Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][N:9]([CH2:16][CH:17]([F:19])[F:18])[C:10]2[CH2:14][O:13][C:12](=[O:15])[CH:11]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[Br:27]N1C(=O)CCC1=O>C(#N)C>[Br:27][C:11]1[C:12](=[O:15])[O:13][CH2:14][C:10]=1[N:9]([CH2:8][C:5]1[CH:6]=[N:7][C:2]([Cl:1])=[CH:3][CH:4]=1)[CH2:16][CH:17]([F:19])[F:18]
Reactant: O=C1C=C(N(Cc2ccc(Cl)nc2)CC(F)F)CO1
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=C1OCC(N(Cc2ccc(Cl)nc2)CC(F)F)=C1Br
Reaction time: 3 h
Yield: 78.6 %

Procedure:
313 mg (1.08 mmol) of 4-[[(6-chloropyridin-3-yl)methyl](2,2-difluoroethyl)amino]furan-2(5H)-one (1) are dissolved in 20 ml of acetonitrile, and 166 μl (1.19 mmol) of triethylamine and 386 mg (2.17 mmol) of N-bromosuccinimide are added at room temperature. After 3 hours of stirring, the mixture is concentrated under reduced pressure. Purification of the residue by column chromatography on silica gel (silica gel 60—Merck, particle size: 0.04 to 0.063 mm) using the mobile phase mixture ethyl acetate:cyclohexane (2:1) gives 312 mg (63% of theory) of 3-bromo-4-[[(6-chloropyridin-3-yl)methyl](2,2-difluoroethyl)amino]furan-2(5H)-one.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:15]([NH:17][C@H:18]([C:27]([OH:29])=O)[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=1)=[O:16])[CH2:13][OH:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ON1C(=O)CCC1=O.Cl.[CH2:39]([O:41][C:42](=[O:45])[CH2:43][NH2:44])[CH3:40].C1(N=C=NC2CCCCC2)CCCCC1>C(N(CC)CC)C.CN(C)C=O>[CH2:39]([O:41][C:42](=[O:45])[CH2:43][NH:44][C:27](=[O:29])[C@H:18]([CH2:19][C:20]1[CH:21]=[CH:22][C:23]([OH:26])=[CH:24][CH:25]=1)[NH:17][C:15](=[O:16])[C@H:12]([CH2:13][OH:14])[NH:11][C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10])[CH3:40]
Reactant: CCOC(=O)CN
Reactant: O=C(N[C@@H](CO)C(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)O)OCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: O=C1CCC(=O)N1O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)CNC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@H](CO)NC(=O)OCc1ccccc1

Procedure:
To a stirred mixture consisting of 4.82 g. of N-benzyloxycarbonyl-L-seryl-L-tyrosine, 1.519 g. of N-hydroxysuccinimide, 1.675 g. of glycine ethyl ester hydrochloride, and 60 ml. of N,N-dimethylformamide, cooled to -15° C., is added first 1.68 ml. of triethylamine and then 2.48 g. of dicyclohexylcarbodiimide, and the resulting mixture is stirred at -15° C. for 2 hours and at room temperature for 25 hours. The mixture is then concentrated to remove solvent, and the residue is partitioned between dilute hydrochloric acid and ethyl acetate. The organic layer is separated, washed with saturated aqueous sodium chloride, with saturated aqueous sodium bicarbonate, and with saturated aqueous sodium chloride again, dried, and evaporated to give a solid residue of N-benzyloxycarbonyl-L-seryl-L-tyrosylglycine ethyl ester; m.p. 166°-169° C., following crystallization from ethyl acetate; [α]D25 -23.2° (2% in methanol).
Reaction SMILES: CS(O[CH:6]([CH2:10][CH3:11])[CH2:7][O:8][CH3:9])(=O)=O.[N-:12]=[N+:13]=[N-:14].[Na+]>CN(C=O)C>[CH3:9][O:8][CH2:7][CH:6]([N:12]=[N+:13]=[N-:14])[CH2:10][CH3:11]
Reactant: CCC(COC)OS(C)(=O)=O
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCC(COC)N=[N+]=[N-]
Temperature: 57.5 °C

