Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:6]=[C:5]([C:7]([OH:9])=[O:8])[N:4]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:3]=1.[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(=O)([O-])[O-].[K+].[K+].Cl>CN(C)C=O>[CH2:16]([O:1][C:2]1[CH:6]=[C:5]([C:7]([O:9][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:8])[N:4]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:3]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C(O)c1cc(O)nn1-c1ccccc1
Reactant: BrCc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(OCc1ccccc1)c1cc(OCc2ccccc2)nn1-c1ccccc1
Temperature: 90 °C
Reaction time: 8 h
Yield: 92 %

Procedure:
A mixture of 3-hydroxy-1-phenyl-1H-pyrazole-5-carboxylic acid (29.55 g), benzyl bromide (35 ml), potassium carbonate (40.99 g) and N,N-dimethylformamide (300 ml) was stirred overnight at 90° C. The reaction mixture was poured into dilute hydrochloric acid and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and benzyl 3-benzyloxy-1-phenyl-1H-pyrazole-5-carboxylate (51.33 g, yield 92%) was obtained as a colorless oil from a fraction eluted with ethyl acetate-hexane (1:2, volume ratio).
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:9]([CH2:12][C:13]2[C:14]3[N:23]=[CH:22][CH:21]=[CH:20][C:15]=3[C:16](=[O:19])[NH:17][N:18]=2)=[CH:8][C:3]=1[C:4](OC)=[O:5].[NH3:24]>CO>[F:1][C:2]1[CH:11]=[CH:10][C:9]([CH2:12][C:13]2[C:14]3[N:23]=[CH:22][CH:21]=[CH:20][C:15]=3[C:16](=[O:19])[NH:17][N:18]=2)=[CH:8][C:3]=1[C:4]([NH2:24])=[O:5]
Reactant: N
Reactant: COC(=O)c1cc(Cc2n[nH]c(=O)c3cccnc23)ccc1F
Solvent: CO
Product: NC(=O)c1cc(Cc2n[nH]c(=O)c3cccnc23)ccc1F
Temperature: 25 °C

Procedure:
A solution of EXAMPLE 462A (1 g, 3.2 mmol) in 7N ammonia in methanol (5 ml) was heated at 70° C. overnight, and cooled to room temperature. The solid was collected by filtration, washed with methanol and dried to provide the title compound. MS (DCI/NH3) m/z 299 (M+H)+.
Reaction SMILES: [CH:1]([O:4][C:5]([C:7]1[N:8]=[CH:9][C:10]2[NH:11][C:12]3[C:17]([C:18]=2[C:19]=1[CH2:20][O:21][CH3:22])=[CH:16][C:15]([O:23][Si:24]([CH:31]([CH3:33])[CH3:32])([CH:28]([CH3:30])[CH3:29])[CH:25]([CH3:27])[CH3:26])=[CH:14][CH:13]=3)=[O:6])([CH3:3])[CH3:2].C(N(CC)CC)C.[S:41](Cl)([C:44]1[CH:50]=[CH:49][C:47]([CH3:48])=[CH:46][CH:45]=1)(=[O:43])=[O:42]>CN(C)C1C=CN=CC=1.ClCCl>[CH:1]([O:4][C:5]([C:7]1[N:8]=[CH:9][C:10]2[N:11]([S:41]([C:44]3[CH:50]=[CH:49][C:47]([CH3:48])=[CH:46][CH:45]=3)(=[O:43])=[O:42])[C:12]3[C:17]([C:18]=2[C:19]=1[CH2:20][O:21][CH3:22])=[CH:16][C:15]([O:23][Si:24]([CH:31]([CH3:33])[CH3:32])([CH:28]([CH3:30])[CH3:29])[CH:25]([CH3:27])[CH3:26])=[CH:14][CH:13]=3)=[O:6])([CH3:3])[CH3:2]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COCc1c(C(=O)OC(C)C)ncc2[nH]c3ccc(O[Si](C(C)C)(C(C)C)C(C)C)cc3c12
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COCc1c(C(=O)OC(C)C)ncc2c1c1cc(O[Si](C(C)C)(C(C)C)C(C)C)ccc1n2S(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1 g of 4-methoxymethyl-6-(triisopropylsilyloxy)-beta-carboline-3-carboxylic acid isopropyl ester, 132 mg of 4-dimethylaminopyridine and 0.45 ml of triethylamine were mixed in 10 ml of dichloromethane at about 4° C. with 615 m of tosyl chloride and then stirred at room temperature for 1 hour. After 16 hours of standing at room temperature, it was diluted with dichloromethane and washed with saturated sodium bicarbonate solution and saturated sodium chloride solution. After chromatography on silica gel in the system of cyclohexane/ethyl acetate 1:1, 1.32 g of the title compound was obtained from the isolated organic phase.
Reaction SMILES: C(O)(C(F)(F)F)=O.[C:8]([C:10]1[N:11]=[CH:12][C:13]([NH:18][C:19]2[N:24]=[CH:23][N:22]=[C:21]([NH:25][CH2:26][CH:27]3[CH2:32][CH2:31][N:30](C(OC(C)(C)C)=O)[CH2:29][CH2:28]3)[CH:20]=2)=[N:14][C:15]=1[O:16][CH3:17])#[N:9]>ClCCl>[CH3:17][O:16][C:15]1[C:10]([C:8]#[N:9])=[N:11][CH:12]=[C:13]([NH:18][C:19]2[CH:20]=[C:21]([NH:25][CH2:26][CH:27]3[CH2:28][CH2:29][NH:30][CH2:31][CH2:32]3)[N:22]=[CH:23][N:24]=2)[N:14]=1
Reactant: COc1nc(Nc2cc(NCC3CCN(C(=O)OC(C)(C)C)CC3)ncn2)cnc1C#N
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1nc(Nc2cc(NCC3CCNCC3)ncn2)cnc1C#N
Reaction time: 2 h
Yield: 64.8 %

