Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[S:12][C:13]([C:15]([N:17]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[Cl:25])[CH3:18])=[O:16])=[CH:14][C:10]=3[CH2:9][CH2:8][O:7][C:6]=2[CH:26]=1.[N:27]1[CH:32]=[CH:31][CH:30]=[C:29](B(O)O)[CH:28]=1>>[Cl:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[N:17]([CH3:18])[C:15]([C:13]1[S:12][C:11]2[C:5]3[CH:4]=[CH:3][C:2]([C:29]4[CH:28]=[N:27][CH:32]=[CH:31][CH:30]=4)=[CH:26][C:6]=3[O:7][CH2:8][CH2:9][C:10]=2[CH:14]=1)=[O:16]
Reactant: CN(C(=O)c1cc2c(s1)-c1ccc(Br)cc1OCC2)c1ccccc1Cl
Reactant: OB(O)c1cccnc1
Product: CN(C(=O)c1cc2c(s1)-c1ccc(-c3cccnc3)cc1OCC2)c1ccccc1Cl

Procedure:
Following Examples 44 and 60 and General Procedure C, 8-bromo-N-(2-chlorophenyl)-N-methyl-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxamide 150 and 3-pyridylboronic acid were reacted to give 122. MS: (ESI+) 447.1
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][NH:12][CH2:13][CH2:14][N:15]2[CH2:20][CH2:19][N:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:17][CH2:16]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].CCN(CC)CC.[C:34](Cl)(=[O:37])[CH2:35][CH3:36]>C(Cl)Cl>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][N:12]([CH2:13][CH2:14][N:15]2[CH2:16][CH2:17][N:18]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH2:19][CH2:20]2)[C:34](=[O:37])[CH2:35][CH3:36])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: CCC(=O)Cl
Reactant: O=[N+]([O-])c1ccc(CCNCCN2CCN(c3ccccc3)CC2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC(=O)N(CCc1ccc([N+](=O)[O-])cc1)CCN1CCN(c2ccccc2)CC1
Reaction time: 2 h
Yield: 89 %

Procedure:
To a stirred solution of [2-(4-nitro-phenyl)-ethyl]-[2-(4-phenyl-piperazin-1-yl)-ethyl]-amine 27a (0.375 g, 1.05 mmol), Et3N (0.267 g, 2.64 mmol) in 25 mL of dry CH2Cl2 under nitrogen at 0° C. was added a solution of propionyl chloride (0.137 g, 1.48 mmol). The temperature was allowed to rise to room temperature, the mixture stirred for 2 h, and then washed with water. The aqueous layer was extracted with dichloromethane. The combined organic phase was dried (Na2SO4) and concentrated. The crude product was purified by column chromatography over silica gel (EtOAc/Hex=9/1) to give 28a as a colorless oil: 0.39 g (89% yield). 1H NMR (CDCl3, 400 MHz): δ 1.16 (3H, t, J=7.2, CH3), 2.38 (2H, q, J=7.2, CH2), 2.51 (2H, t, J=7.2 Hz, CH2Ar), 2.62 (4H, t, J=4.8, (CH2)2N), 2.99 (2H, t, J=7.2, CH2—CH2NCO), 3.15-3.20 (4H, m, (CH2)2NHPh, 3.32 (2H, t, J=7.2, CH2—CH2Ar), 3.58 (2H, t, J=7.2, CH2NCO), 6.83-6.93 (3H, m, ArH), 7.23-7.28 (2H, m, ArH), 7.34 (1H, d, J=8.0, ArH), 7.38 (1H, d, J=8.8, ArH, 8.15 (1H, d, J=8.8, ArH), 8.18 (1H, d, J=8.4, ArH).
Reaction SMILES: Cl[C:2]1[S:10][C:9]2[S:8](=[O:12])(=[O:11])[N:7]([CH2:13][CH2:14][CH2:15][O:16][CH3:17])[CH:6]=[CH:5][C:4]=2[CH:3]=1.C([Li])CCC.[S:23](=[O:25])=[O:24].O.O.O.C([O-])(=O)C.[Na+:33].[NH2:34]OS(O)(=O)=O>C1COCC1>[Na+:33].[CH3:17][O:16][CH2:15][CH2:14][CH2:13][N:7]1[CH:6]=[CH:5][C:4]2[CH:3]=[C:2]([S:23]([NH-:34])(=[O:25])=[O:24])[S:10][C:9]=2[S:8]1(=[O:12])=[O:11]
Reactant: O=S=O
Reactant: NOS(=O)(=O)O
Reactant: COCCCN1C=Cc2cc(Cl)sc2S1(=O)=O
Agent: CC(=O)[O-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COCCCN1C=Cc2cc(S([NH-])(=O)=O)sc2S1(=O)=O
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 34 %

