Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([C:9]2[C:13]([C:14](Cl)=[O:15])=[CH:12][S:11][N:10]=2)[CH:4]=1.[CH:19]([NH2:22])([CH3:21])[CH3:20]>C1COCC1>[CH:19]([NH:22][C:14]([C:13]1[C:9]([C:5]2[CH:4]=[C:3]([C:2]([F:18])([F:17])[F:1])[CH:8]=[CH:7][CH:6]=2)=[N:10][S:11][CH:12]=1)=[O:15])([CH3:21])[CH3:20]
Reactant: CC(C)N
Reactant: O=C(Cl)c1csnc1-c1cccc(C(F)(F)F)c1
Solvent: C1CCOC1
Product: CC(C)NC(=O)c1csnc1-c1cccc(C(F)(F)F)c1
Yield: 88 %

Procedure:
To a solution of 1.0 g (0.0034 mol) of 3-(α,α,α-trifluoro-m-tolyl)-4-isothiazolecarbonyl chloride and 20 cc of THF was added 0.45 g (2.1 equivalents) of isopropylamine. The reaction mixture was heated on a steam bath for 20 minutes. The isopropylamine hydrochloride was filtered off and the filtrate was concentrated to a solid. The solid was washed with H2O, dissolved in THF, dried (CaSO4), and concentrated under vacuum to give 0.94 g of solid. The solid was recrystallized from EtOAc/hexane to give 0.4 g white solid, m.p. 166°-167°. The filtrate gave another 0.3 g of white solid, m.p. 166.5°-168°. (Total yield=88%).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([S:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:5][CH:4]=1)#[N:2].[Al](Br)(Br)Br.[Cl:20][C:21]([Cl:25])([Cl:24])[C:22]#[N:23].[ClH:26]>>[Cl:20][C:21]([Cl:25])([Cl:24])[C:22]1[N:23]=[C:22]([C:21]([Cl:24])([Cl:20])[Cl:26])[N:23]=[C:1]([C:3]2[CH:4]=[CH:5][C:6]([S:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:7][CH:8]=2)[N:2]=1
Reactant: CCOC(=O)CSc1ccc(C#N)cc1
Reactant: N#CC(Cl)(Cl)Cl
Reactant: Cl
Agent: Br[Al](Br)Br
Product: CCOC(=O)CSc1ccc(-c2nc(C(Cl)(Cl)Cl)nc(C(Cl)(Cl)Cl)n2)cc1

Procedure:
The mixed solution of 10 g of ethyl 2-(4-cyanophenyl thio)acetate (45.2 mmol), 0.8 g of AlBr3, and 50 g of trichloroacetonitrile were bubbled with dry HCl at room temperature.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH:47]([C:50]1[S:51][C:52]2[CH2:58][CH2:57][NH:56][CH2:55][CH2:54][C:53]=2[N:59]=1)([CH3:49])[CH3:48]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:56]3[CH2:57][CH2:58][C:52]4[S:51][C:50]([CH:47]([CH3:49])[CH3:48])=[N:59][C:53]=4[CH2:54][CH2:55]3)=[O:13])[CH:10]=2)[CH:7]=1
Reactant: O=C(O)c1cc2ncc(Cl)cn2n1
Reactant: CC(C)c1nc2c(s1)CCNCC2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)c1nc2c(s1)CCN(C(=O)c1cc3ncc(Cl)cn3n1)CC2