Procedure:
A solution of crude mesylate 1 (90.0 g, 0.495 mol) in DMF (500 mL) was treated with NaN3 (48.22g, 0.74 mol, 1.5 equiv) at 25° C. under N2. The resulting reaction mixture was warmed to 55-60° C. for 6-8 h with stirring before being quenched with H2O (500 mL). The pale-yellow solution was then extracted with EtOAc or Et2O (4×200 mL). The combined EtOAc (or Et2O) extracts were washed with H2O (3×500 mL), dried (MgSO4), and concentrated in vacuo. The residual solution was found to contain desired azide 2 (60.3 g, 64.5 g theoretical, 94%), which was found to be pure enough and directly used in the following reaction without further purification.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH2:21](I)[CH3:22]>>[Cl:1][C:2]1[N:11]=[C:10]([N:12]([CH2:21][CH3:22])[C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: CCI
Reactant: COc1ccc(Nc2nc(Cl)nc3ccccc23)cc1
Product: CCN(c1ccc(OC)cc1)c1nc(Cl)nc2ccccc12

Procedure:
The title compound was prepared from (2-chloro-quinazolin-4-yl)-(4-methoxy-phenyl)-amine and ethyl iodide by a procedure similar to Example 36 (58% yield). 1H NMR (CDCl3): 7.69-7.72 (m, 1H), 7.53 (ddd, J=8.1, 6.9 and 1.5 Hz, 1H), 7.09-7.14 (m, 2H), 6.94-6.70 (m, 3H), 6.83-6.87 (m, 1H), 4.13 (q, J=7.2 Hz, 2H), 3.87 (s, 1H), 1.30 (t, J=6.9 Hz, 3H).
Reaction SMILES: C1(=O)[N:5]([CH2:6][CH2:7][S:8]([NH:11][C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[NH:17][C:16]([C:21]([N:23]2[CH2:28][CH2:27][CH:26]([N:29]([CH3:40])[C:30]4[C:35]([NH:36][CH:37]([CH3:39])[CH3:38])=[CH:34][CH:33]=[CH:32][N:31]=4)[CH2:25][CH2:24]2)=[O:22])=[CH:15]3)(=[O:10])=[O:9])C(=O)C2=CC=CC=C12.O.NN>C(O)C>[NH2:5][CH2:6][CH2:7][S:8]([NH:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[NH:17][C:16]([C:21]([N:23]1[CH2:28][CH2:27][CH:26]([N:29]([CH3:40])[C:30]3[C:35]([NH:36][CH:37]([CH3:38])[CH3:39])=[CH:34][CH:33]=[CH:32][N:31]=3)[CH2:25][CH2:24]1)=[O:22])=[CH:15]2)(=[O:9])=[O:10]
Reactant: CC(C)Nc1cccnc1N(C)C1CCN(C(=O)c2cc3cc(NS(=O)(=O)CCN4C(=O)c5ccccc5C4=O)ccc3[nH]2)CC1
Agent: NN
Solvent: CCO
Solvent: O
Product: CC(C)Nc1cccnc1N(C)C1CCN(C(=O)c2cc3cc(NS(=O)(=O)CCN)ccc3[nH]2)CC1
Reaction time: 0.17 h