Procedure:
TFA (0.1 mL) was added to a solution of tert-butyl 4-((6-(5-cyano-6-methoxypyrazin-2-ylamino)-pyrimidin-4-ylamino)methyl)piperidine-1-carboxylate (3 mg, 0.0068 mmol) in dichloromethane (3 mL) at room temperature. After 2 hr, the solution was evaporated to dryness and purified by ion exchange on SCX-II acidic resin (500 mg), eluting with methanol then 2M ammonia-methanol. The basic fractions were combined and the solvent was removed in vacuo to give the title compound as yellow oil (1.5 mg, 65%).
Reaction SMILES: [NH:1]1[CH2:10][CH2:9][CH2:8][CH2:7][CH:2]1[C:3](OC)=O.OCCN.[Cl-].ClCC1CCCC[NH2+]1.[CH3:24][C:25]1[CH:30]=[C:29]([N+:31]([O-:33])=[O:32])[CH:28]=[CH:27][C:26]=1[N:34]=[C:35]=[S:36]>>[CH3:24][C:25]1[CH:30]=[C:29]([N+:31]([O-:33])=[O:32])[CH:28]=[CH:27][C:26]=1[N:34]=[C:35]1[N:1]2[CH:2]([CH2:7][CH2:8][CH2:9][CH2:10]2)[CH2:3][S:36]1
Reactant: Cc1cc([N+](=O)[O-])ccc1N=C=S
Reactant: COC(=O)C1CCCCN1
Agent: ClCC1CCCC[NH2+]1
Agent: [Cl-]
Solvent: NCCO
Product: Cc1cc([N+](=O)[O-])ccc1N=C1SCC2CCCCN12