Procedure:
The title compound was prepared in accordance with the general method of example 1 from 0.25 mmol 6-chloro-pyrazolo[1,5-A]pyrimidine-2-carboxylic acid, 0.30 mmol HATU, 1.27 mmol DIPEA and 0.51 mmol 2-isopropyl-5,6,7,8-tetrahydro-4H-thiazolo[4,5-d]azepine in 1 mL DMF. The reaction mixture was purified by HPLC chromatography and lyophilized. Yield: 24 mg (25% of theory). ESI-MS: m/z=376 (M+H)+.
Reaction SMILES: [CH2:1]([NH:4][C:5]([C:7]1[N:8]=[CH:9][N:10]2[C:16]3[CH:17]=[CH:18][CH:19]=[C:20]([Cl:21])[C:15]=3[C:14](=[O:22])[N:13]3[CH2:23][CH2:24][C@H:12]3[C:11]=12)=[O:6])[C:2]#[CH:3].IN1C(=O)CCC1=O.[CH2:33]([NH:36][CH2:37][CH2:38][CH3:39])[CH2:34][CH3:35]>C(O)(=O)C>[Cl:21][C:20]1[C:15]2[C:14](=[O:22])[N:13]3[CH2:23][CH2:24][C@H:12]3[C:11]3[N:10]([CH:9]=[N:8][C:7]=3[C:5]3[O:6][C:2]([CH2:3][N:36]([CH2:37][CH2:38][CH3:39])[CH2:33][CH2:34][CH3:35])=[CH:1][N:4]=3)[C:16]=2[CH:17]=[CH:18][CH:19]=1
Reactant: C#CCNC(=O)c1ncn2c1[C@@H]1CCN1C(=O)c1c(Cl)cccc1-2
Reactant: CCCNCCC
Agent: O=C1CCC(=O)N1I
Solvent: CC(=O)O
Product: CCCN(CCC)Cc1cnc(-c2ncn3c2[C@@H]2CCN2C(=O)c2c(Cl)cccc2-3)o1
Temperature: 25 °C
Reaction time: 24 h
Yield: 27.6 %

Procedure:
A solution of 3.30 g (0.0098 mol) of (S)-8-chloro-9-oxo-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepine-1-carboxylic acid prop-2-ynylamide in 60 ml of acetic acid was treated with 3.30 g (0.0147 mol) of N-iodosuccinimide while gassing with argon. After stirring at room temperature for 24 hrs. the dark brown suspension obtained was completely freed from the solvents and dried azeotropically several times with toluene. The dark viscous residue was dissolved in 60 ml of THF, treated with 11.9 ml (0.0865 mol) of dipropylamine and stirred at room temperature for 24 hrs. The suspension obtained was filtered and the solution was completely freed from the solvents, the residue was partitioned between ethyl acetate and dilute aqueous hydrochloric acid and extracted. The aqueous-acidic phase was made basic and extracted with ethyl acetate. The organic phase was concentrated and the residue was chromatographed over silica gel with dichloromethane/methanol 98:2 as the eluent. There were obtained 1.19 g (28%) of (S)-8-chloro-1-(5-dipropylaminomethyl-oxazol-2-yl)-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepin-9-one as yellow crystals; m.p. 148-151° (dec.) and [α]D20 =-101.7° (MeOH, c=1%).
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][NH:6][CH2:5][CH2:4][N:3]1[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].C(N(CC)C(C)C)(C)C.Cl[C:25]1[C:26]2[C:33]([CH3:34])=[CH:32][NH:31][C:27]=2[N:28]=[CH:29][N:30]=1>C(O)(C)C>[CH3:1][C@H:2]1[CH2:7][N:6]([C:25]2[C:26]3[C:33]([CH3:34])=[CH:32][NH:31][C:27]=3[N:28]=[CH:29][N:30]=2)[CH2:5][CH2:4][N:3]1[C:8]([O:10][C:11]([CH3:13])([CH3:12])[CH3:14])=[O:9]
Reactant: C[C@H]1CNCCN1C(=O)OC(C)(C)C
Reactant: Cc1c[nH]c2ncnc(Cl)c12
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: Cc1c[nH]c2ncnc(N3CCN(C(=O)OC(C)(C)C)[C@@H](C)C3)c12
Temperature: 120 °C
Yield: 37.5 %

