Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[Al](C)C.[CH3:5][N:6]1[CH2:12][CH2:11][C:10]2[CH:13]=[C:14]([NH2:17])[CH:15]=[CH:16][C:9]=2[CH2:8][CH2:7]1.C([O:20][C:21]([C:23]([NH:29][C:30]([C:32]1[S:33][C:34]([Cl:37])=[CH:35][CH:36]=1)=[O:31])([CH3:28])[CH2:24][CH2:25][O:26][CH3:27])=O)C>C1(C)C=CC=CC=1.ClCCl>[CH3:27][O:26][CH2:25][CH2:24][C:23]([NH:29][C:30]([C:32]1[S:33][C:34]([Cl:37])=[CH:35][CH:36]=1)=[O:31])([CH3:28])[C:21](=[O:20])[NH:17][C:14]1[CH:15]=[CH:16][C:9]2[CH2:8][CH2:7][N:6]([CH3:5])[CH2:12][CH2:11][C:10]=2[CH:13]=1
Reactant: CN1CCc2ccc(N)cc2CC1
Reactant: CCOC(=O)C(C)(CCOC)NC(=O)c1ccc(Cl)s1
Agent: C[Al](C)C
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: COCCC(C)(NC(=O)c1ccc(Cl)s1)C(=O)Nc1ccc2c(c1)CCN(C)CC2
Reaction time: 0.25 h

Procedure:
0.60 ml of a 2M solution of trimethylaluminium in toluene are added to a mixture of 130 mg (0.738 mmol) 3-methyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine in dichloromethane and stirred for 15 min. Then the mixture is added to 233 mg (0.729 mmol) 5-chloro-thiophene-2-carboxylic acid-N-(1-ethoxycarbonyl-3-methoxy-1-methyl-propyl)-amide and stirred for 3 days. Then it is poured onto ice water/2 N NaOH, extracted several times with ethyl acetate and dried with sodium sulphate. The crude product is purified by chromatography.
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:13][CH2:14][CH3:15])=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][C:8]([Cl:12])=[CH:7]2.[Cl:16][C:17]1[CH:25]=[CH:24][C:20]([C:21](O)=O)=[CH:19][CH:18]=1.[OH-].[Na+]>>[Cl:16][C:17]1[CH:25]=[CH:24][C:20]([C:21]2[N:13]([CH2:14][CH3:15])[C:3]3[CH:4]=[CH:5][C:6]4[CH:7]=[C:8]([Cl:12])[CH:9]=[N:10][C:11]=4[C:2]=3[N:1]=2)=[CH:19][CH:18]=1
Reactant: CCNc1ccc2cc(Cl)cnc2c1N
Reactant: O=C(O)c1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Product: CCn1c(-c2ccc(Cl)cc2)nc2c3ncc(Cl)cc3ccc21
Temperature: 120 °C

Procedure:
A mixture of 4.1 g (20 mmol) of 8-amino-3-chloro-7-ethylaminoquinoline, 3.1 g (20 mmol) of 4-chlorobenzoic acid and 20 ml of polyphosphoric acid is heated at 120° C. for 1 hour. It is allowed to cool to 90° C., and 100 g of ice are slowly added to the solution. The mixture is then poured into 200 g of ice, and the pH is adjusted to 12 with concentrated sodium hydroxide solution. The precipitate is filtered off with suction, washed thoroughly with hot water, dried at 70° C. under reduced pressure and recrystallized from ethyl acetate.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[C:5](O)=[O:6].S(Cl)([Cl:15])=O>>[F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[C:5]([Cl:15])=[O:6]
Reactant: COc1ccc(C(=O)O)cc1F
Reactant: O=S(Cl)Cl
Product: COc1ccc(C(=O)Cl)cc1F

