Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6].[C:13](Cl)(=[O:18])[CH2:14][CH2:15][CH2:16][CH3:17].C(=O)([O-])O.[Na+]>CN(C)C(=O)C>[C:13]([NH:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6])(=[O:18])[CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: CCCCC(=O)Cl
Reactant: CCOC(=O)c1cccc(N)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CCCCC(=O)Nc1cccc(C(=O)OCC)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of ethyl 3-aminobenzoate (5.02 g) in N,N-dimethylacetamide (DMA, 50 ml) was added dropwise pentanoyl chloride (4.0 ml), and the mixture was stirred at room temperature for 1 hr. Saturated aqueous sodium hydrogencarbonate was added to the reaction mixture, and the mixture was stirred for 1 hr. The mixture was partitioned and extracted by adding ethyl acetate, and the extract was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated to give ethyl 3-(N-pentanoyl)aminobenzoate (7.55 g). To a solution of the obtained amide compound in DMA (100 ml) was added potassium tert-butoxide (4.09 g), and the mixture was stirred for 30 min. To the reaction mixture was added [4-[2-(3-triphenylmethyl-3H-tetrazol-5-yl)phenyl]phenyl]methylbromide (18.6 g), and the mixture was stirred at 50° C. for 3 hrs. The reaction mixture was added to ethyl acetate-water and, after partitioning and extraction, the extract was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (eluted with hexane-ethyl acetate:3-2 v/v) to give the object compound (20.6 g, yield 93.6%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([CH3:11])[CH:10]=1)[C:7]1([CH2:16][C:15](=[O:17])[CH:14]([C:18](=O)[CH2:19][CH3:20])[C:13](=[O:22])[CH2:12]1)[CH2:6][CH2:5]2.[CH2:23]([O:25][NH2:26])[CH3:24]>>[CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([CH3:11])[CH:10]=1)[C:7]1([CH2:16][C:15](=[O:17])[CH:14]([C:18](=[N:26][O:25][CH2:23][CH3:24])[CH2:19][CH3:20])[C:13](=[O:22])[CH2:12]1)[CH2:6][CH2:5]2
Reactant: CCC(=O)C1C(=O)CC2(CCc3cc(C)cc(C)c32)CC1=O
Reactant: CCON
Product: CCON=C(CC)C1C(=O)CC2(CCc3cc(C)cc(C)c32)CC1=O

Procedure:
Reaction of 5',7'-dimethyl-4-propionylspiro[cyclohexane-1,1'-indan]-3,5-dione with ethoxyamine according to the procedure described in Example 1 part (c) gave 5',7'-dimethyl-4-[1-(ethoxyimino)propyl]spiro[cyclohexane-1,1'indan]-3,5-dione (1) as a pale yellow oil which was characterized by its proton magnetic resonance spectrum and the spectroscopic data is recorded in Table 2, Example 12.
Reaction SMILES: [Br:1][CH2:2][C:3](Br)=[O:4].[C:6]([N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7].C(N(CC)CC)C>C(Cl)Cl>[C:9]([O:8][C:6]([N:13]1[CH2:18][CH2:17][N:16]([C:3](=[O:4])[CH2:2][Br:1])[CH2:15][CH2:14]1)=[O:7])([CH3:12])([CH3:10])[CH3:11]
Reactant: O=C(Br)CBr
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCN(C(=O)CBr)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 59.9 %

Procedure:
A solution of bromoacetyl bromide (8.5 ml, 97 mmol) in DCM (250 ml) at 0° C. was treated dropwise with a solution of 1-Boc-piperazine (15.9, 85.3 mmol) and triethylamine (18.0 ml, 130 mmol) in DCM (150 ml). After addition was complete, the mixture was stirred at room temperature for 4 h. The solution was washed with ice-cold 1M HCl, sat. aq. NaHCO3, dried and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluant; 20% EtOAc:80% cyclohexane to 50% EtOAc:50% cyclohexane) to yield the title compound (15.7 g, 60.0%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([O:13][CH2:14][CH3:15])[CH:12]=1)[C:6]([O:8][CH3:9])=[O:7])#[N:2].[N-:16]=[N+:17]=[N-:18].[Na+].Cl.C(N(CC)CC)C.[OH-].[Na+]>CN(C=O)C>[CH2:14]([O:13][C:11]1[CH:10]=[C:5]([CH:4]=[C:3]([C:1]2[NH:18][N:17]=[N:16][N:2]=2)[CH:12]=1)[C:6]([O:8][CH3:9])=[O:7])[CH3:15]
Reactant: CCOc1cc(C#N)cc(C(=O)OC)c1
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOc1cc(C(=O)OC)cc(-c2nnn[nH]2)c1
Temperature: 100 °C
Reaction time: 12 h