Procedure:
To a solution of 1-[5-(2-phthalimidoethanesulfonamido)indole-2-carbonyl]-4-[N-methyl-N-(3-(1-methylethylamino)-2-pyridinyl)amino]piperidine (EXAMPLE 31, 675 mg) in 95% ethanol (10 ml) under nitrogen is added hydrazine monohydrate (53 μl). The mixture is stirred at 70°-75° for 20 hrs during which additional hydrazine monohydrate (10 μl) is added, concentrated to remove ethanol, diluted with water (10 ml), acidified to pH 2 with 1M hydrochloric acid and stirred for 10 min. The mixture is then filtered, the filtrate is adjusted to pH 10-11, and the resulting precipitate is isolated by filtration to give the title compound, NMR (CDCl3) 9.86, 7.70, 7.56, 7.29, 7.10, 6.94, 6.84, 6.68, 4.60, 4.50, 3.56, 3.44, 3.40-2.80, 2.62, 1.93, 1.65 and 1.22 δ. The basic filtrate is extracted with methylene chloride (2×15 ml) which is then washed with saline (10 ml), dried over sodium sulfate, and concentrated under reduced pressure to give an additional amount of the title compound.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[CH2:8][C:7](=[O:9])[NH:6][CH:5]2[CH2:10][CH2:11][CH2:12][CH2:13][CH:4]2[NH:3]1.[CH2:15]1[O:17][CH2:16]1>C(O)C.C1C=CC=CC=1>[OH:17][CH2:16][CH2:15][N:3]1[CH:4]2[CH2:13][CH2:12][CH2:11][CH2:10][CH:5]2[NH:6][C:7](=[O:9])[CH2:8][C:2]1([CH3:14])[CH3:1]
Reactant: CC1(C)CC(=O)NC2CCCCC2N1
Reactant: C1CO1
Solvent: c1ccccc1
Solvent: CCO
Product: CC1(C)CC(=O)NC2CCCCC2N1CCO

Procedure:
38.6 g 4,4-dimethyl-decahydro-1,5-benzodiazepin-2-one is placed in a 250 ml flask with a slight molar excess of ethylene oxide (about 13.2 g) dissolved in ethyl alcohol. The reaction is run in an autoclave at 170°-180° C. A viscous brown paste is obtained which is dissolved in benzene. Upon recrystallization from benzene a white solid is obtained having a melting pt. 154°-156° C.
Reaction SMILES: [Cl:1][C:2]1[C:10]([CH3:11])=[C:9]2[C:5]([C:6](=O)[C:7]([CH3:14])([CH3:13])[C:8]2=O)=[C:4]([CH3:16])[CH:3]=1.C1C=CC=CC=1>Cl.C(O)C>[Cl:1][C:2]1[C:10]([CH3:11])=[C:9]2[C:5]([CH2:6][C:7]([CH3:13])([CH3:14])[CH2:8]2)=[C:4]([CH3:16])[CH:3]=1
Reactant: Cc1cc(Cl)c(C)c2c1C(=O)C(C)(C)C2=O
Agent: Cl
Solvent: c1ccccc1
Solvent: CCO
Product: Cc1cc(Cl)c(C)c2c1CC(C)(C)C2
Temperature: 25 °C
Yield: 65 %

Procedure:
To a mixture of 100 g of 7% Zn/Hg in 200 ml of 20% hydrochloric acid and 70ml of ethanol was added 27.32 g of the 6-chloro-2,2,4,7-tetramethylindan-1,3-dione with stirring. After refluxing for 6 hours, the reaction mixture was added 100 ml of benzene and refluxed for 1 hour. The reaction mixture was cooled to room temperature and extracted with diethyl ether. The combined organic layer was dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure. The residue was purified by silica-gel column chromatography to afford 15.67 g of the title compound as yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:16]=[CH:15][C:6]([CH2:7][NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.CC(C)([O-])C.[K+].[Br:23][C:24]1[N:28]2[N:29]=[C:30]([Cl:34])[CH:31]=[C:32](Br)[C:27]2=[N:26][CH:25]=1>CN(C=O)C.C(OCC)(=O)C>[Br:23][C:24]1[N:28]2[N:29]=[C:30]([Cl:34])[CH:31]=[C:32]([N:8]([CH2:7][C:6]3[CH:15]=[CH:16][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:27]2=[N:26][CH:25]=1
Reactant: COc1ccc(CNc2ccccc2)cc1
Reactant: Clc1cc(Br)c2ncc(Br)n2n1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccc(CN(c2ccccc2)c2cc(Cl)nn3c(Br)cnc23)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 60.8 %

