Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](=[O:8])([S:6][CH3:7])[O:2][CH:3](Cl)[CH3:4].[C:9]([OH:14])(=[O:13])[CH:10]([CH3:12])[CH3:11].C(N(C(C)C)CC)(C)C>CCOCC>[C:1](=[O:8])([S:6][CH3:7])[O:2][CH:3]([O:14][C:9](=[O:13])[CH:10]([CH3:12])[CH3:11])[CH3:4]
Reactant: CSC(=O)OC(C)Cl
Reactant: CC(C)C(=O)O
Solvent: CCOCC
Solvent: CCN(C(C)C)C(C)C
Product: CSC(=O)OC(C)OC(=O)C(C)C
Temperature: 55 °C
Yield: 97 %

Procedure:
Compound (1) (308 mg, 2 mmol) was dissolved in isobutyric acid (264 mg, 3 mmol). This mixture was slowly added to a pre-mixed solution of isobutyric acid (264 mg, 3 mmol) and diisopropylethylamine (387 mg, 3 mmol) and the reaction mixture heated to 55° C. for 16 h, diluted with ether (50 mL), washed with water (2×10 mL), saturated bicarbonate solution (2×10 mL) and brine (10 mL), then dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give the title compound (6) as colorless liquid (400 mg, 97%). The product was further purified by vacuum distillation (135° C./20 Torr). 1H NMR (CDCl3, 400 MHz): δ 1.17 (d, J=6.8 Hz, 6H), 1.49 (d, J=5.6 Hz, 3H), 2.33 (s, 3H), 2.54 (m, 1H), 6.91 (q, J=5.2 Hz, 1H).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([S:11][CH2:12][CH2:13][CH3:14])=[CH:7][C:6]=1[N+:15]([O-:17])=[O:16])(=[O:3])[CH3:2].C(Cl)(Cl)Cl.C(OO)(=[O:24])C>CO>[C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([S:11]([CH2:12][CH2:13][CH3:14])=[O:24])=[CH:7][C:6]=1[N+:15]([O-:17])=[O:16])(=[O:3])[CH3:2]
Reactant: CCCSc1ccc(NC(C)=O)c([N+](=O)[O-])c1
Reactant: CC(=O)OO
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CCCS(=O)c1ccc(NC(C)=O)c([N+](=O)[O-])c1

Procedure:
A solution of 3.0 g. of 1-acetamido-2-nitro-4-n-propylthiobenzene in 30 ml. chloroform is cooled to -15° C. and treated with a solution of 2.5 g. of 40% peracetic acid in 4 ml. methanol. After the addition the temperature is allowed to rise slowly to 20° C whereupon the solution is washed with sodium bisulfite solution and then with sodium bicarbonate solution. The product is isolated by evaporation of the solvent and purified by treatment with ether to afford 1-acetamido2-nitro-4-n-propylsulfinylbenzene.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].Cl.[CH3:6][N:7]1[C:16]2[NH:15][C:14]3[CH:17]=[C:18]([CH3:21])[CH:19]=[CH:20][C:13]=3[N:12]([C:22]([CH:24]3[CH2:29][CH2:28][CH:27]([CH2:30][NH:31][C:32](=[O:40])[CH2:33][CH:34]4[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]4)[CH2:26][CH2:25]3)=[O:23])[CH2:11][C:10]=2[CH:9]=[N:8]1>ClCCl.C(N(CC)CC)C>[C:1]([N:37]1[CH2:38][CH2:39][CH:34]([CH2:33][C:32]([NH:31][CH2:30][CH:27]2[CH2:26][CH2:25][CH:24]([C:22]([N:12]3[CH2:11][C:10]4[CH:9]=[N:8][N:7]([CH3:6])[C:16]=4[NH:15][C:14]4[CH:17]=[C:18]([CH3:21])[CH:19]=[CH:20][C:13]3=4)=[O:23])[CH2:29][CH2:28]2)=[O:40])[CH2:35][CH2:36]1)(=[O:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: Cc1ccc2c(c1)Nc1c(cnn1C)CN2C(=O)C1CCC(CNC(=O)CC2CCNCC2)CC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N1CCC(CC(=O)NCC2CCC(C(=O)N3Cc4cnn(C)c4Nc4cc(C)ccc43)CC2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of acetyl chloride (0.39 mg, 0.005 mmol) in dichloromethane (0.05 ml) was added to a solution of N-[4-(3,6-dimethyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-cyclohexylmethyl]-2-piperidin-4-yl-acetamide hydrochloride from Example E17 (2.57 mg, 0.005 mmol) in dichloromethane (0.05 ml) and triethylamine (0.0035 ml). The mixture was stirred at room temperature for 1 h then solvents were removed in vacuo to yield the title compound. (ESI)+: [M+H]+=521.5
Reaction SMILES: [CH2:1]([S:17][CH2:18][CH:19]([N:41]1[N:45]=[N:44][C:43]([CH3:46])=[N:42]1)[CH2:20][O:21]C(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.CC1N=NN(C(COC(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)CO)N=1>CO.O1CCCC1>[CH2:1]([S:17][CH2:18][CH:19]([N:41]1[N:45]=[N:44][C:43]([CH3:46])=[N:42]1)[CH2:20][OH:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCCCCCCCCCSCC(COC(c1ccccc1)(c1ccccc1)c1ccccc1)n1nnc(C)n1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cc1nnn(C(CO)COC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CCCCCCCCCCCCCCCCSCC(CO)n1nnc(C)n1