Procedure:
A mixture of methyl 3-cyano-5-ethoxybenzoate (182 mg, 0.89 mmol), sodium azide (173 mg, 2.66 mmol), triethylamine hydrochloride (366 mg, 2.66 mmol) and DMF (4.4 mL) was stirred in a nitrogen atmosphere at 100° C. for 12 hours. After left cooled, aqueous 5 N sodium hydroxide solution (0.53 mL, 2.66 mmol) was added to the reaction mixture, and washed with chloroform. The aqueous layer was made to have a pH of 2 with 5 N hydrochloric acid, and extracted with chloroform. The organic layer was dried with sodium sulfate, concentrated under reduced pressure, and the residue was purified through silica gel column chromatography to obtain the title compound as a colorless solid.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH2:4][CH2:3]1.[Cl:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[Mg]Br.BrC1C=CC=CC=1CO.C([Li])CCC>>[Cl:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:2]1([OH:1])[CH2:3][CH2:4][N:5]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH2:6][CH2:7]1
Reactant: O=C1CCN(C(=O)OCc2ccccc2)CC1
Reactant: Clc1ccccc1[Mg]Br
Agent: OCc1ccccc1Br
Agent: [Li]CCCC
Product: O=C(OCc1ccccc1)N1CCC(O)(c2ccccc2Cl)CC1

Procedure:
9.74 g of the entitled compound was obtained as a pale yellow oily substance in the same manner as in Production Example 8-3, for which, however, benzyl 4-oxopiperidine-1-carboxylate was used in place of tert-butyl 3-oxo-8-aza-bicyclo-[3.2.1]octane-8-carboxylate used in Production Example 8-3, and 2-chlorophenylmagnesium bromide was used in place of the lithium reagent prepared from 2-bromobenzyl alcohol and n-butyllithium.
Reaction SMILES: [C:1]([O:4][N:5]=[C:6]([C:23]1[NH:24][C:25](=[NH:28])[S:26][CH:27]=1)[C:7]([O:9][CH:10]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8])(=[O:3])[CH3:2].C(N(CC)CC)C.[Cl:36][CH2:37][C:38](Cl)=[O:39].C(=O)([O-])O.[Na+]>CN(C)C=O.O>[C:1]([O:4][N:5]=[C:6]([C:23]1[NH:24][C:25](=[N:28][C:38](=[O:39])[CH2:37][Cl:36])[S:26][CH:27]=1)[C:7]([O:9][CH:10]([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8])(=[O:3])[CH3:2]
Reactant: O=C(Cl)CCl
Reactant: CC(=O)ON=C(C(=O)OC(c1ccccc1)c1ccccc1)c1csc(=N)[nH]1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)ON=C(C(=O)OC(c1ccccc1)c1ccccc1)c1csc(=NC(=O)CCl)[nH]1
Reaction time: 0.33 h

Procedure:
In 100 ml of N,N-dimethylformamide there were suspended 19.7 g of benzhydryl 2-acetoxyimino-2-(2-imino-4-thiazolin-4-yl)acetate, followed by the addition of 6.02 g of triethylamine. Under ice-cooling and stirring, 4.98 ml of chloroacetyl chloride were added dropwise. The mixture was further stirred at that temperature for 10 minutes and, then, at room temperature for 20 minutes. Thereafter, 1.50 ml of chloroacetyl chloride was added dropwise and the mixture were stirred for 20 minutes. The reaction mixture was poured into a solution of 4.4 g of sodium hydrogen carbonate in 200 ml of water and extracted with 500 ml of ethyl acetate in three installments. The ethyl acetate layers were pooled, washed twice with 100 ml of a 1e aqueous solution of sodium hydrogen carbonate and further washed with a saturated aqueous solution of sodium chloride. The drying with magnesium sulfate and the decolorization with activated carbon were concurrently carried out and, after filtering, the solvent was distilled off. To the residue there were added 20 ml of ethyl acetate and the mixture was allowed to stand. The resultant crystals were recovered by filtration and dried. By the above procedure there were obtained 12.7 g of benzhydryl 2-acetoxyimino-2-(2-chloroacetylimino-4-thiazolin-4-yl)acetate (syn-isomer). This product contained a small amount of the anti-isomer, which was removed by the following procedure.
Reaction SMILES: [O:1]=[C:2]([CH:8]=[CH2:9])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH3:10][NH:11][CH3:12]>CCOCC>[CH3:10][N:11]([CH2:9][CH2:8][C:2](=[O:1])[C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH3:12]
Reactant: C=CC(=O)C(=O)OCC
Reactant: CNC
Solvent: CCOCC
Product: CCOC(=O)C(=O)CCN(C)C
Reaction time: 24 h