Procedure:
3-Fluoro-4-methoxybenzoic acid (830 mg, 4.88 mmol) and thionyl chloride (10 mL) were refluxed for 2 h. The excess thionyl chloride was removed by repeated evaporation with dry toluene in vacuo, giving the subtitle compound as a brown solid, which would be used for the next step directly.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([C:11]([OH:13])=O)=[CH:8][C:7]=2[CH:14]=1.[CH2:17]([N:19]([CH2:26][CH3:27])[CH2:20][C@@H:21]1[CH2:25][CH2:24][CH2:23][NH:22]1)[CH3:18]>>[CH2:17]([N:19]([CH2:20][C@@H:21]1[CH2:25][CH2:24][CH2:23][N:22]1[C:11]([C:9]1[O:10][C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:16])[F:15])=[CH:14][C:7]=2[CH:8]=1)=[O:13])[CH2:26][CH3:27])[CH3:18]
Reactant: CCN(CC)C[C@@H]1CCCN1
Reactant: O=C(O)c1cc2cc(C(F)(F)F)ccc2o1
Product: CCN(CC)C[C@@H]1CCCN1C(=O)c1cc2cc(C(F)(F)F)ccc2o1

Procedure:
110 mg of the title compound were synthesized as described for (E)-3-(4-bromophenyl)-1-((S)-2-((pyrrolidin-1-yl)methyl)pyrrolidin-1-yl)propenone, using 5-(trifluoromethyl)benzofuran-2-carboxylic acid instead of (E)-4-bromocinnamic acid and N,N-diethyl-N-(((S)-pyrrolidin-2-yl)methyl)amine instead of (S)-2-((pyrrolidin-1-yl)methyl)pyrrolidine.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.F[C:8]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[CH:12][C:9]=1[C:10]#[N:11]>CS(C)=O.CCOC(C)=O>[C:10]([C:9]1[CH:12]=[CH:13][C:14]([C:16]([F:17])([F:18])[F:19])=[CH:15][C:8]=1[N:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1)#[N:11]
Reactant: C1CNCCN1
Reactant: N#Cc1ccc(C(F)(F)F)cc1F
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: N#Cc1ccc(C(F)(F)F)cc1N1CCNCC1
Reaction time: 8 h
Yield: 96.6 %

Procedure:
To a solution of piperazine (13.7 g, 159 mmol) in 20 mL DMSO was added 2-fluoro-4-trifluoromethylbenzonitrile (10 g, 52.9 mmol). After stirring overnight, the solution was diluted with 200 mL of EtOAc, washed with water and brine, and then dried (Na2SO4), filtered and concentrated to afford about 13.0 g (51.1 mmol, 96%) of 4-(2-cyano-5-trifluoromethyl-phenyl)piperazine. LRMS (ESI+): 256.1 [M+1]. The tide compound was prepared from 4-(2-cyano-5-trifluoromethyl-phenyl)piperazine in the same manner as described in Preparation 67A except that dimethyl amine was used to displace the mesylate. LRMS (ESI+): 388.1 [M+1]
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrBr.[CH2:22]([N:24]([CH2:37][CH3:38])[C:25](=[O:36])[C:26]1[CH:31]=[CH:30][C:29]([F:32])=[C:28]([F:33])[C:27]=1[CH2:34]O)[CH3:23].[NH:39]1[CH:43]=[CH:42][N:41]=[CH:40]1>ClCCl.C(OCC)(=O)C.C(#N)C>[CH2:22]([N:24]([CH2:37][CH3:38])[C:25](=[O:36])[C:26]1[CH:31]=[CH:30][C:29]([F:32])=[C:28]([F:33])[C:27]=1[CH2:34][N:39]1[CH:43]=[CH:42][N:41]=[CH:40]1)[CH3:23]
Reactant: c1c[nH]cn1
Reactant: CCN(CC)C(=O)c1ccc(F)c(F)c1CO
Agent: BrBr
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCN(CC)C(=O)c1ccc(F)c(F)c1Cn1ccnc1
Temperature: 70 °C
Reaction time: 0.08 h