Procedure:
(S)-tert-butyl 2-methylpiperazine-1-carboxylate (3 g, 15 mmol), N,N-diisopropylethylamine (3 ml), and 4-chloro-5-methyl-7H-pyrrolo[2,3-d]pyrimidine (2 g, 12 mmol) were added to isopropanol (10 ml). The solution was heated at 120° C. in a sealed pressure tube for 12 hours. The reaction was concentrated under vacuum, and the residue was purified by flash chromatography (80 g SiO2, 0-5% MeOH: CH2Cl2, 50 min) to give clean (S)-tert-butyl 2-methyl-4-(5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazine-1-carboxylate (1.5 g, 4.5 mmol, 38%).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]#[N:15])[CH2:10][CH2:9]1)=O)(C)(C)C.[F:16][C:17]([F:22])([F:21])[C:18]([OH:20])=[O:19]>>[F:16][C:17]([F:22])([F:21])[C:18]([OH:20])=[O:19].[NH:8]1[CH2:13][CH2:12][CH:11]([C:14]#[N:15])[CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCC(C#N)CC1
Solvent: O=C(O)C(F)(F)F
Product: N#CC1CCNCC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
4-Cyanopiperidine-1-carboxylic acid t-butyl ester (5.35 g) was added to trifluoroacetic acid (20 mL) and the mixture was stirred at room temperature for 10 minutes. Trifluoroacetic acid was evaporated under reduced pressure to give the title compound as colorless crystal (5.62 g). Yield: 99%.
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH3:14])=[CH:9][CH:8]=1>>[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH3:14])=[CH:9][C:8]=1[S:2]([Cl:1])(=[O:5])=[O:3]
Reactant: O=S(=O)(O)Cl
Reactant: CCc1ccc(Cl)cc1
Product: CCc1ccc(Cl)c(S(=O)(=O)Cl)c1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 22.9 %

Procedure:
Chlorosulfonic acid (4.0 mL, 59 mmol) was cooled to 0° C. and 1-chloro-4-ethylbenzene (1.0 mL, 7.5 mmol) was added dropwise over 30 min. The reaction mixture was stirred for 45 min at 0° C., poured with stirring onto 125 mL of crushed ice, and then extracted with ethyl acetate (2×100 mL). The ethyl acetate layers were combined, washed with water (100 mL), and dried over magnesium sulfate. The ethyl acetate was concentrated under reduced pressure to obtain an oil determined to be approximately a 1:1 mixture of isomers. This mixture was chromatographed on silica gel eluting with a hexane/ethyl acetate gradient to afford 0.41 g of the title compound. 1H NMR (CDCl3) δ 7.97 (s, 1H), 7.53 (d, 1H), 7.49 (d, 1H), 2.75 (q, 2H), 1.29 (t, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[Cl:17][C:18]1[N:23]=[C:22](Cl)[C:21]([Cl:25])=[CH:20][N:19]=1.C(=O)([O-])[O-].[K+].[K+]>C1COCC1.O>[Cl:17][C:18]1[N:23]=[C:22]([NH:1][C:2]2[CH:10]=[CH:9][C:8]([N:11]3[CH2:12][CH2:13][O:14][CH2:15][CH2:16]3)=[CH:7][C:3]=2[C:4]([NH2:6])=[O:5])[C:21]([Cl:25])=[CH:20][N:19]=1
Reactant: Clc1ncc(Cl)c(Cl)n1
Reactant: NC(=O)c1cc(N2CCOCC2)ccc1N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: NC(=O)c1cc(N2CCOCC2)ccc1Nc1nc(Cl)ncc1Cl
Temperature: 50 °C
Reaction time: 144 h
Yield: 54.9 %