Procedure:
To a stirred solution of 12.8 g (0.10 mole) of ethyl 2-oxo-3-butenoate in 200 ml of anhydrous ether under a nitrogen atmosphere (in an ice bath) is added over about 1 hr. a cold solution of 4.5 g (0.10 mole) of dimethylamine in 200 ml of anhydrous ether. The reaction is stirred at 0° for several hours, and then at 20°-25° for one day. The solvent is removed, and the resulting crude product is purified by flash chromatography on silica gel using chloroform/methanol as eluant.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([C:15]([C:17]2[CH:22]=[CH:21][C:20]([N:23]3[C@H:27]([CH2:28][OH:29])[CH2:26][CH2:25][S:24]3(=[O:31])=[O:30])=[CH:19][C:18]=2[S:32]([CH3:35])(=[O:34])=[O:33])=[O:16])[CH2:11][CH2:10]1.S(C1C=CC(C)=CC=1)(O[CH3:40])(=O)=O>>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([C:15]([C:17]2[CH:22]=[CH:21][C:20]([N:23]3[C@H:27]([CH2:28][O:29][CH3:40])[CH2:26][CH2:25][S:24]3(=[O:30])=[O:31])=[CH:19][C:18]=2[S:32]([CH3:35])(=[O:33])=[O:34])=[O:16])[CH2:11][CH2:10]1
Reactant: COS(=O)(=O)c1ccc(C)cc1
Reactant: Cc1ccc(N2CCN(C(=O)c3ccc(N4[C@H](CO)CCS4(=O)=O)cc3S(C)(=O)=O)CC2)c(C)c1
Product: COC[C@@H]1CCS(=O)(=O)N1c1ccc(C(=O)N2CCN(c3ccc(C)cc3C)CC2)c(S(C)(=O)=O)c1

Procedure:
Using (S)-[4-(2,4-dimethylphenyl)piperazin-1-yl][4-(3-hydroxymethyl-1,1-dioxo-1λ6-isothiazolidin-2-yl)-2-methanesulfonylphenyl]methanone (880 mg) described in Example 29 and methyl tosylate (0.25 mL) and by the reaction and treatment in the same manner as in Example 36, the title compound (71 mg) was obtained.
Reaction SMILES: C([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH2:17][C:18]2([O:52][CH3:53])[C:24](=[O:25])[N:23]([CH2:26][C:27]([N:29]([CH:38]([CH3:40])[CH3:39])[C:30]3[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=3)=[O:28])[C:22]3[CH:41]=[CH:42][CH:43]=[CH:44][C:21]=3[N:20]([C:45]3[CH:46]=[N:47][CH:48]=[CH:49][CH:50]=3)[C:19]2=[O:51])=[N:9]1)C1C=CC=CC=1.C(O)=O>[Cl-].[Na+].O.C(OCC)(=O)C.[Pd]>[NH:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH2:17][C:18]2([O:52][CH3:53])[C:24](=[O:25])[N:23]([CH2:26][C:27]([N:29]([CH:38]([CH3:40])[CH3:39])[C:30]3[CH:31]=[CH:32][C:33]([O:36][CH3:37])=[CH:34][CH:35]=3)=[O:28])[C:22]3[CH:41]=[CH:42][CH:43]=[CH:44][C:21]=3[N:20]([C:45]3[CH:46]=[N:47][CH:48]=[CH:49][CH:50]=3)[C:19]2=[O:51])=[N:9]1
Reactant: COc1ccc(N(C(=O)CN2C(=O)C(Cc3nn(Cc4ccccc4)c4ccccc34)(OC)C(=O)N(c3cccnc3)c3ccccc32)C(C)C)cc1
Agent: [Pd]
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: O=CO
Product: COc1ccc(N(C(=O)CN2C(=O)C(Cc3n[nH]c4ccccc34)(OC)C(=O)N(c3cccnc3)c3ccccc32)C(C)C)cc1
Temperature: 25 °C
Yield: 54.8 %