Procedure:
The product from Step B (2.31 g, 7.86 mmol) was dissolved in dry THF (35 mL) and cooled in a dry ice/isopropanol bath (-78° C.) under nitrogen. n-Butyllithium (4.1 mL of a 2.1M solution in hexanes, 8.65 mmol) was added dropwise and the mixture stirred for 45 min; excess sulfur dioxide was introduced into the flask until the solution tested acidic to moist litmus paper. The reaction mixture was evaporated to a residue which was dissolved in water (40 mL) followed by the addition of sodium acetate trihydrate (5.35 g, 39.3 mmol) and hydroxylamine-O-sulfonic acid (2,67 g, 23.58 mmol). This mixture was stirred at room temperature for 4 hr and extracted with ethyl acetate (5×8 mL). The combined extracts were washed with a saturated aqueous sodium chloride solution, dried (MgSO4) and evaporated to a residue which was purified by column chromatography (silica, gradient 3:1 hexane/ethyl acetate to 7:3 methylene chloride/methanol) to give the desired product as an oil (0.91 g, 34%). This oil was converted to the sodium salt by dissolving it in ethanol (1.5 mL) and adding 2N NaOH (1.26 mL). Ethyl ether was added to the cloud point and the product which precipitated was isolated by filtration under nitrogen to give the desired salt (0.81 g, 90%): mp 90°-92° C. Analysis. Calculated for C10H13N2O2S3Na-H2O: C, 30.30; H, 4.32; N, 7.07. Found: C, 30.29; H, 4.13; N, 6.97.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].S(Cl)(Cl)=O.[CH2:16](O)[CH3:17]>C(OCC)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7]([O:9][CH2:16][CH3:17])=[O:8]
Reactant: Cc1ccc(Cl)cc1C(=O)O
Reactant: CCO
Solvent: CCOCC
Solvent: O=S(Cl)Cl
Product: CCOC(=O)c1cc(Cl)ccc1C
Temperature: 0 °C