Procedure:
2-Piperidenemethanol was made from methyl pipecolinate as described in Method B1b. The 2-hydroxyethylamine was converted to 2-chloromethylpiperidinium chloride according to Method B7a. 2-Methyl4-nitrophenyl isothiocyanate was reacted with 2-chloromethylpiperidinium chloride according according to Method C1a to give 9-(2-methyl-4-nitrophenylimino)-1-aza-8-thiabicyclo[4.3.0]nonane.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[O:10][C:9]([C:11]2(Br)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)=[N:8][C:7]=1[CH2:18]Br)=[O:5])C.C[O-].[Na+].[C:23](O)(=[O:25])C>CO>[CH3:1][O:3][C:4]([C:6]1[O:10][C:9]([C:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH:12]=2)=[N:8][C:7]=1[CH2:18][O:25][CH3:23])=[O:5]
Reactant: CC(=O)O
Reactant: CCOC(=O)c1oc(C2(Br)CCCCC2)nc1CBr
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COCc1nc(C2=CCCCC2)oc1C(=O)OC
Temperature: 65 °C
Reaction time: 1 h

Procedure:
14.7 g 2-(1-Bromo-cyclohexyl)-4-bromomethyl-oxazole-5-carboxylic acid ethyl ester were dissolved in 150 ml methanol. 6.03 g sodium methylate were added and the reaction mixture stirred at 65° C. for one hour. The cooled reaction mixture was acidified by addition of acetic acid (pH˜6). The solvent was removed in vacuo. The residue was dissolved in 250 ml ethyl acetate and washed with 80 ml water and brine, dried over MgSO4 and then the solvent was removed in vacuo. The residue was purified by reversed phase HPLC to obtain 5.30 g 2-Cyclohex-1-enyl-4-methoxymethyl-oxazole-5-carboxylic acid methyl ester as an oil.
Reaction SMILES: Cl.Cl.[C:3]1([CH2:9][N:10]2[CH2:16][CH2:15][NH:14][NH:13][CH2:12][CH2:11]2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.F[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[N+:24]([O-:26])=[O:25].C(N(CC)C(C)C)(C)C>CN(C)C=O>[N+:24]([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[N:14]1[CH2:15][CH2:16][N:10]([CH2:9][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:11][CH2:12][NH:13]1)([O-:26])=[O:25]
Reactant: c1ccc(CN2CCNNCC2)cc1
Reactant: O=[N+]([O-])c1ccccc1F
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccccc1N1CCN(Cc2ccccc2)CCN1

Procedure:
A mixture of hexahydro-5-(phenylmethyl)-1H-1,2,5-triazepine dihydrochloride (35.0 g), 1-fluoro-2-nitrobenzene (21 ml), N,N-diisopropylethylamine (81 ml) in N,N-dimethylformamide (400 ml) was stirred and heated at 75°-80° (under reflux) under nitrogen for 5 hours. The solution was evaporated to a syrup under oil pump vacuum and the residue was mixed with chloroform and dilute sodium hydroxide. The aqueous phase was extracted several times with chloroform. The combined extracts were dried (MgSO4) and evaporated to a syrup wich was subjected to an oil pump vacuum. The syrup in toluene was applied to a column (94×8.7 cm) of dry column grade neutral alumina prepacked in toluene. Elution with toluene removed a faster moving yellow impurity. Fractions were monitored by t.l.c. on Alox-25 uv254 plates (Brinkmann) with chloroform as developer. As soon as the major component started to issue the eluting solvent was changed to toluene-chloroform (4:1), toluene-chloroform (1:1) and finally chloroform. Appropriate fractions were evaporated to a syrup which was crystallized from ether-heptane; wt. 35.7 g (86%), mp=90°-92°. Recrystallization from chloroform-ether-heptane gave pure titled product, mp=90°-92°.
Reaction SMILES: Cl.[Br:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9]N)=[CH:5][CH:4]=1.O=[C:12]([CH3:28])[CH2:13][S:14][CH:15]1[CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17][CH2:16]1.Cl.CCOCC>C(O)(C)C>[Br:2][C:3]1[CH:8]=[C:7]2[C:6](=[CH:5][CH:4]=1)[NH:9][C:12]([CH3:28])=[C:13]2[S:14][CH:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1
Reactant: NNc1ccc(Br)cc1
Reactant: CC(=O)CSC1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: CC(C)O
Solvent: CCOCC
Product: Cc1[nH]c2ccc(Br)cc2c1SC1CCNCC1
Reaction time: 4 h