Procedure:
To a stirring solution of 350 mg (0.49 mmol) of 2-[3-(1-Benzyl-1H-indazol-3-ylmethyl)-3-methoxy-2,4-dioxo-5-pyridin-3-yl-2,3,4,5-tetrahydro-benzo[b][1,4]diazepin-1-yl]-N-isopropyl-N-(4-methoxy-phenyl)-acetamide, prepared as in Intermediate 55, in a 10 mL solution of 5% formic acid (v/v) in absolute ethanol/DMF 1/1 is added 350 mg of 10% palladium on carbon. The resulting mixture is heated to reflux for 3 h, then cooled to RT and filtered through a pad of Celite to remove the catalyst. The filtrate is concentrated, then poured into 50 mL of EtOAc and washed successively with 1N NaOH (1×50 mL) and H2O (1×50 mL). The organic layer is separated, dried (MgSO4), and the solvents removed in vacuo. Purification by silica gel flash column chromatography using hexane/EtOAc 1/2 as eluent afforded 166 mg of the title compound as a white solid: mp 207°-209° C.; 1H NMR (CDCl3, 400 MHz) δ10.05 (s, br, 1H), 8.43 (d, 1H, J=4.6), 8.29 (s, 1H), 7.94 (d, 1H, J=8.2), 7.56 (d, 1H, J=7.2), 7.39 (d, 1H, J=7.8), 7.29 (m, 2H), 7.25-7.09 (m, 5H), 6.98 (m, 3H), 6.65 (d, 1H, J=8.1), 5.06 (m, 1H), 4.25 (dd, 2H, J=16.0, 198.0), 4.07 (dd, 2H, J=16.2, 107.8), 3.84 (s, 3H), 3.21 (s, 3H), 1.12 (2×d, 6H, J=7.2); low resolution MS (FAB)m/e 619 (MH+), 618 (M+); Anal. (C35H34N6O5) Calcd. C, 67.95; H, 5.54; N, 13.58 Found C, 67.85; H, 5.51; N, 13.59.
Reaction SMILES: [Br:1][C:2]1[S:14][C:5]2=[N:6][CH:7]=[C:8]([C:11]([OH:13])=[O:12])[C:9]([OH:10])=[C:4]2[CH:3]=1.[OH-].[K+].S(OC)(O[CH3:21])(=O)=O>>[Br:1][C:2]1[S:14][C:5]2[N:6]([CH3:21])[CH:7]=[C:8]([C:11]([OH:13])=[O:12])[C:9](=[O:10])[C:4]=2[CH:3]=1
Reactant: COS(=O)(=O)OC
Reactant: O=C(O)c1cnc2sc(Br)cc2c1O
Agent: [K+]
Agent: [OH-]
Product: Cn1cc(C(=O)O)c(=O)c2cc(Br)sc21

Procedure:
To a solution of 0.274 part of 2-bromo-4-hydroxythieno(2,3-b)-pyridine-5-carboxylic acid in 3 parts by volume of a 2N aqueous solution of potassium hydroxide is added 0.24 part by volume of dimethyl sulfate. Treatment of the mixture in the manner described in Example 20 gives 2-bromo-4,7-dihydro-7-methyl-4-oxothieno(2,3-b)-pyridine-5-carboxylic acid as crystals. Recrystallization from dimethylformamide-water gives colorless needles melting at 288°-290° C.
Reaction SMILES: [F:1][C:2]1[C:7]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.C(=O)([O-])[O-].[K+].[K+].I[CH2:25][CH3:26]>C(#N)C>[CH2:25]([N:15]1[CH2:16][CH2:17][CH:12]([C:3]2[CH:4]=[CH:5][CH:6]=[C:7]([S:8]([CH3:11])(=[O:10])=[O:9])[C:2]=2[F:1])[CH2:13][CH2:14]1)[CH3:26]
Reactant: CCI
Reactant: CS(=O)(=O)c1cccc(C2CCNCC2)c1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCN1CCC(c2cccc(S(C)(=O)=O)c2F)CC1