Procedure:
Using 10.2 g of crude 1-hexadecylthio-2-(5-methyl-2H-tetrazol-2-yl)-3-triphenylmethoxypropane 5h and 500 mg (2.6 mM) of p-toluene sulfonic acid monohydrate in 200 ml of methanol-tetrahydrofurane (1:1) mixture is converted to 3.17 g (49% from the compound 4h) of the title compound Vh1 by the same procedure as described in (81).
Reaction SMILES: [Br:1][C:2]1[C:3]([N:21]2[CH2:26][CH2:25][CH2:24][C@@H:23]([NH:27]C(=O)OC(C)(C)C)[CH2:22]2)=[C:4]2[C:10]([NH:11][C:12](=[O:20])[C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[CH:14]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.C(O)(C(F)(F)F)=O.C(Cl)[Cl:43]>>[ClH:43].[NH2:27][C@@H:23]1[CH2:24][CH2:25][CH2:26][N:21]([C:3]2[C:2]([Br:1])=[CH:7][N:6]=[C:5]3[NH:8][CH:9]=[C:10]([NH:11][C:12](=[O:20])[C:13]4[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[CH:14]=4)[C:4]=23)[CH2:22]1
Reactant: ClCCl
Reactant: Cc1cccc(C(=O)Nc2c[nH]c3ncc(Br)c(N4CCC[C@@H](NC(=O)OC(C)(C)C)C4)c23)c1
Solvent: O=C(O)C(F)(F)F
Product: Cc1cccc(C(=O)Nc2c[nH]c3ncc(Br)c(N4CCC[C@@H](N)C4)c23)c1
Product: Cl
Reaction time: 1 h
Yield: 87.4 %

Procedure:
(R)-tert-Butyl 1-(5-bromo-3-(3-methylbenzamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate (123 mg, 0.233 mmol) in DCM (3 mL) at room temperature was treated with TFA (1 mL), and the reaction was stirred for 1 hour. The reaction mixture was then concentrated to dryness. The resulting residue was dissolved in minimal DCM and added to a stirring solution of 1M HCl in ether. The solid formed was filtered, washed with ether and dried to give (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-3-methylbenzamide hydrochloride (0.102 g, 87.4% yield). 1H NMR (400 MHz, D2O) δ 8.02 (s, 1H), 7.64 (s, 1H), 7.62-7.52 (m, 1H), 7.42-7.38 (m, 3H), 3.49-3.42 (m, 1H), 3.27-3.18 (m, 2H), 3.17-3.06 (m, 2H), 2.29 (s, 3H), 1.81-1.71 (m, 1H), 1.68-1.57 (m, 1H), 1.49-1.26 (m, 2H); LCMS (APCI+) m/z 428, 430 (M+H)+, Retention time=2.68 minutes (Method 2).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][CH:3]=1.C(Cl)(C(Cl)=O)=O.[F:17][C:18]1[CH:24]=[CH:23][C:21]([NH2:22])=[CH:20][C:19]=1[N+:25]([O-:27])=[O:26].CCN(C(C)C)C(C)C>C(Cl)Cl.CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([NH:22][C:21]2[CH:23]=[CH:24][C:18]([F:17])=[C:19]([N+:25]([O-:27])=[O:26])[CH:20]=2)=[O:8])=[CH:9][CH:10]=1
Reactant: O=C(O)c1ccc(Cl)cc1
Reactant: Nc1ccc(F)c([N+](=O)[O-])c1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(F)c([N+](=O)[O-])c1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 39592.9 %