Procedure:
4-Bromophenylhydrazine hydrochloride (11.5 g) is solubilized in a solution of 1,1-dimethylethyl 4-[(2-oxopropyl)thio]piperidine-1-carboxylate (prepared in Example 10) in isopropanol (100 ml) under nitrogen. The solution is cooled to 0° C. and saturated with gaseous hydrogen chloride. After 4 hours at room temperature, the precipitate is filtered off, taken up in sodium hydroxide and extracted with ether and then with methylene chloride. The organic phases are combined, dried over sodium sulfate and concentrated. The solid obtained is taken up in the minimum amount of ether and recrystallized from xylene to give 5-bromo-2-methyl-3-(piperidin-4-ylthio) -1H-indole (9.5 g).
Reaction SMILES: [H-].[Na+].[CH:3]([CH:5]1[NH:9][C:8](=[O:10])[CH2:7][CH2:6]1)=[CH2:4].[CH3:11][C:12]([Si:15]([CH3:29])([CH3:28])[O:16][C@@H:17]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:18](Cl)=[O:19])([CH3:14])[CH3:13]>O1CCCC1.C(Cl)Cl>[CH3:14][C:12]([Si:15]([CH3:28])([CH3:29])[O:16][C@@H:17]([CH2:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[C:18]([N:9]1[C@H:5]([CH:3]=[CH2:4])[CH2:6][CH2:7][C:8]1=[O:10])=[O:19])([CH3:11])[CH3:13]
Reactant: C=CC1CCC(=O)N1
Reactant: CC(C)(C)[Si](C)(C)O[C@@H](Cc1ccccc1)C(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: C=C[C@@H]1CCC(=O)N1C(=O)[C@H](Cc1ccccc1)O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Yield: 45.8 %

Procedure:
To 60% sodium hydride (336 mg, 10 mmol, in mineral oil) in tetrahydrofuran (20 mL) at 0° C. was added dropwise a solution of 5-vinylpyrrolidin-2-one (1.0 g, 9.0 mmol) in tetrahydrofuran (10 mL) over a 5 min period. The cooling bath was removed and the solution was allowed to warm to 25° C. to ensure complete anion generation. To the anion at 25° C. was added dropwise a solution of (2S)-2-((1,1-dimethylethyl)dimethylsilyloxy)-3-phenylpropanoyl chloride (4, 2.98 g, 10 mmol) in tetrahydrofuran (10 mL) over a 5 min period. TLC indicated that the reaction was complete upon addition of the acid chloride (silica gel plates; hexane and ethyl acetate, 9:1). The solvent was removed by rotary evaporation affording a thick slug. The slug was dissolved in methylene chloride (75 mL) and washed with water (1×50 mL), a saturated aqueous sodium bicarbonate solution (1×50 mL) and dried (MgSO 4). Concentration and purification by flash chromatography on silica gel (EM 60, 0.040-0.063 partical size, 230-400 Mesh, column size: 4.5 cm diameter×15 cm length) using hexane and ethyl acetate (19:1) afforded 1.54 g (46%) of (5S)-N-((2S)-2-((1,1-dimethylethyl)-dimethylsilyloxy)-3-phenylpropanoyl)-5-ethenylpyrrolidin-2-one (5a) as a white crystalline material: mp 92°-93.5° C.; 1H NMR (CDCl3) δ-0.316 (s,3 H), -0.217 (s,3 H), 0.703 (s, 9 H), 1.94 (t, J=9.6 Hz, 1 H), 2.29 (p, J=11.7 Hz, 1 H), 2.50-2.75 (m, 3 H), 3.11 (d, J=12.8 Hz, 1 H), 4.97-5.13 (m, 1 H), 5.12-5.18 (m, 2 H), 5.45 (d, J=9.8 Hz, 1 H), 5.75-5.86 (m, 1 H); 13C NMR (CDCl3) δ175.1, 174.1, 137.9, 135.4, 130.0, 128.0, 126.4, 115.8, 74.2, 58.1, 41.2, 31.7, 25.5, 24.3, 18.1, -5.50, -5.76.
Reaction SMILES: [CH:1]1[CH2:5][CH:4]=[CH:3][CH:2]=1.[CH3:6][C:7]([CH:10]=O)([CH3:9])[CH3:8].N1CCCC1>CO>[C:7]([C:10]1[C:2](=[CH2:3])[CH:1]=[CH:5][CH:4]=1)([CH3:9])([CH3:8])[CH3:6]
Reactant: C1=CCC=C1
Reactant: CC(C)(C)C=O
Solvent: CO
Solvent: C1CCNC1
Product: C=C1C=CC=C1C(C)(C)C