Procedure:
A mixture of 5-chloro-2-methylbenzoic acid (3.00 g, 17.5 mmol) in ethanol (30 mL) was cooled to 0° C. with an ice bath and thionyl chloride (12.5 mL, 105.5 mmol) was added dropwise, over 30 minutes. After this time, the mixture was warmed to room temperature for 1 h, then transferred to an oil bath, and heated to 70° C. overnight. The mixture was then cooled to room temperature and concentrated under reduced pressure. The solids obtained were then redissolved in diethyl ether (50 mL) and washed with 1 N sodium hydroxide (50 mL), brine (50 mL), dried over magnesium sulfate, and concentrated under reduced pressure to afford ethyl 5-chloro-2-methylbenzoate as a clear oil: 1H NMR (500 MHz, CDC13) δ 7.88 (d, J=2.5 Hz, 1H), 7.34 (dd, J=8.5, 2.5 Hz, 1H), 7.17 (d, J=8.5 Hz, 1H), 4.36 (q, J=7.5 Hz, 2H), 2.56 (s, 3H), 1.39 (t, J=7.5 Hz, 3H); ESI MS m/z 199 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:32])=[C:6]([CH:31]=1)[O:7][CH2:8][C:9]1[C:18]([C:19]2[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][C:20]=2[O:26][CH3:27])=[CH:17][CH:16]=[C:15]2[C:10]=1[C:11]([CH3:30])=[CH:12][C:13]([CH3:29])([CH3:28])[NH:14]2.[CH3:33][N:34]([CH3:38])[C:35](Cl)=[O:36]>N1C=CC=CC=1.C(OCC)(=O)C>[CH3:33][N:34]([CH3:38])[C:35]([O:25][C:22]1[CH:23]=[CH:24][C:19]([C:18]2[C:9]([CH2:8][O:7][C:6]3[CH:31]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=3[CH3:32])=[C:10]3[C:15](=[CH:16][CH:17]=2)[NH:14][C:13]([CH3:28])([CH3:29])[CH:12]=[C:11]3[CH3:30])=[C:20]([O:26][CH3:27])[CH:21]=1)=[O:36]
Reactant: CN(C)C(=O)Cl
Reactant: COc1cc(O)ccc1-c1ccc2c(c1COc1cc(F)ccc1C)C(C)=CC(C)(C)N2
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: COc1cc(OC(=O)N(C)C)ccc1-c1ccc2c(c1COc1cc(F)ccc1C)C(C)=CC(C)(C)N2
Temperature: 100 °C
Reaction time: 3 h
Yield: 29 %

Procedure:
5-(5-Fluoro-2-methylphenoxymethyl)-6-(4-hydroxy-2-methoxyphenyl)-2,2,4-trimethyl-1,2-dihydroquinoline (Reference Compound No. 5-1, 25 mg, 0.058 mmol) was dissolved in pyridine (1 mL), N,N-dimethylcarbamoyl chloride (6.9 μL, 0.075 mmol) was added thereto, and then the mixture was stirred at 100° C. for 3 hours. N,N-Dimethylcarbamoyl chloride (3.0 μL, 0.033 mmol) was added to the reaction mixture and the mixture was stirred at 100° C. for 1 hour. The reaction mixture was diluted with ethyl acetate (20 mL). The mixture was washed with 0.2 N aqueous HCl solution (75 mL), water (50 mL), and saturated brine (50 mL) successively, dried over anhydrous magnesium sulfate, and then the solvent was removed under reduced pressure. The obtained residue was purified by silica gel column chromatography (1st time: hexane-ethyl acetate, 2nd time: toluene-ethyl acetate) to give the titled compound (8.5 mg) as a colorless amorphous product. (Yield 29%)
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([NH:6][C:7](=[O:16])[C:8]([C:12]([O:14][CH3:15])=[O:13])=[N:9]2)=[CH:4][CH:3]=1.[N+:17]([O-])([OH:19])=[O:18].O>C(O)(=O)C>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([NH:6][C:7](=[O:16])[C:8]([C:12]([O:14][CH3:15])=[O:13])=[N:9]2)=[CH:4][C:3]=1[N+:17]([O-:19])=[O:18]
Reactant: O=[N+]([O-])O
Reactant: COC(=O)c1nc2cc(Cl)ccc2[nH]c1=O
Solvent: O
Solvent: CC(=O)O
Product: COC(=O)c1nc2cc(Cl)c([N+](=O)[O-])cc2[nH]c1=O
Temperature: 60 °C
Reaction time: 1 h
Yield: 52.9 %