Procedure:
To the solution of 4-chlorobenzoic acid (19) (9.36 g, 0.06 mmol) in DCM (150 mL) was added (COCl)2 (17.4 mL, 0.3 mol) dropwise and cat. amount of DMF at 0° C. The mixture was stirred at room temperature for 2 h and evaporated. The residue was again dissolved in DCM (150 mL) and added to a mixture of 4-fluoro-3-nitroaniline (6.24 g, 0.04 mol) and DIEA (20.9 mL, 0.12 mol) in CH2Cl2 (100 mL) at 0° C. The mixture was allowed to stir at room temperature overnight. The solvent was removed under vacuo and the residue was washed with sat.NaHCO3 aq. (50 mL) and brine (50 mL). The organic layer was separated, dried and purified by crystallization to give 20 (7 g, 60%).
Reaction SMILES: I[C:2]1[C:7]2[N:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH:9]=[N:10][C:6]=2[CH:5]=[C:4]([C:17]([F:20])([F:19])[F:18])[CH:3]=1.[NH2:21][C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[CH:26][CH:27]=1.C(=O)([O-])[O-].[Na+].[Na+].C(O)CCO>O.C(COC)OC.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:21][C:22]1[CH:27]=[C:26]([C:2]2[C:7]3[N:8]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)[CH:9]=[N:10][C:6]=3[CH:5]=[C:4]([C:17]([F:20])([F:19])[F:18])[CH:3]=2)[CH:25]=[CH:24][CH:23]=1
Reactant: FC(F)(F)c1cc(I)c2c(c1)ncn2-c1ccccc1
Reactant: Nc1cccc(B(O)O)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: OCCCO
Solvent: O
Product: Nc1cccc(-c2cc(C(F)(F)F)cc3ncn(-c4ccccc4)c23)c1

Procedure:
A mixture of 7-iodo-1-phenyl-5-trifluoromethylbenzimidazole (3.2 g, 8.2 mmol), 3-aminophenyl boronic acid (1.68 g, 12.3 mmol), sodium carbonate (5.68 g, 41 mmol), 1,3-propanediol (2.94 ml, 41 mmol) and bis(triphenylphosphin)palladium dichloride (200 mg, 0.28 mmol) in a mixture of water (13 ml) and dimethoxyethane (26 ml) was stirred at reflux overnight The cooled reaction mixture was partitioned between ethyl acetate and water, and the organic extract was purified by column chromatography on silica gel eluting with a mixture of dichloromethane and methanol (99:1, v/v). The product was isolated by removal of solvent from appropriate eluate fractions followed by crystallisation of the residue from 2-propanol (50 ml). Yield: 2.7 g (93%), m/z, 354.1 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:31][CH2:32]OS(C)(=O)=O)[CH2:13][N:12]([CH2:14][C:15]3[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[C:17]([C:25]([F:28])([F:27])[F:26])[CH:16]=3)[C:11](=[O:29])[N:10]2[CH3:30])[CH:5]=[CH:6][C:7]=1[Cl:8].[C:38]1([CH:44]2[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]2)[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1.O.Cl>CN(C=O)C.CCOCC>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:31][CH2:32][N:47]3[CH2:48][CH2:49][CH:44]([C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)[CH2:45][CH2:46]3)[CH2:13][N:12]([CH2:14][C:15]3[CH:16]=[C:17]([C:25]([F:26])([F:28])[F:27])[CH:18]=[C:19]([C:21]([F:22])([F:24])[F:23])[CH:20]=3)[C:11](=[O:29])[N:10]2[CH3:30])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: c1ccc(C2CCNCC2)cc1
Reactant: CN1C(=O)N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)CC1(CCOS(C)(=O)=O)c1ccc(Cl)c(Cl)c1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOCC
Solvent: O
Product: CN1C(=O)N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)CC1(CCN1CCC(c2ccccc2)CC1)c1ccc(Cl)c(Cl)c1
Yield: 77.6 %