Procedure:
A flask is charged with polymer-supported triphenylphosphine (1.48 mmol/g, 6.87 g, 10.17 mmol) and dichloromethane (70 mL). Bromine (1.58 g, 9.77 mmol) is added at r.t., followed with N,N-diethyl-3,4-difluoro-2-hydroxymethyl-benzamide (1.100 g, 4.070 mmol) in dichloromethane (15 mL). After 5 min, the mixture is filtered and the resin is washed several times with dichloromethane. The resulting filtrate is concentrated in vacuo to yield an oil. Imidazole (2.80 g, 40.70 mmol) is added, followed with acetonitrile (30 mL) and the mixture is heated to 70° C. After 5 min at 70° C., the mixture is allowed to cool down, diluted with ethyl acetate and extracted three times with 1M aqueous HCl. The combined aqueous phase is washed once with dichloromethane. The aqueous phase is then cooled to 0° C. and the pH is adjusted to 12 with cold 4M aqueous NaOH. The aqueous phase is then extracted with dichloromethane. The combined extraction fractions are dried over MgSO4 and filtered. The sample is concentrated in vacuo, taken up in ethyl acetate and washed with water (three times), and brine. The organic phase is dried over MgSO4, filtered and concentrated in vacuo to give N,N-diethyl-3,4-difluoro-2-imidazol-1-ylmethyl-benzamide as a yellow oil; 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.95 (t, J=7.1 Hz, 3 H), 1.26 (t, J=7.1 Hz, 3 H), 2.82 (q, J=7.1 Hz, 2 H), 3.52 (q, J=7.1 Hz, 2 H), 5.25 (br. s., 2 H), 6.96 (s, 1 H), 6.98-7.03 (m, 1 H), 7.01 (s, 1 H), 7.16-7.25 (m, 1 H), 7.51 (s, 1 H).
Reaction SMILES: Br[C:2]1[C:10]([O:11][CH3:12])=[C:9]([C:13]([CH3:16])([CH3:15])[CH3:14])[CH:8]=[C:7]2[C:3]=1[CH2:4][CH:5]([CH3:18])[C:6]2=[O:17].[C:19]([C:23]1[CH:24]=[C:25](B(O)O)[CH:26]=[C:27]([C:29]([CH3:32])([CH3:31])[CH3:30])[CH:28]=1)([CH3:22])([CH3:21])[CH3:20].C([O-])([O-])=O.[Na+].[Na+].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>CC([O-])=O.CC([O-])=O.[Pd+2].COCCOC.O>[C:13]([C:9]1[CH:8]=[C:7]2[C:3]([CH2:4][CH:5]([CH3:18])[C:6]2=[O:17])=[C:2]([C:25]2[CH:24]=[C:23]([C:19]([CH3:21])([CH3:20])[CH3:22])[CH:28]=[C:27]([C:29]([CH3:32])([CH3:31])[CH3:30])[CH:26]=2)[C:10]=1[O:11][CH3:12])([CH3:16])([CH3:15])[CH3:14]
Reactant: COc1c(C(C)(C)C)cc2c(c1Br)CC(C)C2=O
Reactant: CC(C)(C)c1cc(B(O)O)cc(C(C)(C)C)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: COCCOC
Solvent: O
Product: COc1c(C(C)(C)C)cc2c(c1-c1cc(C(C)(C)C)cc(C(C)(C)C)c1)CC(C)C2=O
Yield: 44.6 %