Procedure:
6,-tert-butyl-fulvene was prepared analogously by reaction of cyclopentadiene (31.7 g, 480 mmole), pivaldehyde (19.825 g, 230 mmol), and pyrrolidine (25 ml, 300 mmole) in methanol (250 ml). The yellow oil is kugel-rohr distilled at 70° C. and <1 torr yielding a bright yellow oil; 20.5 g (66.4%).
Reaction SMILES: [CH2:1](OC1C=CC=CC=1)[C:2]1C=CC=[CH:4][CH:3]=1.[CH2:15]([N:22]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[C:29]1([N:22]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:15][C:16]2[C:17]3[C:18](=[CH:1][CH:2]=[CH:3][CH:4]=3)[CH:19]=[CH:20][CH:21]=2)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: c1ccc(COc2ccccc2)cc1
Reactant: c1ccc(CN(c2ccccc2)c2ccccc2)cc1
Product: c1ccc(N(Cc2cccc3ccccc23)c2ccccc2)cc1
Yield: 74 %

Procedure:
N-phenylnaphthaldimine (2.20 g, 0.010 mol) and benzylphenyl ether (1.84 g, 0.010 mol) were reacted as above for the preparation of benzyldiphenylamine. Aqueous work-up afforded a precipitate which was isolated by filtration and recrystallized from 95% ethanol to yield 2.3 g (74%) of needles, mp 170°-172° C. Anal. calcd. for C23H19N: C 89.28, H 6.19, N 4.53%; found: C 89.11, H 6.26, N 4.44%. 1H NMR (200 MHz, CDCl3) δ (assignment): 5.52 (s, 2H, CH2), 7.00-8.10 (m, 17H, aromatic). MS [m/e (70 ev, % of base peak)] (C10H7)CH2N(C6H5)2 309 (M+., 4.8), 308 (M+-H., 29.0), 168 (M+-((C10H7)CH2)., 18.0), 141 (((C10H7)CH2)+., 100 ). FTIR (CDCl3): 3063, 3040, 1606, 1602, 1594, 1584, 1574, 1559, 1512, 1501, 1497, 1488, 1485, 1474, 1465, 1460, 1451 cm-1.
Reaction SMILES: [Br:1][C:2]1[C:3]([NH2:18])=[C:4]([N+:15]([O-])=O)[C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]2)=[N:6][CH:7]=1.[O-]S(S([O-])=O)=O.[Na+].[Na+].O>C(O)C>[Br:1][C:2]1[C:3]([NH2:18])=[C:4]([NH2:15])[C:5]([N:8]2[CH2:9][CH2:10][N:11]([CH3:14])[CH2:12][CH2:13]2)=[N:6][CH:7]=1
Reactant: CN1CCN(c2ncc(Br)c(N)c2[N+](=O)[O-])CC1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CN1CCN(c2ncc(Br)c(N)c2N)CC1
Yield: 81.8 %