Procedure:
A mixture of 0.55 g of the compound obtained in step C of EXAMPLE 30, 0.47 g of 4-phenylpiperidine and -0.5 g of K2Co3 in 4 ml of DMF is heated at 80 C for 5 hours. After cooling, the reaction mixture is poured into iced water and extracted with AcOEt, the organic phase is washed with 1 N NaOH solution and with water and dried over MgSO4 and the solvent is evaporated off under vacuum. The residue is chromatographed on silica H using DCM and then a DCM/MeOH mixture (98/2; v/v) as the eluent. The product obtained is dissolved in ether, a saturated solution of gaseous HCl in ether is added until the pH is 1, and the precipitate formed is wrung to give 0.25 g of the expected product. M.p.=208° C.
Reaction SMILES: C([Li])CCC.Br[C:7]1[N:12]=[C:11]2[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:10]2=[CH:9][C:8]=1[CH3:18].[Cl:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=1)[CH:23]=[O:24].O>CCCCCC.C1(C)C=CC=CC=1>[Cl:19][C:20]1[CH:21]=[C:22]([CH:23]([C:7]2[N:12]=[C:11]3[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:10]3=[CH:9][C:8]=2[CH3:18])[OH:24])[CH:25]=[CH:26][CH:27]=1
Reactant: O=Cc1cccc(Cl)c1
Reactant: Cc1cc2c(nc1Br)CCCCC2
Agent: [Li]CCCC
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCCCCC
Product: Cc1cc2c(nc1C(O)c1cccc(Cl)c1)CCCCC2
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 57.2 %

Procedure:
To a solution of 1.6M n-butyl lithium in n-hexane (16.5 ml) in toluene (20 ml) at -20° C. under nitrogen was added a solution of 2-bromo-6,7,8,9-tetrahydro-3-methyl -5H-cyclohepta[b]pyridine (6.0 g, 0.025 m) in toluene (30 ml). The reaction mixture was kept at -20° C. for 0.25 hours and then blown over into a cooled solution of 3-chlorobenzaldehyde (3.7 g) in toluene (30 ml) at -20° C., and allowed to warm to room temperature. Water was added and the separated organic phase extracted with 2N hydrochloric acid. This was basified with solid potassium carbonate and extracted with chloroform. The combined chloroform extracts were washed with water, dried (MgSO4) and evaporated. The solid was purified by passing through a short silica column, eluted with chloroform, then re-crystallised from diethyl ether to give the title compound (4.31 g) m.p. 123°-5° C.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH:19]([C:27]([O:29]C)=[O:28])[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[Cl:26])=[CH:14][CH:13]=2)[C:7](=[O:10])[NH:8][N:9]=1)[CH2:2][CH2:3][CH3:4].[H-].[Na+].[CH2:33](Br)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>CN(C=O)C>[CH2:33]([N:8]1[C:7](=[O:10])[N:6]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH:19]([C:27]([OH:29])=[O:28])[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[Cl:26])=[CH:14][CH:13]=2)[C:5]([CH2:1][CH2:2][CH2:3][CH3:4])=[N:9]1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: BrCc1ccccc1
Reactant: CCCCc1n[nH]c(=O)n1Cc1ccc(OC(C(=O)OC)c2ccccc2Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCc1nn(Cc2ccccc2)c(=O)n1Cc1ccc(OC(C(=O)O)c2ccccc2Cl)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of the above ester (Step G), sodium hydride (3 equivalents), and dry DMF is stirred under N2 at room temperature for 2 hours. Next, benzyl bromide (5 equivalents) is added, and stirring at room temperature is continued for an additional 1.5 hours or until TLC indicates complete reaction. The mixture is quenched by cautious addition of sufficient acetic acid to destroy the excess sodium hydride and then partitioned between ethyl acetate and H2O. The ethyl acetate phase is washed repeatedly with H2O, then dried (Na2SO4), filtered, and concentrated in vacuo. Chromatography of the residue on silica gel affords the title compound.
Reaction SMILES: [N+:1]([CH:4]([CH3:6])[CH3:5])([O-:3])=[O:2].[CH3:7][NH:8][CH2:9][CH2:10][OH:11].[OH-].[Na+].[CH2:14]=O.Cl>C(O)(C)C.O>[CH3:7][N:8]([CH2:5][C:4]([CH3:14])([N+:1]([O-:3])=[O:2])[CH3:6])[CH2:9][CH2:10][OH:11]
Reactant: CC(C)[N+](=O)[O-]
Reactant: C=O
Reactant: CNCCO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)O
Product: CN(CCO)CC(C)(C)[N+](=O)[O-]
Reaction time: 17 h