Procedure:
A mixture of 30.7 g (98.6 mmol) of 4-bromo-6-tertbutyl-5-methoxy-2-methylindanone, 30.6 g (128 mmol) 3,5-di-tert-butylphenylboronic acid, 29.7 g (280 mmol) of Na2CO3, 1.35 g (5.92 mmol; 6 mol. %) of Pd(OAc)2, 3.15 g (11.8 mmol; 12 mol. %) of PPh3, 130 ml of water, and 380 ml of 1,2-dimethoxyethane was refluxed for 12 h. Further on, the reaction mixture was quenched with water, solvents were evaporated. The residue was dissolved in 500 ml of dichloromethane, and this solution was washed by 500 ml of water. The organic layer was separated, the aqueous layer was additionally extracted with 100 ml of dichloromethane. The combined organic extract was dried over Na2SO4, then evaporated to dryness. The crude product isolated from the residue using flash chromatography on silica gel 60 (40-63 um, hexanes-dichloromethane=2:1, vol.) was then re-crystallized from n-hexane to give 18.5 g (43%) of a white solid.
Reaction SMILES: Cl.CS[C:4]1[NH:5][CH2:6][CH:7]([C:9]2[C:14]([Cl:15])=[CH:13][CH:12]=[CH:11][C:10]=2[Cl:16])[N:8]=1.[CH2:17]([NH2:23])[C:18]1[O:22][CH:21]=[CH:20][CH:19]=1>C(O)C>[ClH:15].[CH2:17]([NH:23][C:4]1[NH:5][CH2:6][CH:7]([C:9]2[C:14]([Cl:15])=[CH:13][CH:12]=[CH:11][C:10]=2[Cl:16])[N:8]=1)[C:18]1[O:22][CH:21]=[CH:20][CH:19]=1
Reactant: CSC1=NC(c2c(Cl)cccc2Cl)CN1
Reactant: NCc1ccco1
Agent: Cl
Solvent: CCO
Product: Clc1cccc(Cl)c1C1CNC(NCc2ccco2)=N1
Temperature: 140 °C

Procedure:
A mixture consisting fo 6.0 gm (0.0202 mol) of 2-methylmercapto-4-(2',6'-dichloro-phenyl)-2-imidazoline hydrochloride and 2.8 gm (0.029 mol) of furfurylamine was heated for 30 minutes at 140° C. The resulting dark-brown mass was dissolved in ethanol and then crystallized by addition of acetone and ether; for further purification, the crystallizate was again dissolved in ethanol and acetone, reprecipitated by addition of ether, and recrystallized from water, yielding 2.5 gm (35.7% of theory) of the yellow crystalline compound of the formula ##STR12## which had a melting point of 191° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][C:2]1=[O:7].[O:8](C(OC(C)(C)C)=O)[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=O>C(#N)C>[O:7]=[C:2]1[NH:1][CH2:6][CH2:5][N:4]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:8])[CH2:3]1
Reactant: O=C1CNCCN1
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCNC(=O)C1
Reaction time: 3 h

Procedure:
A solution of Example 500A (500 mg, 4.99 mmol) in acetonitrile (25 mL) at room temperature was treated with BOC2O (1198 mg, 5.49 mmol), stirred for 3 hours, and concentrated. The concentrate was purified by flash column chromatography on silica gel with 95:5 ethyl acetate/methanol to provide the desired product.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH:8][C@@H:9]2[CH2:13][C@H:12]([CH2:14][OH:15])[CH:11]=[CH:10]2)[C:5]([NH:16][CH:17]=O)=[C:4]([Cl:19])[N:3]=1.C(OC(OCC)OCC)C.Cl>CO.[OH-].[Na+]>[ClH:19].[NH2:1][C:2]1[N:7]=[C:6]2[C:5]([N:16]=[CH:17][N:8]2[C@@H:9]2[CH2:13][C@H:12]([CH2:14][OH:15])[CH:11]=[CH:10]2)=[C:4]([Cl:19])[N:3]=1
Reactant: Nc1nc(Cl)c(NC=O)c(N[C@H]2C=C[C@@H](CO)C2)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(OCC)OCC
Product: Nc1nc(Cl)c2ncn([C@H]3C=C[C@@H](CO)C3)c2n1
Reaction time: 4 h
Yield: 184.4 %