Procedure:
A 250 mL round bottom flask was charged with 5-bromo-2-(4-methylpiperazin-1-yl)-3-nitropyridin-4-amine (1.5 g, 4.7 mmol), Na2S2O4 (2.0 g, 11 mmol), water (10 mL) and ethanol (20 mL). The mixture was heated at reflux for 0.5 h. Work-up: the solvent was evaporated. The residue was re-suspended in triethylamine (15 mL) and ethyl acetate (300 mL), and then filtered. The filtrate was concentrated in vacuo, to afford 1.1 g (80%) of the product as a pale-red solid. MS m/z: 286 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]3[C:21]([CH3:22])=[C:20]([CH3:23])[S:19][C:10]=3[NH:11][C:12](=O)[C@@:13]3([CH2:16][C@H:15]3[CH3:17])[N:14]=2)=[CH:4][CH:3]=1.C1(C)C=CC=CC=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=S)=CC=1.[NH2:53][NH2:54]>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]3[C:21]([CH3:22])=[C:20]([CH3:23])[S:19][C:10]=3[NH:11][C:12](=[N:53][NH2:54])[C@@:13]3([CH2:16][C@H:15]3[CH3:17])[N:14]=2)=[CH:4][CH:3]=1
Reactant: NN
Reactant: Cc1sc2c(c1C)C(c1ccc(Cl)cc1)=N[C@]1(C[C@H]1C)C(=O)N2
Agent: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: Cc1sc2c(c1C)C(c1ccc(Cl)cc1)=N[C@]1(C[C@H]1C)C(=NN)N2
Temperature: 110 °C
Yield: 82.8 %

Procedure:
A round bottomed flask was charged with (1S,2R)-5′-(4-chlorophenyl)-2,6′,7′-trimethylspiro[cyclopropane-1,3′-thieno[2,3-e][1,4]diazepin]-2′(1′H)-one (289 mg, 0.838 mmol) and a stir bar. Toluene (8.5 mL, 0.1 M) added, followed by Lawesson's Reagent (186 mg, 0.461 mmol), and the reaction was stirred at 110° C. After conversion to the thioamide intermediate, as determined by LC/MS, the reaction was cooled and diluted with THF (20 mL) for the addition of hydrazine (263 μl, 8.38 mmol). The reaction was stirred at room temperature before being concentrated and purified by column chromatography to give (1S,2R)-5′-(4-chlorophenyl)-2′-hydrazono-2,6′,7′-trimethyl-1′,2′-dihydrospiro[cyclopropane-1,3′-thieno[2,3-e][1,4]diazepine] (249 mg). LRMS (M+H)+: 359 m/z
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[CH:8][C:9]([C:12]([O:14][CH3:15])=[O:13])=[N:10][CH:11]=1)=[CH2:5])C.C1C(=O)N([Br:23])C(=O)C1>C1COCC1.O>[Br:23][CH2:3][C:4]([C:6]1[CH:7]=[CH:8][C:9]([C:12]([O:14][CH3:15])=[O:13])=[N:10][CH:11]=1)=[O:5]
Reactant: C=C(OCC)c1ccc(C(=O)OC)nc1
Reactant: O=C1CCC(=O)N1Br
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1ccc(C(=O)CBr)cn1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of step 1 product (780 mg, 3.76 mmol) in THF (37.5 ml) and H2O (2.5 ml) was added NBS (670 mg, 3.76 mmol) in one portion. The solution was stirred at rt for 10 min, solvent was removed and purified on silica gel column eluting a gradient of 8-75% EtOAc in hexane to afford methyl 5-(bromoacetyl)pyridine-2-carboxylate (0.92 g) LCMS: [M+H]+=258.1, 260.1.
Reaction SMILES: [NH2:1][CH:2]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:3]1([N:8]([CH3:10])[CH3:9])[CH2:7][CH2:6][CH2:5][CH2:4]1.C(N(CC)CC)C.[F:24][C:25]1[CH:33]=[C:32]([CH3:34])[C:28]([C:29](Cl)=[O:30])=[C:27]([CH3:35])[CH:26]=1>C(Cl)Cl>[CH3:9][N:8]([CH3:10])[C:3]1([CH:2]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[NH:1][C:29](=[O:30])[C:28]2[C:27]([CH3:35])=[CH:26][C:25]([F:24])=[CH:33][C:32]=2[CH3:34])[CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: Cc1cc(F)cc(C)c1C(=O)Cl
Reactant: CN(C)C1(C(N)c2ccccc2)CCCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(F)cc(C)c1C(=O)NC(c1ccccc1)C1(N(C)C)CCCC1
Yield: 100 %