Procedure:
To a stirred solution of 2-nitropropane (20.0 g, 0.22 mol), 2-(methylamino)ethanol (19.7 mL, 1.1 equiv, 0.24 mol) and 5 N NaOH (0.24 mL, 0.005 equiv, 1.2 mmol) in a mixture of isopropanol (34 mL) and water (3.4 mL) was added dropwise a 37% solution of formaldehyde (18.2 mL, 1.1 equiv, 0.24 mol) over 15 min. The reaction was left to stir for 17 h then the solvent was removed in vacuo. 4 M HCl in dioxanes (66 mL, 0.26 mol) was added to the residue and the solvent removed in vacuo to give an oily residue. The oil was triturated with a mixture of isopropanol and anhydrous diethyl ether to give a hygroscopic white powder. The white powder was dissolved into water (100 mL) and 5 N NaOH (35 mL) was added to give a pale yellow green oil. The oil was extracted with DCM (150 mL) and the organic layer washed with water (2×100 mL), dried over anhydrous MgSO4, filtered and concentrated to a pale yellow green oil (28.0 g, 71.6%). 1H NMR (CDCl3, 400 MHz): δ 1.59 (s, 6H), 2.30 (s, 3H), 2.35-2.38 (t, J=11.2, 1H), 2.63-2.65 (t, J=5.6, 2H), 2.93 (s, 2H), 3.53-3.57 (q, J=5.3, 2H). LRMS (ESI+) for C7H16N2O3 (176.1); Found: 177 (MH+).
Reaction SMILES: C(OC([N:8]1[CH2:18][CH:17]2[CH2:19][CH:10]([C:11]3[CH:12]=[CH:13][C:14]([C:20]#[N:21])=[CH:15][C:16]=32)[CH2:9]1)=O)(C)(C)C.[ClH:22].CCOC(C)=O>>[ClH:22].[CH:17]12[CH2:19][CH:10]([CH2:9][NH:8][CH2:18]1)[C:11]1[CH:12]=[CH:13][C:14]([C:20]#[N:21])=[CH:15][C:16]2=1
Reactant: CC(C)(C)OC(=O)N1CC2CC(C1)c1cc(C#N)ccc12
Agent: Cl
Solvent: CCOC(C)=O
Product: N#Cc1ccc2c(c1)C1CNCC2C1
Reaction time: 18 h

Procedure:
4-Cyano-10-aza-tricyclo[6.3.1.02,7]dodeca-2(7),3,5-triene-10-carboxylic acid tert-butyl ester was treated with 3N HCl EtOAc (6 mL) and warmed to reflux for 2 hours, then concentrated, dissolved in a minimum of MeOH which was saturated with Et2O and stirred 18 hours. The product was collected by filtration (49 mg, 73%). 1H NMR (400 MHz, DMSO-d6) δ 9.66 (br s, NH), 7.86 (br s, NH), 7.74-7.70 (m, 2H), 7.49 (d, J=7.5 Hz, 1H), 3.33-2.97 (m, 6H), 2.17 (m, 1H), 2.01 (d, J=11.0 Hz, 1H). GCMS m/e 184 (M+). mp 268-273° C.
Reaction SMILES: [C:1]([C:3]([CH3:12])([CH3:11])[CH:4]([OH:10])[CH2:5][C:6](OC)=[O:7])#[N:2].CO.[BH4-].[Na+].Cl>C1COCC1.C(OCC)(=O)C>[C:1]([C:3]([CH3:12])([CH3:11])[CH:4]([OH:10])[CH2:5][CH2:6][OH:7])#[N:2]
Reactant: COC(=O)CC(O)C(C)(C)C#N
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C#N)C(O)CCO
Temperature: 25 °C
Reaction time: 3 h
Yield: 67 %

