23][NH:22][CH:21]=1)[NH:7][C:8](=[O:18])[C@H:9]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[NH2:10].C1(=O)N([O:31][C:32](=O)[C@H:33]([CH2:42][C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[NH:34][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])C(=O)CC1.C(OCC)(=O)C>CN(C)C=O.C(N(CC)CC)C>[CH3:3][O:4][C:5](=[O:25])[C@H:6]([CH2:19][C:20]1[N:24]=[CH:23][NH:22][CH:21]=1)[NH:7][C:8](=[O:18])[C@H:9]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[NH:10][C:32](=[O:31])[C@H:33]([CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[NH:34][C:35]([O:37][C:38]([CH3:41])([CH3:39])[CH3:40])=[O:36]
Reactant: COC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@@H](N)Cc1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)ON1C(=O)CCC1=O
Agent: Br
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.7 %

Procedure:
L-Phenylalanyl-L-histidine methyl ester dihydrobromide(1.75 g) is dissolved in a mixture of dimethylformamide (10 ml) and triethylamine(1.4 ml), and N-tert-butoxycarbonyl-L-phenylalanine succinimido ester (1.34 g) is added thereto. The mixture is stirred at room temperature overnight. Ethyl acetate is added to the mixture, and insoluble materials are filtered off. The filtrate is washed with an aqueous sodium bicarbonate solution, and an aqueous sodium chloride solution is added thereto. The precipitated crystals are washed with ethyl acetate and water and then dried to give N-tert-butoxycarbonyl-L-phenylalanyl-L-phenylalanyl-L-histidine methyl ester(1.5 g) as colorless crystals. Yield: 71.8%
Reaction SMILES: [OH:1][C@@H:2]1[CH2:18][C@@H:6]2[O:7][C:8]3[CH:13]=[C:12]([CH2:14][CH:15]=[CH2:16])[C:11]([OH:17])=[CH:10][C:9]=3[C@@H:5]2[CH2:4][CH2:3]1>C(OCC)(=O)C.[Pd]>[OH:1][C@@H:2]1[CH2:18][C@@H:6]2[O:7][C:8]3[CH:13]=[C:12]([CH2:14][CH2:15][CH3:16])[C:11]([OH:17])=[CH:10][C:9]=3[C@@H:5]2[CH2:4][CH2:3]1
Reactant: C=CCc1cc2c(cc1O)[C@@H]1CC[C@H](O)C[C@@H]1O2
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCCc1cc2c(cc1O)[C@@H]1CC[C@H](O)C[C@@H]1O2
Yield: 81.9 %

Procedure:
A solution of 0.125 g (0.59 mmol) of the product of Example 5, Step C and 50 mg of 5% Pd/C in 10 mL of ethyl acetate was shaken under 40 psi H2 for 1 h. The solution was filtered through Celite and the filtrate concentrated to a colorless oil that crystallized from ethyl acetate-hexane to afford 0.120 g (98%) of white prisms.