Procedure:
To a solution of methyl 7-chloro-3,4-dihydro-3-oxoquinoxaline-2-carboxylate (106 mg, 444 μmol) in acetic acid (1 ml) was added a solution of fuming nitric acid (39.5 μl, 888 μmol) in acetic acid (0.2 ml), and the mixture was stirred for 1 hour at 60° C. Water (10 ml) was added to the reaction mixture. The precidpitate was collected by filtration, washed with water, and then air-dried to obtain 66.6 mg of the title compound as yellow powder. Yield 53%.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][CH2:5][C:6]1[C:7](=[O:20])[N:8]([CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[F:19])[CH2:9][CH:10]=1.[NH2:22][O:23][K].C(O)(=O)C>CO.CO.C(Cl)(Cl)Cl>[F:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[CH2:12][CH2:11][N:8]1[CH2:9][CH:10]=[C:6]([CH2:5][CH2:4][C:3]([NH:22][OH:23])=[O:2])[C:7]1=[O:20]
Reactant: COC(=O)CCC1=CCN(CCc2ccccc2F)C1=O
Reactant: NO[K]
Solvent: CO
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: O=C(CCC1=CCN(CCc2ccccc2F)C1=O)NO
Temperature: 0 °C
Reaction time: 8 h
Yield: 65 %

Procedure:
38 mg of 3-{1-[2-(2-fluoro-phenyl)-ethyl]-2-oxo-2,5-dihydro-1H-pyrrol-3-yl}-propionic acid methyl ester (x) prepared by the above Step 4 was dissolved in methanol solution (0.13 mM) and then 1.7 M methanolic suspension solution containing NH2OK (0.38 ml, 0.65 mM) was added thereto at 0° C. and the resulting mixture was stirred for 8 hrs at room temperature. The resulting mixture was neutralized with 0.02 ml of acetic acid, diluted with 10% methanol/chloroform solution, filtered and concentrated in vacuo. The resulting compound was purified by Silica gel column chromatography with a solvent mixture mixed with methanol and chloroform (1:9) as an eluant to give 25 mg of 3-{1-[2-(2-fluoro-phenyl)-ethyl]-2-oxo-2,5-dihydro-1H-pyrrol-3-yl}-N-hydroxy-propionamide (28y) (yield: 65%).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([C:14]([NH2:17])=[CH:15][CH:16]=1)[C:5]([NH:7][CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])=[O:6].C(N(CC)CC)C.[Br:25][CH2:26][C:27](Br)=[O:28]>ClCCl>[I:1][C:2]1[CH:3]=[C:4]([C:14]([NH:17][C:27](=[O:28])[CH2:26][Br:25])=[CH:15][CH:16]=1)[C:5]([NH:7][CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])=[O:6]
Reactant: O=C(Br)CBr
Reactant: COC(=O)CCNC(=O)c1cc(I)ccc1N
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)CCNC(=O)c1cc(I)ccc1NC(=O)CBr
Temperature: 25 °C
Reaction time: 2 h
Yield: 92 %

Procedure:
21.0 g (60.5 mmol) of 3-iodo-6-amino-N-(2-methoxycarbonylethyl)benzamide prepared as in Example 1b) were dissolved in 270 ml of dichloromethane, and 12.5 ml (90.7 mmol) of triethylamine were added. At -30° C., 7.8 ml (90.7 mmol) of bromoacetyl bromide in 80 ml of dichloromethane were added dropwise. The mixture was stirred at room temperature for 2 h and then washed with 10% strength citric acid solution and sodium bicarbonate solution, dried and concentrated. The product was recrystallized from dichloromethane, resulting in 26.1 g (92%) of pale yellow crystals.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH2:11][C:12]3[CH:13]=[C:14]4[C:18](=[CH:19][CH:20]=3)[N:17]([CH3:21])[N:16]=[CH:15]4)=[CH:9][N:10]=2)[N:7]=1.C([Sn](CCCC)(CCCC)[C:27]([O:29][CH2:30][CH3:31])=[CH2:28])CCC>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:30]([O:29][C:27]([C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH2:11][C:12]3[CH:13]=[C:14]4[C:18](=[CH:19][CH:20]=3)[N:17]([CH3:21])[N:16]=[CH:15]4)=[CH:9][N:10]=2)[N:7]=1)=[CH2:28])[CH3:31]
Reactant: Cn1ncc2cc(Cc3cnc4ccc(Cl)nn34)ccc21
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: C=C(OCC)c1ccc2ncc(Cc3ccc4c(cnn4C)c3)n2n1
Temperature: 110 °C
Reaction time: 8 h