Procedure:
Preparation according to Example 1: 4-[2-fluoro-3-(methylsulfonyl)phenyl]-piperidine (0.185 g, 0.72 mmol), acetonitrile (10 ml), potassium carbonate (0.2 g, 1.44 mmol), 1-iodoethane (0.06 ml, 0.75 mmol). Yield: 0.15 g (73%). The amine was converted to several different salts and recrystallized from ethanol/diethyl ether. Hydrochloric acid salt m.p. 273-275° C., hydrobromic acid salt m.p. 267-268° C., fumaric acid salt m.p. 204-206° C., oxalic acid salt m.p. 163-165° C., sulfate salt m.p. 263-265° C., maleic acid salt m.p. 112-113° C. MS m/z (relative intensity, 70 eV) 285 (M+, 12), 271 (15), 270 (bp), 147 (7) 133 (8).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][CH:9]2[CH2:14][C:13]([CH3:16])([CH3:15])[NH:12][C:11]([CH3:18])([CH3:17])[CH2:10]2)[N:3]=1.[CH3:19][S:20][C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)CC.CCOC(C)=O.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>[CH3:19][S:20][C:21]1[CH:26]=[CH:25][C:24]([C:2]2[CH:7]=[CH:6][N:5]=[C:4]([NH:8][CH:9]3[CH2:14][C:13]([CH3:16])([CH3:15])[NH:12][C:11]([CH3:18])([CH3:17])[CH2:10]3)[N:3]=2)=[CH:23][CH:22]=1
Reactant: CSc1ccc(B(O)O)cc1
Reactant: CC1(C)CC(Nc2nccc(Cl)n2)CC(C)(C)N1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCCO
Solvent: CCOC(C)=O
Product: CSc1ccc(-c2ccnc(NC3CC(C)(C)NC(C)(C)C3)n2)cc1
Temperature: 85 °C
Reaction time: 2 h

Procedure:
The title compound was prepared according to Method C. To a degassed suspension of (4-chloro-pyrimidin-2-yl)-(2,2,6,6-tetramethyl-piperidin-4-yl)-amine (1.07 g, 3.97 mmol) in 10 ml of 1-propanol were added bis(triphenylphosphine)palladium dichloride (112 mg, 0.16 mmol), 4-(methylthio)phenylboronic acid (1.00 g, 5.95 mmol) and 8 ml of 2N-solution of sodium carbonate. The mixture was stirred at 85° C. for 2 hours. The reaction mixture was diluted with EtOAc, filtered through Celite and washed with water. The organic layer was dried and concentrated. The solid was purified by chromatography on silicagel (EtOAc/MeOH/ammonia:66/33/1) and crystallization from n-hexane. Yield: 1.12 g (79%).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:11]=[C:12]([O:14][CH3:15])[N:13]=1)[C:5]([NH:7][CH:8]1[CH2:10][CH2:9]1)=[O:6].[CH3:16][O:17][CH2:18]/[CH:19]=[CH:20]/B1OC(C)(C)C(C)(C)O1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C.[Pd](Br)Br>[CH:8]1([NH:7][C:5](=[O:6])[C:4]2[CH:3]=[C:2](/[CH:20]=[CH:19]/[CH2:18][O:17][CH3:16])[N:13]=[C:12]([O:14][CH3:15])[CH:11]=2)[CH2:10][CH2:9]1
Reactant: COC/C=C/B1OC(C)(C)C(C)(C)O1
Reactant: COc1cc(C(=O)NC2CC2)cc(Cl)n1
Agent: Br[Pd]Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC/C=C/c1cc(C(=O)NC2CC2)cc(OC)n1
Temperature: 100 °C