Procedure:
To {1-[amino(phenyl)methyl]cyclopentyl}dimethylamine D3 enantiomer 2 (0.904 g; 4.147 mmol) in DCM (45 ml) under argon at room temperature was added triethylamine (0.573 ml; 4.15 mmol), followed by a solution of 4-fluoro-2,6-dimethylbenzoyl chloride (0.773 g: 4.144 mmol) in DCM (5 ml). After 16 h. the reaction was washed with water, dried with MgSO4 and evaporated. The residue was chromatographed on silica gel eluting with an ethyl acetate-hexane 0 to 100% gradient to give the title compound (1.57 g; 100%). 1H NMR (CDCl3) δ: 0.85-1.00 (1H, m), 1.30-1.60 (3H, m), 1.60-1.75 (2H, m), 1.75-1.90 (2H, m), 2.22 (6H, s), 2.31 (6H, m), 5.18 (1H, d, J=6 Hz), 6.73 (2H, d, J=9.6 Hz overlaps 1H, br s), 7.20-7.35 (3H, m), 7.42 (2H, m). Mass Spectrum (Electrospray LC/MS): Found 369 (MH+). C23H29FN2O requires 368. Ret. time 1.99 min. The free base was dissolved in methanol. 1M HCl/diethylether was added to the stirred solution and stirring continued at room temperature for 5 minutes. The solution was then evaporated under reduced pressure, redissolved in DCM and evaporated at reduced pressure. The resulting foam was dried for 16 hours at reduced pressure. The hydrochloride salt was obtained as a white foam (1.45 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:9][OH:10])=[C:6]([OH:8])[CH:7]=1.[CH2:11](Br)[CH3:12]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:9][OH:10])=[C:6]([O:8][CH2:11][CH3:12])[CH:7]=1
Reactant: CCBr
Reactant: OCc1ccc(Cl)cc1O
Product: CCOc1cc(Cl)ccc1CO

Procedure:
The title compound was prepared from 5-chloro-2-(hydroxymethyl)phenol (PREPARATION 7) and ethylbromide according to the procedure for the preparation of Example 111, part A. 1H NMR (400 MHz, CDCl3): δ 1.44 (3H, t, J=6.8 Hz), 2.24 (1H, s), 4.07 (2H, q, J=6.8 Hz), 4.64 (2H, s), 6.85 (1H, d, J=1.6 Hz), 6.91 (1H, dd, J=1.6 Hz, 7.6 Hz), 7.20 (1H, d, J=8.0 Hz).
Reaction SMILES: [CH:1]1[C:6](/[CH:7]=[CH:8]/[C:9]([OH:11])=[O:10])=[CH:5][CH:4]=[C:3]([OH:12])[CH:2]=1.[OH-].[K+].Cl[C:16]([O:18][CH2:19][CH3:20])=[O:17].Cl>O>[CH2:19]([O:18][C:16]([O:12][C:3]1[CH:4]=[CH:5][C:6](/[CH:7]=[CH:8]/[C:9]([OH:11])=[O:10])=[CH:1][CH:2]=1)=[O:17])[CH3:20]
Reactant: CCOC(=O)Cl
Reactant: O=C(O)/C=C/c1ccc(O)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: CCOC(=O)Oc1ccc(/C=C/C(=O)O)cc1
Yield: 98.4 %

Procedure:
67 g (0.41 mol) p-cumaric acid are added to a mixture of 50.4 g (0.90 mol) potassium hydroxide and 600 ml water. 53.1 g (0.50 mol) ethyl chloroformate are added dropwise at 0° C. The reaction temperature rises to 10° C. The reaction mixture is subsequently allowed to react for 2 hours at 25° C. and acidified to pH=1 with 200 ml hydrochloric acid 7N. The product is filtered off, washed with water and dried under vacuum to give 95.3 g of (2E)-3-{4-[(ethoxycarbonyl)oxy]phenyl}acrylic acid as white powder.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([O:13][C:14]([F:17])([F:16])[F:15])[C:8]=2[OH:18])[CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].I[CH2:26][CH2:27][OH:28]>C(#N)C>[OH:28][CH2:27][CH2:26][N:1]1[CH2:6][CH2:5][CH:4]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([O:13][C:14]([F:16])([F:17])[F:15])[C:8]=2[OH:18])[CH2:3][CH2:2]1
Reactant: Oc1c(OC(F)(F)F)cccc1C1CCNCC1
Reactant: OCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: OCCN1CCC(c2cccc(OC(F)(F)F)c2O)CC1