Procedure:
A suspension of 6-chloro-3-((1-methyl-1H-indazol-5-yl)methyl)imidazo[1,2-b]pyridazine (180.0 mg, 36% purity, 0.22 mmol), tributyl(1-ethoxyvinyl)stannane (94 mg, 0.26 mmol) and Pd(PPh3)4 (25.1 mg, 0.02 mmol) in 10 mL of DMF was flushed with nitrogen, then heated at 110° C. and stirred overnight. Solvent was removed under reduced pressure; the residue was diluted with DCM, washed sequentially with aqueous KF and water. The organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by flash chromatography (DCM:MeOH=20:1) to give the title compound containing some triphenylphosphine oxide impurity but used in the next step without further purification (49 mg, 47%, 70% purity). LCMS (method A): [MH]+=334, tR=5.71 min.
Reaction SMILES: [CH2:1]([OH:12])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][OH:11].Cl[C:14]1[CH:23]=[CH:22][C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:15]=1>>[N:15]1[C:16]2[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:22]=[CH:23][C:14]=1[O:12][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][OH:11]
Reactant: Clc1ccc2ccccc2n1
Reactant: OCCCCCCCCCCO
Product: OCCCCCCCCCCOc1ccc2ccccc2n1

Procedure:
1,10-Decanediol (ex. Lancaster) was reacted with 2-chloroquinoline, by analogy with compound 33, step (i), to give 10-(2-quinolinyloxy)decan-1-ol. The latter was subjected to Swern oxidation (cf. example XIV) and the aldehyde reacted with ethyl fluoroacetate and diethyl oxalate to give (2Z) ethyl 2-fluoro-12-(2-quinoliny-loxy)dodec-2-enoate. The latter was converted to the title compound by analogy with compound 33, step (iv).
Reaction SMILES: C(O)(C(F)(F)F)=O.[NH2:8][CH2:9][CH2:10][CH2:11][C@:12]([C@@H:21]1[CH2:26][CH2:25][CH2:24][N:23]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:22]1)([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=1)[OH:13].[S:34](N)([NH2:37])(=[O:36])=[O:35].CCN(C(C)C)C(C)C>O1CCOCC1>[NH2:37][S:34]([NH:8][CH2:9][CH2:10][CH2:11][C@:12]([C@@H:21]1[CH2:26][CH2:25][CH2:24][N:23]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:22]1)([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=1)[OH:13])(=[O:36])=[O:35]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]([C@@](O)(CCCN)c2cccc(Cl)c2)C1
Reactant: NS(N)(=O)=O
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCC[C@@H]([C@@](O)(CCCNS(N)(=O)=O)c2cccc(Cl)c2)C1
Temperature: 110 °C
Reaction time: 0.03 h
Yield: 59.3 %