Procedure:
To a solution of 2-chloro-N-cyclopropyl-6-methoxyisonicotinamide from the previous step (1 eq.) in DMF (0.3 M) was added (2-[(1E)-3-methoxyprop-1-en-1-yl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1 eq.), palladium bromide (5% loading), triphenylphosphine (10% loading) and sodium carbonate (2 M aqueous solution, 3 eq.). The resulting suspension was heated at 100° C. for 7 h. The reaction mixture was quenched with water and extracted with ether. The combined organic extracts were washed with sat. aq. NaHCO3 and brine. Drying over Na2SO4, filtration and concentration of the filtrate in vacuo afforded the crude product as a brown tar. Purification by way of column chromatography (SiO2, 1:1 (v/v) Hex:EtOAc) followed by recrystallization from Hex:ether afforded the title compound as a white solid.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][C:5]1[N:6]([CH2:31][CH2:32][CH2:33][N:34]2[CH2:38][CH2:37][CH2:36][C:35]2=[O:39])[C:7]2[C:16]3[CH:15]=[C:14]([CH:17]=[CH:18][N:19]4[C:27](=[O:28])[C:26]5[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=5)[C:20]4=[O:29])[CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:30]=1>[Pd].CO>[CH3:1][O:2][CH2:3][CH2:4][C:5]1[N:6]([CH2:31][CH2:32][CH2:33][N:34]2[CH2:38][CH2:37][CH2:36][C:35]2=[O:39])[C:7]2[C:16]3[CH:15]=[C:14]([CH2:17][CH2:18][N:19]4[C:20](=[O:29])[C:21]5[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=5)[C:27]4=[O:28])[CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:30]=1
Reactant: COCCc1nc2cnc3ccc(C=CN4C(=O)c5ccccc5C4=O)cc3c2n1CCCN1CCCC1=O
Agent: [Pd]
Solvent: CO
Product: COCCc1nc2cnc3ccc(CCN4C(=O)c5ccccc5C4=O)cc3c2n1CCCN1CCCC1=O
Temperature: 50 °C
Reaction time: 18 h
Yield: 105.1 %

Procedure:
A glass Parr vessel was charged with 10% palladium on carbon (0.2 g), methanol (75 mL) and 2-(2-{2-(2-methoxyethyl)-1-[3-(2-oxopyrrolidin-1-yl)propyl]-1H-imidazo[4,5-c]quinolin-8-yl}ethenyl)-1H-isoindole-1,3(2H)-dione (2.0 g, 3.8 mmol). The vessel was evacuated and charged with hydrogen gas (40 psi, 2.8×105 Pa). The reaction was shaken at 50° C. for approximately 18 hours. After cooling to ambient temperature, the reaction mixture was filtered followed by concentration under reduced pressure to provide 2.1 g of 2-(2-{2-(2-methoxyethyl)-1-[3-(2-oxo-pyrrolidin-1-yl)propyl]-1H-imidazo[4,5-c]quinolin-8-yl}ethyl)-1H-isoindole-1,3(2H)-dione as a pale yellow solid. MS (ESI) m/z 526 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:11]([S:12]([NH:15][CH:16]2[CH2:18][CH2:17]2)(=[O:14])=[O:13])=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6]C)=[O:5].[OH-].[Na+]>>[Cl:1][C:2]1[C:11]([S:12]([NH:15][CH:16]2[CH2:17][CH2:18]2)(=[O:14])=[O:13])=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: COC(=O)c1cccc(S(=O)(=O)NC2CC2)c1Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)c1cccc(S(=O)(=O)NC2CC2)c1Cl

Procedure:
To a solution of methyl 2-chloro-3-(chlorosulfonyl)benzoate (608 mg, 2.26 mmol) and K2CO3 (770 mg, 5.6 mmol) in 10 mL benzene was added cyclopropylamine (0.78 mL, 11.2 mmol). Purification of the product provided methyl 2-chloro-3-[(cyclopropylamino)sulfonyl]benzoate (355 mg, 54%) as a solid. 1H NMR (400 MHz, CDCl3), δ 8.28 (dd, 1H, J=7.9, 1.7 Hz), 7.90 (dd, 1H, J=7.8, 1.7 Hz), 7.48 (t, 1H, J=7.8 Hz), 5.63 (s, 1H), 3.93 (s, 3H), 2.17 (m, 1H), 0.65-0.58 (m, 2H), 0.57-0.50 (m, 2H); ESI-MS 290 (M+H), 312 (M+Na). Methyl 2-chloro-3-[(cyclopropylamino)sulfonyl]benzoate was hydrolyzed using aqueous NaOH to provide 2-chloro-3-[(cyclopropylamino)sulfonyl]benzoic acid as a solid, which was used without further purification. ESI-MS 276 (M+H), 298 (M+Na).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:24])[N:10]([CH2:12][CH2:13][C@H:14]2[CH2:19][CH2:18][C@H:17](/[CH:20]=[CH:21]/[CH2:22]Cl)[CH2:16][CH2:15]2)[CH3:11])=[CH:4][CH:3]=1.[CH2:25]([NH:28][CH3:29])[CH:26]=[CH2:27]>CN(C)C(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:24])[N:10]([CH2:12][CH2:13][C@H:14]2[CH2:19][CH2:18][C@H:17](/[CH:20]=[CH:21]/[CH2:22][N:28]([CH2:25][CH:26]=[CH2:27])[CH3:29])[CH2:16][CH2:15]2)[CH3:11])=[CH:4][CH:3]=1
Reactant: C=CCNC
Reactant: CN(CC[C@H]1CC[C@H](/C=C/CCl)CC1)C(=O)Oc1ccc(Cl)cc1
Solvent: CC(=O)N(C)C
Product: C=CCN(C)C/C=C/[C@H]1CC[C@H](CCN(C)C(=O)Oc2ccc(Cl)cc2)CC1