Procedure:
A mixture of (1S,4R)-4-[(2-amino-6-chloro-5-formamido-4-pyrimidinyl)amino]-2-cyclopentene-1-methanol (Example 7, 1.00 g, 3.50 mmol) and triethylorthoformate (Aldrich, Sure Seal, 18 mL) was stirred while concentrated hydrochloric acid (37%, 1.25 mL) was added in one portion. The resulting clear, colorless solution was stirred under nitrogen. A white precipitate began to form after 15 minutes. After 4 hours, TLC of a drop of the reaction mixture dissolved in methanol and neutralized with sodium hydroxide (silica gel plates developed in 10% methanol-chloroform, visualized in UV light) showed almost complete conversion of VIa to a higher-Rf material. The precipitate was filtered, washed with t-butyl methyl ether (15 mL) and dried at 0.2 mm Hg/25° C. for 18 hours to give the title compound as a white powder (975 mg, 92%), m.p.>300° C. dec.; mass spectrum (CI/CH4): 266(M+1); 1H-NMR (DMSO-d6)δ: 8.18 (s, 1, purine CH), 7.2-6.7 (br s, NH2, OH overlapped by water), 6.20 and 5.90 (both m, 1 each, CH=CH), 5.48 (m, 1, NCH), 3.47 (d, J=5.7 Hz, 2, CH2O), 2.90 (m, 1, CH), 2.75-2.55 and 1.75-1.60 (both m, 1 each, CH2).
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([C:7](=[O:13])[CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:4][CH:3]=1.[Cl:14][C:15]1[CH:22]=[CH:21][C:18]([CH:19]=O)=[CH:17][CH:16]=1.N1CCCCC1.C1C=CC=CC=1.C(O)(=O)C>>[Br:1][C:2]1[S:6][C:5]([C:7](/[C:8](=[CH:19]/[C:18]2[CH:21]=[CH:22][C:15]([Cl:14])=[CH:16][CH:17]=2)/[C:9]([O:11][CH3:12])=[O:10])=[O:13])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(Cl)cc1
Reactant: COC(=O)CC(=O)c1ccc(Br)s1
Solvent: C1CCNCC1
Solvent: CC(=O)O
Solvent: c1ccccc1
Product: COC(=O)/C(=C\c1ccc(Cl)cc1)C(=O)c1ccc(Br)s1
Temperature: 92 °C
Yield: 97 %

Procedure:
To a 500 mL round bottom flask was added a solution of methyl 3-(5-bromo-2-thienyl)-3-oxopropanoate (4.402 g, 16.73 mmol), 4-chlorobenzaldehyde (2.822 g, 20.08 mmol) and piperidine (0.165 mL, 1.673 mmol) in anhydrous benzene (200.0 mL, 2238 mmol). Acetic acid (0.665 mL, 11.712 mmol) was added and the reaction mixture was fitted with a Dean-Stark trap and the bath was heated to 92° C. and allowed to reflux for 18 hours. The reaction was cooled to ambient temperature and concentrated under reduced pressure. The crude material was split in half and dry loaded onto silica gel and then purified using a ISCO (40 g cartridge, gradient hexanes to 40% EtOAc over 30 min) to afford the title compound (6.26 g, 92%) as a yellow solid. LC/MS (AA) ES− 385, 387, 389(dmso-d6, 400 MHz): δ 7.89 (s, 1H), 7.34-7.24 (m, 5H), 7.00 (d, 1H), 3.71 (s, 3H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:7]F.[F:9][C:10]([F:16])([F:15])[S:11]([O-:14])(=[O:13])=[O:12].[Na+]>C(#N)C>[F:9][C:10]([F:16])([F:15])[S:11]([O-:14])(=[O:13])=[O:12].[F:7][N+:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: FF
Reactant: c1ccncc1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Na+]
Solvent: CC#N
Product: F[n+]1ccccc1
Temperature: -40 °C