Procedure:
To a 50 mL round bottom flask were added the TFA salt of (R)-tert-butyl 3-((S)-4-amino-1-(3-chlorophenyl)-1-hydroxybutyl)piperidine-1-carboxylate (0.0803 g, 0.16 mmol, 1.0 equiv), sulfamide (0.2368 g, 2.46 mmol, 15 equiv), 1,4-dioxane (5 mL) and DIEA (1 mL). The resulting mixture was heated at 110° C. for 2 h. After the solvents were removed in vacuo, the residue was purified by reversed-phase HPLC (Phenomenex® Luna 5μ C18(2) 100 A, 250×21.20 mm, 5 micron, 70%→90% CH3CN/H2O, 0.1% CF3COOH over 8 min and then 90% CH3CN/H2O, 0.1% CF3COOH over 1.5 min, flow rate 25 mL/min) to give 0.0438 g (59%) of (R)-tert-butyl 3-((S)-4-(aminosulfonylamino)-1-(3-chlorophenyl)-1-hydroxybutyl)piperidine-1-carboxylate. LC-MS (3 min) tR=1.74 min, m/z 486, 484 (MNa+), 362.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:19])[NH:10][C:11]([CH3:18])([CH2:13][CH2:14][N:15]([CH3:17])[CH3:16])[CH3:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:20][CH2:21][CH2:22][CH:23](CC)[CH2:24][O:25][CH2:26][CH:27](CCCl)CC>>[Cl-:20].[CH2:1]([O:8][C:9]([NH:10][C:11]([CH3:12])([CH3:18])[CH2:13][CH2:14][N+:15]([CH2:27][CH2:26][O:25][CH2:24][CH2:23][CH2:22][CH3:21])([CH3:16])[CH3:17])=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCC(CCCl)COCC(CC)CCCl
Reactant: CN(C)CCC(C)(C)NC(=O)OCc1ccccc1
Product: CCCCOCC[N+](C)(C)CCC(C)(C)NC(=O)OCc1ccccc1
Product: [Cl-]
Temperature: 75 °C
Reaction time: 8 h
Yield: 50.9 %

Procedure:
A mixture of benzyl(4-(dimethylamino)-2-methylbutan-2-yl)carbamate (500 mg, 1.9 mmol, preparation described in previous experiment) and 2-(chloroethyl)-n-butyl ether (517 mg, 3.8 mmol) was stirred overnight at 75° C. An additional portion of 2-(chloroethyl)-n-butyl ether (517 mg, 3.8 mmol) was added and the mixture stirred for 24 hours at 80° C. The resultant white precipitate was collected on a glass fritted filter and washed with ether to give 388 mg of a white solid (51%). 1H NMR (400 MHz, MeOD) δ 0.86-0.89 (t, J=7.4 Hz, 3H), 1.23 (s, 6H), 1.27-1.33 (sext, J=7.5 Hz, 2H), 1.45-1.50 (m, 2H), 2.05-2.09 (m, 2H), 3.03 (s, 6H), 3.29-3.34 (m, 2H), 3.39-3.34 (t, J=Hz, 2H), 3.48-3.50 (br m, 2H), 3.74 (br s, 2H), 4.99 (s, 2H), 7.17 (s, 1H), 7.31-7.36 (m, 5H). LRMS (ESI/APCI) m/z 365 [M]+.
Reaction SMILES: [H-].[Na+].[CH2:3]([N:5]1[C:11]2[N:12]=[CH:13][CH:14]=[CH:15][C:10]=2[C:9](=[O:16])[N:8]([CH3:17])[C:7]2[CH:18]=[CH:19][C:20]([C:22]3[CH:26]=[CH:25][NH:24][CH:23]=3)=[N:21][C:6]1=2)[CH3:4].[CH3:27]I.O>CN(C=O)C>[CH2:3]([N:5]1[C:11]2[N:12]=[CH:13][CH:14]=[CH:15][C:10]=2[C:9](=[O:16])[N:8]([CH3:17])[C:7]2[CH:18]=[CH:19][C:20]([C:22]3[CH:26]=[CH:25][N:24]([CH3:27])[CH:23]=3)=[N:21][C:6]1=2)[CH3:4]
Reactant: CI
Reactant: CCN1c2ncccc2C(=O)N(C)c2ccc(-c3cc[nH]c3)nc21
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCN1c2ncccc2C(=O)N(C)c2ccc(-c3ccn(C)c3)nc21
Reaction time: 0.5 h