Procedure:
Optically active methyl 4-cyano-3-hydroxy-4-methylpentanoate (2 g, 11.7 mmol) was dissolved in THF (10 mL) and methanol (5 mL) was added. An aqueous sodium borohydride (885 mg, 23.4 mmol) solution (5 mL) was dropwise added at room temperature. The mixture was stirred at room temperature for 3 hr and then 2N aqueous hydrochloric acid solution (15 mL) was dropwise added at 0° C. Ethyl acetate (20 mL) was added and the mixture was stirred vigorously. An organic layer was extracted. Ethyl acetate (20 mL) was further added to the aqueous layer and the mixture was stirred vigorously. The organic layer was extracted again. This step was repeated three times and the obtained organic layer was dried over anhydrous magnesium sulfate (2 g) and concentrated under reduced pressure to give optically active 4-cyano-4-methyl-3-hydroxy-1-pentanol (1.12 g, 7.84 mmol) (yield relative to optically active methyl 4-cyano-3-hydroxy-4-methylpentanoate: 67%).
Reaction SMILES: [CH3:1][C@H:2]([NH2:11])[C@H:3]([OH:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C(=O)[C:13]1[C:14]([O:19][CH3:20])=[CH:15][CH:16]=[CH:17][CH:18]=1.[C:22](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(O)(=O)C>[OH:10][C@H:3]([C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1)[C@@H:2]([N:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[O:19][CH3:20])[CH3:22])[CH3:1]
Reactant: C[C@H](N)[C@H](O)c1ccccc1
Reactant: COc1ccccc1C=O
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Product: COc1ccccc1N(C)[C@@H](C)[C@H](O)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 61.9 %

Procedure:
A solution of 1.00 g (6.61 mmol) (1R, 2S)-(-)-norephedrine and 1.12 g (8.26 mmol) of o-anisaldehyde in 20 ml of acetic acid was treated with 1.5 g of 3 Å molecular sieves. The mixture was treated with 2.8 g (13.22 mmol) of sodium triacetoxyborohydride in 0.1 g increments over 20 minutes. The reaction mixture was stirred at room temperature for 18 hours under a nitrogen atmosphere. The reaction was judged to be complete by thin layer analysis (eluting with 9:1 methylene chloride:methanol), the mixture was filtered and the filtrate was evaporated in vacuo. The residue was taken up in 25 ml of water and the mixture was treated with 1N HCl until the solution pM was approximately 3. The aqueous phase was extracted twice with ether (25 ml) and was then treated with 2N NaOH until pH 12 was reached. The aqueous layer was again extracted with ether (3×50 ml). The organic layer was dried with magnesium sulfate and was evaporated to dryness. There were obtained 1.11 g (62% yield) of a white solid after chromatography (eluting with 95% ethyl acetate/5% triethyl amine) on silica gel. M.P. 84°-86° C. 1H NMR (CDCl3, 300 MHz) δ 7.39-7.21 (7 H, m), 7.0-6.92 (1H, t, J=8.5 Hz), 6.91-6.88 (1H, d, J=8.0 Hz), 4.82 (d, 1H, J=4.0 Hz), 3.90 (s, 2H), 3.82 (s, 3H), 2.97-2.88 (dq, 1H, J=7 Hz, J=4.0 Hz), 0.82 (d, 3H, J=7 Hz) ppm. 13C NMR (DEPT, CDCl3, 75.47 MHz) δ 157.74 (s), 141.65 (s), 129.86 (d) , 128.50 (d), 128.14 (s), 128.05 (d), 126.93 (d), 126.12 (d), 120.49 (d), 110.36 (d), 72.83 (d), 57.25 (d), 55.23 (q), 46.68 (t), 14.77 (q) ppm. IR (KBr) λ 3500-2400 (br), 1600, 1480, 1460, 1240, 1050, 1030 cm-1. HRMS calc'd for C17H21NO2 : 271.1567. Found 271.1603.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([Cl:9])[C:3]=1[NH2:4].[C:10](Cl)(Cl)=[S:11].C(N(C(C)C)C(C)C)C>C(Cl)Cl>[Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([Cl:9])[C:3]=1[N:4]=[C:10]=[S:11]
Reactant: S=C(Cl)Cl
Reactant: Nc1c(Cl)cccc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: S=C=Nc1c(Cl)cccc1Cl
Yield: 39.7 %