Procedure:
A mixture of 2-amino-5-morpholin-4-yl-benzamide (820.0 mg, 3.71 mmol, Heterocyclic Comm. 2001, 7, 473-480), 2,4,5-trichloropyrimidine (679.8 mg, 3.71 mmol) and potassium carbonate (614.6 mg, 4.45 mol) in THF (10 mL) was stirred at 50° C. for 20 h and at RT for 6 days. The reaction was diluted with water (10 mL) and extracted into EtOAc. The organic layer was washed with NaHCO3, brine and dried by passing through a funnel filled with MgSO4. The filtrate was evaporated and the residue triturated with ether (5×3 mL) to afford 2-(2,5-dichloro-pyrimidin-4-ylamino)-5-morpholin-4-yl-benzamide as a yellow solid (0.75 g) that was used without further purification in the subsequent step.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[CH:8][C:4]=1[CH2:5]CN.[CH3:14][NH:15]CC1C=CC2C(=CC=CC=2)C=1CCC.[NH2:30][C:31]1[N:36]=[CH:35][C:34](/[CH:37]=[CH:38]/[C:39]([OH:41])=O)=[CH:33][CH:32]=1.Cl.CN1CC2C=C(/C=C/C(O)=O)C=NC=2NC(=O)C1>>[NH2:30][C:31]1[N:36]=[CH:35][C:34](/[CH:37]=[CH:38]/[C:39]([N:15]([CH2:5][C:4]2[CH:8]=[CH:9][CH:10]=[C:11]([O:12][CH3:13])[C:3]=2[O:2][CH3:1])[CH3:14])=[O:41])=[CH:33][CH:32]=1
Reactant: CCCc1c(CNC)ccc2ccccc12
Reactant: COc1cccc(CCN)c1OC
Reactant: Nc1ccc(/C=C/C(=O)O)cn1
Agent: CN1CC(=O)Nc2ncc(/C=C/C(=O)O)cc2C1
Agent: Cl
Product: COc1cccc(CN(C)C(=O)/C=C/c2ccc(N)nc2)c1OC

Procedure:
According to the procedure of Example 1 (a), except substituting (2,3-dimethoxy-benzyl)methyl-amine for the methyl-(1-propyl-naphthalen-2-ylmethyl)amine, and substituting (E)-3-(6-amino-pyridin-3-yl)acrylic acid for the (E)-3-(4-methyl-2-oxo-2,3,4,5-tetrahydro-1H-pyrido[2,3-e][1,4]diazepin-7-yl)acrylic acid hydrochloride, the title compound was prepared as a pale yellow solid (434 mg, 53%): 1H NMR (300 MHz, DMSO-d6) δ 8.14 (d, J=11.3 Hz, 1H), 7.89-7.77 (m, 1H), 7.44-7.39 (m, 1H), 7.05-6.94 (m, 3H), 6.68-6.45 (m, 4H), 4.74-4.61 (m, 2H), 3.80 (s, 3H), 3.74 (s, 3H), 3.07-2.86 (m, 3H); MS (ESI) m/e 328 (M+H)+.
Reaction SMILES: CS[C:3]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:12]=1)([CH:8]([CH3:10])[CH3:9])[C:4]([O:6][CH3:7])=[O:5].C(OCC)C>C(O)(=O)C.S([O-])([O-])(=O)=O.[Cu+2].[Zn]>[O:17]([C:13]1[CH:12]=[C:11]([CH:3]([CH:8]([CH3:10])[CH3:9])[C:4]([O:6][CH3:7])=[O:5])[CH:16]=[CH:15][CH:14]=1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: COC(=O)C(SC)(c1cccc(Oc2ccccc2)c1)C(C)C
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Agent: [Zn]
Solvent: CC(=O)O
Solvent: CCOCC
Product: COC(=O)C(c1cccc(Oc2ccccc2)c1)C(C)C
Yield: 87.9 %