Procedure:
Preparation according to Example 1: 2-piperidin-4-yl-6-(trifluoromethoxy)phenol (0.01 g), acetonitrile (2 ml), potassium carbonate (0.01 g) and 2-iodoethanol (0.01 g). MS m/z (relative intensity, 70 eV) 305 (M+, 1), 275 (15), 274 (bp), 117 (5), 70 (20).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:14])=[C:6]([CH:13]=1)[C:7](N(OC)C)=[O:8].[CH3:15][Mg]Br.C(OCC)C.Cl>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:14])=[C:6]([C:7](=[O:8])[CH3:15])[CH:13]=1
Reactant: CON(C)C(=O)c1cc(Br)ccc1F
Reactant: C[Mg]Br
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(=O)c1cc(Br)ccc1F
Temperature: 0 °C
Reaction time: 6.5 h
Yield: 97 %

Procedure:
To a stirred solution of compound 14 (106 g, 404 mmol) in anhydrous THF (1.7 L) was added a solution of methyl magnesium bromide in diethyl ether (3.0 M, 270 mL, 808 mmol) at 0° C. under nitrogen. After addition was completed, the reaction mixture was stirred at 0° C. for 6.5 h. After this time, the solution was poured to a cold 2 N hydrochloric acid (1 L) and warmed to room temperature. The resulting mixture was extracted with ethyl acetate (2×1 L). The combined extracts were washed with saturated aqueous NaHCO3 (500 mL), brine (500 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford 15 (85.2 g, 97%) as an orange oil: 1H NMR (300 MHz, CDCl3) δ 7.98 (dd, J=6.4, 2.6 Hz, 1H), 7.61 (ddd, J=8.7, 4.3, 2.6 Hz, 1H), 7.05 (dd, J=10.4, 8.7, 1H), 2.64 (d, J=4.9, 3H); ESI MS m/z 217 [M+H]+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:15]=[C:14]3[C:10]([CH2:11][C:12](=[O:16])[NH:13]3)=[CH:9][CH:8]=2)[CH:2]=1.[CH3:17][N:18]([CH3:34])[CH2:19][CH2:20][CH2:21][NH:22][C:23]([C:25]1[C:29]([CH3:30])=[C:28]([CH:31]=O)[NH:27][C:26]=1[CH3:33])=[O:24]>>[CH3:34][N:18]([CH3:17])[CH2:19][CH2:20][CH2:21][NH:22][C:23]([C:25]1[C:29]([CH3:30])=[C:28]([CH:31]=[C:11]2[C:10]3[C:14](=[CH:15][C:7]([C:3]4[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=4)=[CH:8][CH:9]=3)[NH:13][C:12]2=[O:16])[NH:27][C:26]=1[CH3:33])=[O:24]
Reactant: O=C1Cc2ccc(-c3cccnc3)cc2N1
Reactant: Cc1[nH]c(C=O)c(C)c1C(=O)NCCCN(C)C
Product: Cc1[nH]c(C=C2C(=O)Nc3cc(-c4cccnc4)ccc32)c(C)c1C(=O)NCCCN(C)C
Yield: 75.9 %

Procedure:
6-Pyridin-3-yl-1,3-dihydroindol-2-one (42 mg, 0.2 mmol) was condensed with 5-formyl-2,4-dimethyl-1H- pyrrole-3-carboxylic acid (3-dimethylaminoproyl)amide (50 mg) to give 67 mg (75%) of the title compound as yellow-brown solid.