Procedure:
Sodium hydride (0.008 g, 60% in oil) was added to a solution of 5,11-dihydro-11-ethyl-5-methyl-2-(3-pyrrolyl)-6H-dipyrido[3,2-b:2',3'-e][1,4]diazepin-6-one (0.065 g) in dry DMF (3 mL) and stirred for 30 min. Methyl iodide (0.2 mL) was added and the reaction mixture was stirred for an additional 2 h. Water was added and the product was extracted with CH2Cl2, dried (anhyd Na2SO4), filtered, and evaporated. The residue was chromatographed over silica gel (ethyl acetate/hexanes, 1:1) and was further purified by preparative plate chromatography (ethyl acetate/hexanes, 1:1) to give 0.040 g of the title compound, mp 187°-188° C.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.C(N(CC)CC)C.[C:15](Cl)([Cl:17])=[O:16]>CCCCCC1C=C(O)C2[C@@H]3C=C(C)CC[C@H]3C(C)(C)OC=2C=1.C1(C)C=CC=CC=1>[CH3:1][CH:2]1[CH2:7][CH2:6][N:5]([C:15]([Cl:17])=[O:16])[CH2:4][CH2:3]1
Reactant: O=C(Cl)Cl
Reactant: CC1CCNCC1
Agent: CCCCCc1cc(O)c2c(c1)OC(C)(C)[C@@H]1CCC(C)=C[C@@H]21
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CC1CCN(C(=O)Cl)CC1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
9 g (90.75 mmol) of 4-methylpiperidine and 13.9 ml (100 mol) of triethylamine were dissolved in 100 ml of THC and, at −30° C., 54.9 ml (100 mmol) of phosgene in toluene (20 percent) were added, and the mixture was stirred for 2.5 h, during which it warmed to room temperature. The reaction mixture was concentrated, the residue was mixed with methylene chloride and filtered off, and the filtrate was concentrated. The crude product (12.7 g) was reacted without further purification.
Reaction SMILES: [Zn](CC)[CH2:2]C.C(O)(C(F)(F)F)=O.ICI.[CH3:16][O:17][C:18](=[O:32])[C:19]1[CH:24]=[C:23]([O:25][CH3:26])[C:22]([O:27][CH3:28])=[C:21]([CH2:29][CH:30]=[CH2:31])[CH:20]=1>C(Cl)Cl>[CH3:16][O:17][C:18](=[O:32])[C:19]1[CH:24]=[C:23]([O:25][CH3:26])[C:22]([O:27][CH3:28])=[C:21]([CH2:29][CH:30]2[CH2:2][CH2:31]2)[CH:20]=1
Reactant: C=CCc1cc(C(=O)OC)cc(OC)c1OC
Reactant: CC[Zn]CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: ICI
Product: COC(=O)c1cc(CC2CC2)c(OC)c(OC)c1
Temperature: 23 °C
Reaction time: 0.33 h
Yield: 76.7 %