Procedure:
In analogy to the method described in example 12.1, trans-{2-[4-(3-chloro-(E)-propenyl)-cyclohexyl]-ethyl}-methyl-carbamic acid 4-chloro-phenyl ester was reacted with N-allyl-methyl-amine in N,N-dimethylacetamide at room temperature to yield trans-(2-{4-[3-(allyl-methyl-amino)-(E)-propenyl]-cyclohexyl}-ethyl)-methyl-carbamic acid 4-chloro-phenyl ester as light yellow viscous oil, MS: 405 (MH+, 1Cl).
Reaction SMILES: [H-].[Na+].[CH2:3]1[C:16]2[C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[NH:9][C:8]=2[CH2:7][CH2:6][N:5]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:4]1.[C:24]1(=[O:28])[O:27][CH2:26][CH2:25]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[C:20]([O:19][C:17]([N:5]1[CH2:4][CH2:3][C:16]2[C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:9]([CH2:26][CH2:25][C:24]([OH:28])=[O:27])[C:8]=2[CH2:7][CH2:6]1)=[O:18])([CH3:23])([CH3:22])[CH3:21]
Reactant: O=C1CCO1
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]c3ccccc3c2CC1
Agent: O=C([O-])[O-]
Agent: [H-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCc2c(n(CCC(=O)O)c3ccccc23)CC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 63.6 %

Procedure:
Sodium hydride (0.302 g, 7.55 mmol, 2.16 equiv., 60% dispersion) was added to a solution of tert-butyl 1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate (1.00 g, 3.49 mmol) in DMF (15 mL) at rt under N2 and the mixture was stirred for 1.66 h. β-Propiolactone (0.55 mL, 0.629 g, 8.73 mmol, 2.5 equiv.) was added in four portions over 1 h, then the reaction mixture was stirred for 72 h at rt. The reaction mixture was partitioned between EtOAc (50 mL) and 10% citric acid (25 mL), and the layers were separated. The organic layer was washed with 10% citric acid. The combined aqueous layers were extracted with EtOAc (25 mL). The combined organic layers were washed with brine (25 mL), dried over MgSO4, filtered, and concentrated. The crude product (2.27 g) was dissolved in CH3OH (30 mL), then water (5 mL) and K2CO3 (2.10 g. 15.2 mmol) was added, and the reaction mixture was stirred overnight. The reaction mixture was concentrated, and the residue was partitioned between EtOAc (100 mL) and water (100 mL). The organic layer was extracted with 10% aq. Na2CO3 (2×50 mL) and 1N NaOH (2×50 mL). The combined aqueous layers were made acidic (pH=2) by the addition of 2.9 M HCl and 10% aq. citric acid. The acidified aqueous mixture was extracted with EtOAc (3×100 mL). The organic extracts were washed with water (50 mL) followed by brine (50 mL), dried over MgSO4, filtered, and concentrated. The crude product (1.06 g) was chromatographed (SiO2 109 g, eluted with 4% MeOH in CH2Cl2 followed by 10% MeOH in CH2Cl2) to give 3-(3-(tert-butoxycarbonyl)-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)propanoic acid (0.796 g) in 63% yield. 1H NMR (300 MHz, CDCl3) δ 1.51 (s, 9H), 2.78, 2.99-3.08, 3.67-3.81, 4.42, 7.13, 7.20, 7.31, 7.49, 10.48; MS (ESI+) for C20H26N2O4 m/z 359.3 (M+H)+.