Procedure:
Methyl α-methylthio-α-(m-phenoxyphenyl)isovalerate (702 mg) was dissolved in 5 ml of acetic acid, and 50 mg of anhydrous copper sulfate and 500 mg of zinc powder was added. The mixture was heated under reflux for 23 hours. Diethyl ether (80 ml) was added, and the insoluble matter was separated by filtration. The filtrate was washed twice with 25 ml of water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was chromatographed on a silica gel column using benzene as an eluent to afford 531 mg of methyl α-(m-phenoxyphenyl)isovalerate in a yield of 88%.
Reaction SMILES: C([O:3][C:4](=[O:23])[CH:5]([CH2:13][CH2:14][O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])C.[OH-].[K+]>O.O1CCOCC1>[C:9]([O:8][C:6](=[O:7])[CH:5]([CH2:13][CH2:14][O:15][CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[C:4]([OH:23])=[O:3])([CH3:12])([CH3:10])[CH3:11]
Reactant: CCOC(=O)C(CCOCc1ccccc1)C(=O)OC(C)(C)C
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)C(CCOCc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-(2-benzyloxyethyl) malonic acid tert-butyl ester ethyl ester (31.3 g, 97.1 mmol) in water (50 mL) and dioxane (200 mL) was added potassium hydroxide (6.6 g, 0.118 mole) while cooling in an ice bath. The mixture was then stirred at room temperature overnight. The solvents were evaporated under vacuum to leave a clear oil which was dissolved in water. The solution was washed with ether and then acidified to pH 3 using 6N hydrogen chloride (HCl) solution. The mixture was extracted twice with ether; the extracts were combined, washed with brine, dried over magnesium sulfate (MgSO4) and concentrated under vacuum to leave 2-(2-benzyloxyethyl) malonic acid mono tert-butyl ester as a clear oil, 23.9 g (84%).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@@H:12]1[CH2:16][C:17]1[C:25]2[C:20](=[CH:21][CH:22]=[C:23](Br)[CH:24]=2)[NH:19][CH:18]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:27]([C:29]1([OH:34])[CH2:33][CH2:32][CH2:31][CH2:30]1)=[CH2:28]>CO>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@@H:12]1[CH2:16][C:17]1[C:25]2[C:20](=[CH:21][CH:22]=[C:23]([CH:28]=[CH:27][C:29]3([OH:34])[CH2:33][CH2:32][CH2:31][CH2:30]3)[CH:24]=2)[NH:19][CH:18]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(OCc1ccccc1)N1CCC[C@@H]1Cc1c[nH]c2ccc(Br)cc12
Reactant: C=CC1(O)CCCC1
Solvent: CO
Product: O=C(OCc1ccccc1)N1CCC[C@@H]1Cc1c[nH]c2ccc(C=CC3(O)CCCC3)cc12

Procedure:
Obtained by a procedure similar to that described in Example 1, from 3-(N-benzyloxycarbonyl-2(R)-pyrrolidinylmethyl)-5-bromo-1H-indole (Preparation 1) and 1-vinylcyclopentanol (Example 5(a)), as a foam. Rf 0.40 (SS 10). [α]D25 -31° (c=0.1, CH3OH). Found: C,75.58; H,7.24; N,6.22. C28H32N2O3 requires C,75.64; H,7.26; N,6.30%.
Reaction SMILES: [Br:1][C:2]1[C:9]([F:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.CO[CH:13](OC)[CH2:14][NH2:15].O>C1(C)C=CC=CC=1>[Br:1][C:2]1[C:9]([F:10])=[CH:8][CH:7]=[C:6]2[C:3]=1[CH:4]=[N:15][CH:14]=[CH:13]2
Reactant: COC(CN)OC
Reactant: O=Cc1cccc(F)c1Br
Solvent: O
Solvent: Cc1ccccc1
Product: Fc1ccc2ccncc2c1Br
Temperature: 130 °C
Reaction time: 0.5 h