Procedure:
To a 100 ml anhydrous acetonitrile solution containing 10 g (0.126 mole) of pyridine a mixed gas of fluorine and nitrogen was introduced at a rate of 90 ml/min. at -40° C. under vigorous stirring. The amount of the fluorine gas introduced amounted to 0.18 mole. Subsequent to the fluorine introduction, 22 g (0.128 mole) of sodium trifluoromethanesulfonate as a XM reactant was added to the reaction solution after which the resultant reaction solution was maintained at -40° C. for 5 hours under stirring. Subsequently, the solvent, after filtering sodium fluoride, was distilled off and the resultant residue was recrystallized from methylene chloride to give 17.5 g (yield: 71%) of N-fluoropyridinium trifluoromethanesulfonate. The product thus obtained was repurified with methylene chloride/acetonitrile to recover 13.8 g (yield: 56%).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:33])[CH2:10][CH2:11][O:12][C:13]1[CH:18]=[C:17]([N+:19]([O-])=O)[C:16]([C:22]([N:24]2[CH2:28][CH2:27][CH2:26][CH:25]2[CH2:29][OH:30])=[O:23])=[CH:15][C:14]=1[O:31][CH3:32])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Sn](Cl)(Cl)(Cl)Cl>CO.C(OCC)(=O)C>[CH2:1]([O:8][C:9](=[O:33])[CH2:10][CH2:11][O:12][C:13]1[CH:18]=[C:17]([NH2:19])[C:16]([C:22]([N:24]2[CH2:28][CH2:27][CH2:26][CH:25]2[CH2:29][OH:30])=[O:23])=[CH:15][C:14]=1[O:31][CH3:32])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc(C(=O)N2CCCC2CO)c([N+](=O)[O-])cc1OCCC(=O)OCc1ccccc1
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: CO
Solvent: CCOC(C)=O
Product: COc1cc(C(=O)N2CCCC2CO)c(N)cc1OCCC(=O)OCc1ccccc1
Reaction time: 2 h

Procedure:
The nitro compound C5 (59 g, 0.128 mol) was dissolved in methanol (650 mL). Tin chloride (130 g, 0.577 mol, 4.5 eq) was added and the mixture was heated under reflux for 6 hours until completion of the reaction (TLC, 5% methanol in ethyl acetate). The methanol was removed under vacuum and the residue was dissolved in ethyl acetate (1 L) in a 5 L flask and 2 L of saturated sodium hydrogen carbonate aqueous solution was carefully added. The mixture was mechanically stirred for 2 hours and the resulting emulsion was then left to settle overnight. The pH was 8. It was filtered through celite. The residue was washed twice with ethyl acetate and the aqueous layer was extracted with ethyl acetate. The organic layers were combined, dried with magnesium sulfate, and concentrated in vacuo to leave the crude product as a black tar (50 g). TLC analysis showed presence of small quantities of impurities but the product was use in the next step with no further purification. 1H NMR (CDCl3) δ 7.36 (m, 5H), 6.74 (s, 1H), 6.28 (s, 1H), 5.19 (s, 2H), 4.28 (t, J=6.2 Hz, 2H), 3.73 (s, 3H), 3.77-3.50 (m, 2H), 2.91 (t, J=6.2 Hz, 2H), 2.15 (m, 1H), 1.88-1.60 (m, 2H).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[C:11]([O:19][C@@H:20]1[CH2:54][N:23]2[C:24](=[O:53])[C@@H:25]([NH:45][C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][C@H:31]([OH:44])[CH2:32][C@@H:33]3[CH2:38][C@@:34]3([C:39]([O:41][CH2:42][CH3:43])=[O:40])[NH:35][C:36](=[O:37])[C@@H:22]2[CH2:21]1)(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C>ClCCl>[C:11]([O:19][C@@H:20]1[CH2:54][N:23]2[C:24](=[O:53])[C@@H:25]([NH:45][C:46]([O:48][C:49]([CH3:51])([CH3:50])[CH3:52])=[O:47])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][C:31](=[O:44])[CH2:32][C@@H:33]3[CH2:38][C@@:34]3([C:39]([O:41][CH2:42][CH3:43])=[O:40])[NH:35][C:36](=[O:37])[C@@H:22]2[CH2:21]1)(=[O:18])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CCOC(=O)[C@@]12C[C@H]1C[C@@H](O)CCCCC[C@H](NC(=O)OC(C)(C)C)C(=O)N1C[C@@H](OC(=O)c3ccccc3)C[C@H]1C(=O)N2
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)[C@@]12C[C@H]1CC(=O)CCCCC[C@H](NC(=O)OC(C)(C)C)C(=O)N1C[C@@H](OC(=O)c3ccccc3)C[C@H]1C(=O)N2
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 84.5 %