Procedure:
The title compound was prepared following the procedure described for intermediate-2 using 2,6-dichloro aniline (2.0 g, 12.34 mmol), thiophosgene (1.41 g, 12.34 mmol) and N-ethyl di-isopropyl amine (7.42 g, 57.51 mmol) in DCM (20 mL) to afford 1.0 g of the desired product. 1HNMR (DMSO-d6): δ 7.62 (d, J=7.8 Hz, 2H), 7.39 (t, J=7.8 Hz, 1H).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[C:12]([F:13])=[C:11]([F:14])[C:7]([C:8](Cl)=[O:9])=[C:6]([F:15])[C:5]=1[F:16].[CH2:17]([OH:19])[CH3:18]>>[CH3:1][O:2][CH2:3][C:4]1[C:12]([F:13])=[C:11]([F:14])[C:7]([C:8]([O:19][CH2:17][CH3:18])=[O:9])=[C:6]([F:15])[C:5]=1[F:16]
Reactant: CCO
Reactant: COCc1c(F)c(F)c(C(=O)Cl)c(F)c1F
Product: CCOC(=O)c1c(F)c(F)c(COC)c(F)c1F
Temperature: 25 °C
Reaction time: 3 h

Procedure:
The acid chloride from stage 1 (1.00 g) was dissolved in dry ethanol (5 cm3) and, when the initial exothermic reaction had subsided, the solution was stirred for a further 3 hours at the ambient temperature. The excess ethanol was evaporated under reduced pressure to yield ethyl 4-(methoxymethyl)-2,3,5,6-tetrafluorobenzoate (0.90 g) as a yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2Cl.[CH3:18][N:19]([CH3:27])[CH2:20][CH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[N:24]1[CH2:25][CH2:26][CH:21]([CH2:20][N:19]([CH3:27])[CH3:18])[CH2:22][CH2:23]1
Reactant: CN(C)CC1CCNCC1
Reactant: O=C(c1cnc2ccc(Br)cc2c1Cl)C1CC1
Product: CN(C)CC1CCN(c2c(C(=O)C3CC3)cnc3ccc(Br)cc23)CC1
Yield: 56.5 %

Procedure:
Following general procedure B, (6-bromo-4-chloroquinolin-3-yl)(cyclopropyl)methanone (211 mg, 0.680 mmol) was reacted with N,N-dimethyl-1-(piperidin-4-yl)methanamine (97 mg, 0.680 mmol) to afford the desired product (160 mg, 46%) as a yellow glass: ESI MS m/z 417 [C21H26BrN3O+H]+.
Reaction SMILES: [OH:1][C:2]1[C:3]([O:24][CH3:25])=[CH:4][C:5]2[C:14]3[CH:15]=[C:16]([O:21][CH3:22])[C:17]([O:19][CH3:20])=[CH:18][C:13]=3[CH2:12][CH:11]3[C:6]=2[C:7]=1[CH2:8][N:9]([CH3:23])[CH2:10]3.[OH-].[C:27]1([N+](C)(C)C)C=CC=CC=1>C1(C)C=CC=CC=1.CN(C)C=O>[CH3:25][O:24][C:3]1[C:2]([O:1][CH3:27])=[C:7]2[CH2:8][N:9]([CH3:23])[CH2:10][CH:11]3[CH2:12][C:13]4[CH:18]=[C:17]([O:19][CH3:20])[C:16]([O:21][CH3:22])=[CH:15][C:14]=4[C:5](=[C:6]23)[CH:4]=1
Reactant: C[N+](C)(C)c1ccccc1
Reactant: COc1cc2c(cc1OC)-c1cc(OC)c(O)c3c1C(C2)CN(C)C3
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: COc1cc2c(cc1OC)-c1cc(OC)c(OC)c3c1C(C2)CN(C)C3

Procedure:
9.1 g. (±)-5,6,6a,7-Tetrahydro-3-hydroxy-2,9,10-trimethoxy-5-methyl-4H-dibenz(de,g)isoquinoline (see Example 2) are reacted with phenyltrimethylammonium hydroxide in toluene/dimethylformamide in a manner analogous to that described in Example 7. When the methylation is finished, the reaction mixture is worked up in the manner described in Example 7. By chromatography of the crude product on silica gel (elution with chloroform +1% triethylamine) and crystallisation from chloroform-diethyl ether, there is obtained (±)-5,6,6a,7-tetrahydro-2,3,9,10-tetramethoxy-5-methyl-4H-dibenz(de,g)isoquinoline in the form of beige crystals; m.p. 170°-177° C.