Procedure:
A mixture of 2-bromo-3-fluorobenzaldehyde (4.06 g, 20 mmol, 1 eq.) and aminoacetaldehyde dimethyl acetal (2.18 mL, 20 mmol, 1 eq.) in toluene (50 mL) was stirred at 130° C. with concomitant removal of H2O (Dean-Stark) for 1 hour. The mixture was concentrated in vacuo and dried under h.v. The resulting imine was added dropwise over 20 min to hot H2SO4 (20 mL) at 140° C. After addition completion, the mixture was stirred at 130° C. for another 30 min. The mixture was allowed to cool to r.t., poured on ice (1 kg). Some black tar was removed by filtration over Celite. The filtrate was basified by addition of 32% aq. NaOH soln. The mixture was extracted with AcOEt (3×200 mL). The comb. org. phases were dried over MgSO4 and concentrated in vacuo. The residue was purified by prep. HPLC (column: Water X-Bridge, 30×75 mm, 10 um, UV/MS, acidic conditions) and concentrated in vacuo to give the title compound.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]1.O[N:19]1[C:23](=[O:24])[C:22]2=[CH:25][CH:26]=[CH:27][CH:28]=[C:21]2[C:20]1=[O:29].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[O:29]=[C:20]1[C:21]2[C:22](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23](=[O:24])[N:19]1[O:1][CH2:2][CH2:3][O:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]1
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: CC(C)(C)OC(=O)N1CCC(OCCO)CC1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(OCCON2C(=O)c3ccccc3C2=O)CC1
Temperature: 0 °C
Reaction time: 16 h
Yield: 48.2 %

Procedure:
To a solution of tert-butyl 4-(2-hydroxyethoxy)piperidine-1-carboxylate 69 (0.9 g, 3.67 mmol, WO 2009/87649 A1) in THF (28 mL) were added N-hydroxyphthalimide (0.9 g, 5.51 mmol), triphenylphosphine (1.44 g, 5.51 mmol) and DIAD (1.07 mL, 5.51 mmol) sequentially at 0° C. under nitrogen. The mixture was stirred at 0° C. for 30 min and at room temperature for 16 h. Solvent was evaporated off and the residue was subjected to chromatography to give 70 (0.69 g, 48%) as a white solid.
Reaction SMILES: [CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:30](=[O:38])[NH:31][S:32]([N:35]([CH3:37])[CH3:36])(=[O:34])=[O:33])=[CH:12][C:13]=3[N:14]3[CH2:20][C:19]([C:21](O)=[O:22])=[CH:18][C:17]4[CH:24]=[C:25]([O:28][CH3:29])[CH:26]=[CH:27][C:16]=4[C:15]=23)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:39]([N:46]1[CH2:51][C@H:50]([CH3:52])[NH:49][C@H:48]([CH3:53])[CH2:47]1)[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1.C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.O.Cl>[CH2:39]([N:46]1[CH2:47][C@H:48]([CH3:53])[N:49]([C:21]([C:19]2[CH2:20][N:14]3[C:13]4[CH:12]=[C:11]([C:30]([NH:31][S:32]([N:35]([CH3:37])[CH3:36])(=[O:34])=[O:33])=[O:38])[CH:10]=[CH:9][C:8]=4[C:7]([CH:1]4[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]4)=[C:15]3[C:16]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][C:17]=3[CH:18]=2)=[O:22])[C@H:50]([CH3:52])[CH2:51]1)[C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1
Reactant: C[C@@H]1CN(Cc2ccccc2)C[C@H](C)N1
Reactant: COc1ccc2c(c1)C=C(C(=O)O)Cn1c-2c(C2CCCCC2)c2ccc(C(=O)NS(=O)(=O)N(C)C)cc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)C=C(C(=O)N1[C@H](C)CN(Cc3ccccc3)C[C@@H]1C)Cn1c-2c(C2CCCCC2)c2ccc(C(=O)NS(=O)(=O)N(C)C)cc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 14.1 %