Procedure:
To a solution of oxalyl chloride (0.092 ml, 1.05 mmol) in dichloromethane (1.75 ml) at −78° C. was added dropwise DMSO (0.149 ml, 2.10 mmol). The reaction mixture was stirred for 10 min and then a solution of (2S,6S,12S,13aS,14aR,16aS)-ethyl 2-(benzoyloxy)-6-(tert-butoxycarbonylamino)-12-hydroxy-5,16-dioxooctadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecine-14a-carboxylate (Example 1b, 0.43 g, 0.698 mmol) in dichloromethane (4 ml) was added dropwise. The reaction mixture was stirred at −78° C. for 30 min and triethylamine (0.730 ml, 5.24 mmol) was added dropwise. The reaction mixture was stirred at −78° C. for 15 min and warmed to room temperature and stirred for 1.5 hr. The reaction mixture was quenched with water, stirred for 30 min and extracted with dichloromethane and the organic layer dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure. The residue was purified by flash chromatography on silica gel (dichloromethane/methanol=40/1) to provide the title compound (2S,6S,13aS,14aR,16aS)-ethyl 2-(benzoyloxy)-6-(tert-butoxycarbonylamino)-5,12,16-trioxooctadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecine-14a-carboxylate (0.36 g, 0.59 mmol, 84% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12](=O)[CH3:13])[CH:5]=[CH:6][C:7]=1[CH2:8][CH:9]([CH3:11])[CH3:10].C([O:17]/[C:18](/[CH3:25])=[CH:19]/C(OCC)=O)C>>[Cl:1][C:2]1[CH:3]=[C:4](/[C:12](/[CH3:13])=[CH:19]/[C:18](=[O:17])[CH3:25])[CH:5]=[CH:6][C:7]=1[CH2:8][CH:9]([CH3:11])[CH3:10]
Reactant: CC(=O)c1ccc(CC(C)C)c(Cl)c1
Reactant: CCOC(=O)/C=C(\C)OCC
Product: CC(=O)/C=C(\C)c1ccc(CC(C)C)c(Cl)c1
Yield: 61 %

Procedure:
(E)-4-(3-chloro-4-isobutyl-phenyl)-3-pentene-2-one was prepared analogous to Example 52 from 3'-chloro-4'-isobutyl-acetophenone (b.p. 89°-93°C at 0.2 mm Hg) and ethyl (E)-3-ethoxy-crotonate with a yield of 61% of theory (after chromatographic purification on silicagel using petroleum-ether/benzene in a volume ratio of 1:1 as eluant). Colorless oil.
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].C(Cl)Cl.[CH3:10][N:11]1C(C(O)=O)=[C:14]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([CH3:25])[N:20]=2)[CH:13]=[N:12]1>CN(C)C=O>[CH3:10][N:11]1[C:1]([C:2]([Cl:4])=[O:3])=[C:14]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([CH3:25])[N:20]=2)[CH:13]=[N:12]1
Reactant: Cc1cccc(-c2cnn(C)c2C(=O)O)n1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1cccc(-c2cnn(C)c2C(=O)Cl)n1
Reaction time: 2 h