Procedure:
To stirred dichloromethane (10 mL) at 0° C. was added Et2Zn (1.0 M in hexane, 10.0 mL, 10 mmol, 2 eq.). The resulting solution was then treated with a solution of TFA (0.77 mL, 10 mmol) in CH2Cl2 (5.0 mL) added over the course of 3 min. After stirring for 20 min at 0° C. diiodomethane (0.80 mL, 10.0 mmol) in CH2Cl2 was added. After 20 min at 0° C., a solution of 3-allyl-4,5-dimethoxybenzoic acid methyl ester (Example 30, Step 1, 1.18 g, 5.0 mmol) in CH2Cl2 (5.0 mL) was added and the reaction was warmed to 23° C. After 50 min the reaction was quenched by addition of 0.1 N HCl (25 mL) and then diluted with hexanes (100 mL). The organic layer was separated, washed with saturated NaHCO3 (100 mL), H2O (100 mL), brine (100 mL) dried MgSO4 and concentrated in vacuo. The crude product was purified by flash column chromatography on silica gel using 20% EtOAc in hexanes as an eluent to furnish 3-cyclopropylmethyl-4,5-dimethoxybenzoic acid methyl ester (0.96 g, 80% yield).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([N:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH2:11][CH2:10][CH2:9]2)[CH2:4][CH2:3]1.C1C(=O)N([Br:25])C(=O)C1.O>CN(C=O)C>[Br:25][C:14]1[CH:13]=[C:12]2[C:17](=[CH:16][CH:15]=1)[N:8]([CH:5]1[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]1)[CH2:9][CH2:10][CH2:11]2
Reactant: O=C1CCC(=O)N1Br
Reactant: CN1CCC(N2CCCc3ccccc32)CC1
Solvent: O
Solvent: CN(C)C=O
Product: CN1CCC(N2CCCc3cc(Br)ccc32)CC1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A solution of 1-(1-methylpiperidin-4-yl)-1,2,3,4-tetrahydroquinoline (500 mg, 2.17 mmol) in 7 mL of DMF was cooled to 0° C. then treated dropwise with NBS (386 mg, 2.17 mmol) in 7 mL DMF. The reaction was stirred at 0° C. for 2 hours then treated with 30 mL H2O. The suspension was extracted with 100 mL EtOAc. The organic layer was dried over MgSO4, filtered and concentrated to give a dark residue, which was filtered through a short plug of silica gel using 5%, 2M NH3 in MeOH/CH2Cl2 (100 mL). The filtrate was concentrated and subjected to flash chromatography on silica gel using 5% MeOH/CH2Cl2 then 5% 2M NH3 in MeOH/CH2Cl2. A light yellow oil was obtained (490 mg, 73.0%). 1H-NMR (CDCl3) δ: 7.10 (dd, J=2.1, 10.8 Hz), 7.04-7.03 (m, 1H), 6.50 (d, J=9.0 Hz, 1H), 3.57-3.47 (m, 1H), 3.18 (t, J=5.7 Hz, 2H), 2.98-2.94 (m, 2H), 2.68 (t, J=6.0 Hz, 2H), 2.31 (s, 3H), 2.10-2.02 (m, 2H), 1.91-1.69 (m, 6H).
Reaction SMILES: [CH3:1][OH:2].[C:3]1([CH3:13])[CH:8]=[CH:7]C(S(O)(=O)=O)=[CH:5][CH:4]=1.C(C(CC)[CH:17]=[O:18])C.[OH-].[Na+]>O.C1CCCCC1>[CH3:1][O:2][CH:13]([O:18][CH3:17])[CH:3]([CH2:8][CH3:7])[CH2:4][CH3:5]
Reactant: CCC(C=O)CC
Reactant: CO
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCCCC1
Product: CCC(CC)C(OC)OC
Reaction time: 0.08 h

Procedure:
417.3 g of methanol, 1625 g of cyclohexane, and 6.2 g of p-toluenesulfonic acid are placed in a 4 liter three-necked flask fitted with a stirrer, dropping funnel, reflux condenser, and internal thermometer. 651.3 g of 2-ethylbutyraldehyde is added with stirring over a 5 minute period. Owing to the acetal formation which starts spontaneously, the internal temperature rises to about 32° C. The mixture is allowed to react at 40° C. for 30 minutes, a pH of 7.0 is then established in the reaction mixture, which is composed of a lower water phase and an upper organic phase, by addition of sodium hydroxide solution (20% aqueous solution), and the water phase is separated. To remove the low-boiling components, the organic phase is subjected to initial distillation at 200 mbar and a bottom temperature up to 105° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([CH:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)=[O:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.C1COCC1.[BH4-].[Na+].C(=O)([O-])O.[Na+]>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH:14]([CH:16]3[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]3)[OH:15])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: O=C(c1ccc(-c2ccc(Cl)cc2)cc1)C1CCCCC1
Agent: O=C([O-])O
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: OC(c1ccc(-c2ccc(Cl)cc2)cc1)C1CCCCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of (4′-chlorobiphenyl-4-yl)(cyclohexyl)methanone (792.1 mg), THF (5.68 mL) and methanol (0.947 mL) was added sodium borohydride (120 mg) at 0° C. The reaction mixture was stirred at room temperature for 2 hr, and saturated aqueous sodium hydrogen carbonate solution was added at 0° C. The mixture was extracted with ethyl acetate, and the extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give the title compound as a crudely purified product. This compound was used in step C without further purification.