Procedure:
To a stirred solution of 13-cyclohexyl-10-(((dimethylamino)sulfonyl)carbamoyl)-3-methoxy-7H-indolo[2,1-a][2]benzazepine-6-carboxylic acid (200 mg, 0.37 mmol), (3R,5S)-1-benzyl-3,5-dimethylpiperazine (115 mg, 0.56 mmol) and diisopropylethylamine (0.26 mL) in DMF (4 mL) was added HATU (212 mg, 0.56 mmol). The reaction mixture was stirred at rt for 2 h, treated with additional (3R,5S)-1-benzyl-3,5-dimethylpiperazine (100 mg, 0.49 mmol) and stirred at 100° C. for 3 h. The reaction was cooled to rt, diluted with H2O (30 mL) and 1M HCl (aq.) (1.5 mL) and extracted with EtOAc (20 mL). The organic layer was separated, washed with brine (10 mL), dried (MsSO4), filtered and concentrated. The residue was diluted with MeOH (5 mL) and purified by preparative HPLC (H2O/CH3CN with 10 mM NH4OAc buffer) to yield rel-6-(((2R,6S)-4-benzyl-2,6-dimethyl-1-piperazinyl)carbonyl)-13-cyclohexyl-N-((dimethylamino)sulfonyl)-3-methoxy-7H-indolo[2,1-a][2]benzazepine-10-carboxamide (38 mg, 0.052 mmol, 14%) as an orange solid. 1HNMR (300 MHz, CD3OD) δ 1.02-2.22 (m, 20H), 2.58-3.03 (m, 3H), 3.05 (s, 6H), 3.27-3.40 (m, 2H), 3.92 (s, 3H), 4.34-4.56 (m, 1H), 4.99-5.19 (m, 1H), 6.89 (s, 1H) 7.08 (d, J=2.6 Hz, 1H), 7.14 (dd, J=8.8, 2.6 Hz, 1H), 7.19-7.33 (m, 5H), 7.55 (d, J=8.4 Hz, 1H), 7.65 (d, J=8.4 Hz, 1H), 7.90 (d, J=8.4 Hz, 1H), 8.17 (s, 1H). LCMS: m/e 724 (M+H)+, ret time 3.37 min, column B, 4 minute gradient.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])[CH2:16]2)(=[O:12])=[O:11].[CH3:23][C:24]1[C:28]([CH2:29][CH2:30][C:31]([N:33]2[CH2:38][CH2:37][N:36]([CH3:39])[CH2:35][CH2:34]2)=[O:32])=[C:27]([CH3:40])[NH:26][C:25]=1[CH:41]=O.N1CCCCC1>C(O)C>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])/[C:16]/2=[CH:41]\[C:25]1[NH:26][C:27]([CH3:40])=[C:28]([CH2:29][CH2:30][C:31]([N:33]2[CH2:34][CH2:35][N:36]([CH3:39])[CH2:37][CH2:38]2)=[O:32])[C:24]=1[CH3:23])(=[O:12])=[O:11]
Reactant: Cc1[nH]c(C=O)c(C)c1CCC(=O)N1CCN(C)CC1
Reactant: O=C1Cc2cc(S(=O)(=O)Cc3c(Cl)cccc3Cl)ccc2N1
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1CCC(=O)N1CCN(C)CC1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A mixture of 5-(2,6-Dichloro-phenylmethanesulfonyl)-1,3-dihydro-indol-2-one (122 mg, 0.34 mmol), 3,5-dimethyl-4-[3-(4-methyl-piperazin-1-yl)-3-oxo-propyl]-1H-pyrrole-2-carbaldehyde (1.4 eq.) and piperidine (0.5 eq.) in ethanol (2 mL) was stirred at rt for 72 hours. The reaction was concentrated and purified on a silica gel column to give the titled compound as a dark orange brown solid. 1HNMR (400 MHz, DMSO-d6) δ 13.44 (s, 1H, NH), 11.25 (s, 1H, NH), 8.18 (d, 1H), 7.75 (s, 11H), 7.48 (s, 1H), 7.46 (s, 1H), 7.38 (m, 2H), 6.99 (d, J=8 Hz, 1H), 4.85 (s, 2H), 3.3-3.42 (m, 2H), 2.62 (m, 2H), 2.44 (m, 2H), 2.30 (s, 3H, CH3), 2.28 (s, 3H, CH3), 2.1-2.2 (m, 4H), 2.11 (s, 3H, CH3). MS m/z 613 [M−1].