Procedure:
Oxalyl chloride (0.85 ml) was added to a mixed solution of methylene chloride (5 ml) and N,N-dimethylformamide (5 μl) containing the 1-methyl-4-(6-methylpyridin-2-yl)-1H-pyrazole-5-carboxylic acid (210 mg) obtained in (Example 3.3) <Step 1>, and the obtained mixture was then stirred for 2 hours. Thereafter, the reaction solution was concentrated under reduced pressure to obtain a crude product (230 mg) of the title compound in the form of an orange solid.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[NH:12][C:11]3[CH:13]=[CH:14][CH:15]=[C:16]([C:17]([NH:19][C:20]4[S:21][CH:22]=[CH:23][N:24]=4)=[O:18])[C:10]=3[N:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[NH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1>CS(C)=O.O>[Cl:1][C:2]1[C:7]([C:8]2[NH:12][C:11]3[CH:13]=[CH:14][CH:15]=[C:16]([C:17]([NH:19][C:20]4[S:21][CH:22]=[CH:23][N:24]=4)=[O:18])[C:10]=3[N:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[O:28]1[CH2:29][CH2:30][N:25]([C:2]2[C:7]([C:8]3[NH:12][C:11]4[CH:13]=[CH:14][CH:15]=[C:16]([C:17]([NH:19][C:20]5[S:21][CH:22]=[CH:23][N:24]=5)=[O:18])[C:10]=4[N:9]=3)=[CH:6][CH:5]=[CH:4][N:3]=2)[CH2:26][CH2:27]1
Reactant: C1COCCN1
Agent: O=C(Nc1nccs1)c1cccc2[nH]c(-c3cccnc3Cl)nc12
Solvent: CS(C)=O
Solvent: O
Product: O=C(Nc1nccs1)c1cccc2[nH]c(-c3cccnc3N3CCOCC3)nc12
Temperature: 140 °C
Reaction time: 0.42 h
Yield: 120.7 %

Procedure:
2-(2-Chloropyridin-3-yl)-N-(thiazol-2-yl)-1H-benzo[d]imidazole-4-carboxamide 9 was prepared according to the general procedure outlined above using the appropriate aldehyde component. A mixture containing this material, namely 2-(2-chloropyridin-3-yl)-N-(thiazol-2-yl)-1H-benzo[d]imidazole-4-carboxamide (9; 19 mg, 0.053 mmol) and morpholine (48; 46 mg, 0.53 mmol) in DMSO (1.2 mL) were stirred at 140° C. in a microwave reactor for 25 min. The reaction mixture was cooled to room temperature and diluted with water. The precipitated solids were collected by filtration and dried. The solids were redissolved in EtOAc and enough petroleum ether was added to precipitate the product out again. The solids were collected by filtration, washed with MeOH and dried to afford 2-(2-morpholinopyridin-3-yl)-N-(thiazol-2-yl)-1H-benzo[d]imidazole-4-carboxamide (Compound 250) as a white solid (13 mg, 60%). MS (ESI) calcd for C20H18N6O2S (m/z): 406.12; found: 407 [M+H].
Reaction SMILES: [NH:1]1[C:6](=O)[CH2:5][O:4][C:3]2[N:8]=[CH:9][CH:10]=[CH:11][C:2]1=2.B.C1COCC1>C1COCC1>[NH:1]1[CH2:6][CH2:5][O:4][C:3]2[N:8]=[CH:9][CH:10]=[CH:11][C:2]1=2
Reactant: O=C1COc2ncccc2N1
Agent: B
Solvent: C1CCOC1
Product: c1cnc2c(c1)NCCO2
Yield: 66.1 %

Procedure:
Using 1H-pyrido[2,3-b][1,4]oxazin-2-one (0.3 g, 2 mmol) and borane-THF (8 mL of a 1M solution in THF, 8 mmol) in THF (20 mL) to yield the title compound as a yellow solid (180 mg, 66%). δH (CDCl3) 3.38-3.46 (2H, m), 3.85 (1H, br s), 4.38-4.45 (2H, m), 6.74 (1H, dd, J 7.7, 4.9 Hz), 6.83-6.88 (1H, m), 7.61 (1H, dd, J 4.7, 1.5 Hz).