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[CH:17]=[CH:16][CH:15]=[C:14]([OH:18])[C:9]=2[C:10]=1[CH:11]1[CH2:13][CH2:12]1)=[O:5])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[Br:25][CH2:26][CH2:27][CH2:28]Br>CN(C)C=O>[CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH2:28][CH2:27][CH2:26][Br:25])[C:9]=2[C:10]=1[CH:11]1[CH2:12][CH2:13]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1oc2cccc(O)c2c1C1CC1
Reactant: BrCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1oc2cccc(OCCCBr)c2c1C1CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of 3-cyclopropyl-4-hydroxy-benzofuran-2-carboxylic acid ethyl ester (92 mg) and potassium carbonate (62 mg) in N,N-dimethylformamide (1.5 ml) was added 1,3-dibromopropane (190 μl) and the reaction mixture was stirred for 2 hours at room temperature. The reaction was quenched with saturated aqueous ammonium chloride solution (5 ml) and diluted with ethyl acetate (8 ml). The organic layer was washed with water (5 ml twice) and brine, dried over anhydrous sodium sulfate, then concentrated in vacuo to dryness. The residue was purified by silica gel column chromatography developed by hexane-ethyl acetate to give 4-(3-bromo-propoxy)-3-cyclopropyl-benzofuran-2-carboxylic acid ethyl ester (120 mg) as a white solid. EI-MS: m/z 368 (M+); 1H-NMR (CDCl3): δ 0.91-0.95 (4H, m), 1.37 (3H, t, J=7.26 Hz), 2.36 (2H, quintet, J=7.26 Hz), 2.47-2.51 (1H, m), 3.60 (2H, t, J=7.26 Hz), 4.16 (2H, t, J=7.26 Hz), 4.37 (2H, q, J=7.26 Hz), 6.58 (1H, d, J=8.25 Hz), 7.07 (1H, d, J=8.25 Hz), 7.24 (1H, dd, J=8.25 Hz, 8.25 Hz).
Reaction SMILES: [C:1]1([N:7]2[CH:11]=[CH:10][CH:9]=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:12](=[O:14])[CH3:13]>>[C:1]1([N:7]2[C:11]([CH:12]([OH:14])[CH3:13])=[CH:10][CH:9]=[N:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(-n2cccn2)cc1
Reactant: CC=O
Product: CC(O)c1ccnn1-c1ccccc1
Yield: 54 %

Procedure:
This compound was prepared from 1-phenyl-1H-pyrazole and acetaldehyde using the method described in example 100B and isolated as a yellow oil in 54% yield.
Reaction SMILES: Cl.[CH3:2][N:3]1[CH2:8][CH2:7][CH2:6][CH:5]([C:9]2[CH:14]=[CH:13][C:12]([O:15]C)=[C:11]([O:17]C)[CH:10]=2)[CH2:4]1.[BrH:19]>>[BrH:19].[CH3:2][N:3]1[CH2:8][CH2:7][CH2:6][CH:5]([C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[C:11]([OH:17])[CH:10]=2)[CH2:4]1
Reactant: COc1ccc(C2CCCN(C)C2)cc1OC
Agent: Br
Agent: Cl
Product: CN1CCCC(c2ccc(O)c(O)c2)C1

Procedure:
A mixture of 8 g of the product of Step D in 40 ml of 66% hydrobromic acid was refluxed for an hour and then distilled to dryness under reduced pressure. The residue was dissolved in hot ethanol and the solution was cooled and vacuum filtered to obtain 2.49 g of N-methyl-3-(3',4'-dihydroxyphenyl)-piperidine hydrobromide as crystals melting at 190° C.