Procedure:
N-(4-Methoxybenzyl)aniline (215 mg, 1 mmol) was dissolved in dry DMF (4 mL), placed under a nitrogen atmosphere, and cooled to 0° C. in an ice bath. Potassium t-butoxide (1 mL, 1 mmol, 1M THF solution) was added and the mixture was allowed to stir for 10 min at 0° C. and room temperature for 30 min. The resulting mixture was cool to 0° C. Solid 3,8-dibromo-6-chloroimidazo[1,2-b]pyridazine (310 mg, 1 mmol) from Example XXIV, step 1a was added. The mixture was allowed to stir for 30 min at 0° C. and overnight at room temperature. The mixture was diluted with ethyl acetate (100 mL), washed sequentially with 10% LiCl, water and brine, and dried over anhydrous magnesium sulfate. The solvent was removed in vacuo and the resulting material was purified by silica gel chromatography (ethyl acetate/heptane, 25 min gradient: 5-50% ethyl acetate) to provide 0.27 g of 3-bromo-6-chloro-N-(4-methoxybenzyl)-N-phenylimidazo[1,2-b]pyridazin-8-amine.
Reaction SMILES: [ClH:1].Cl.[NH2:3][CH2:4][CH2:5][C:6]1[N:10]=[CH:9][NH:8][CH:7]=1.[OH-].[Na+].[CH:13](=O)[CH:14]([CH3:16])[CH3:15].Cl>O.CO>[ClH:1].[ClH:1].[CH:14]([CH:16]1[C:7]2[N:8]=[CH:9][NH:10][C:6]=2[CH2:5][CH2:4][NH:3]1)([CH3:15])[CH3:13]
Reactant: NCCc1c[nH]cn1
Reactant: CC(C)C=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)C1NCCc2[nH]cnc21

Procedure:
To a solution of 20 g of histamine dihydrochloride in 54 ml of water and 440 ml of methanol, 19.6 g of sodium hydroxide dissolved in 54 ml of water and 25 ml of isobutyraldehyde are added and the solution refluxed for 24 h. The solution is then acidified with 200 ml of conc. hydrochloric acid and evaporated in vacuo. The residue is taken up in methanol. The methanolic extract is evaporated in vacuo to give 23 g of 4-isopropyl-4,5,6,7-tetrahydro-imidazo-[4,5-c]-pyridine dihydrochloride, m.p. 238°, from which the free base, m.p. 112°, is obtained by ion-exchange on Amberlite (Trade Mark) IRA 410. A solution of 1.3 g of the base in 10 ml of dioxane is treated with 1.3 g of methyl isothiocyanate and refluxed for 4 h. The solution is cooled and filtered; 1.4 g of 4-isopropyl-5-(N-methyl-thiocarbamoyl)-4,5,6,7-tetrahydro-imidazo-[4,5-c]-pyridine, m.p. 240°, are collected.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][N:27]=1)[C:5]([NH:7][C:8]1[S:9][C:10]2[C:16]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[CH:15][CH:14]=[C:13]([O:23][CH3:24])[C:11]=2[N:12]=1)=[O:6].C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:34][NH:35][CH2:36][CH2:37][N:38]1[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]1>>[CH3:24][O:23][C:13]1[C:11]2[N:12]=[C:8]([NH:7][C:5](=[O:6])[C:4]3[CH:25]=[CH:26][N:27]=[C:2]([N:35]([CH3:34])[CH2:36][CH2:37][N:38]4[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]4)[CH:3]=3)[S:9][C:10]=2[C:16]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)=[CH:15][CH:14]=1
Reactant: COc1ccc(N2CCOCC2)c2sc(NC(=O)c3ccnc(Br)c3)nc12
Reactant: CNCCN1CCCCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: COc1ccc(N2CCOCC2)c2sc(NC(=O)c3ccnc(N(C)CCN4CCCCC4)c3)nc12

Procedure:
From 2-bromo-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-isonicotinamide with cesium carbonate and methyl-(2-piperidin-1-yl-ethyl)-amine. ES-MS m/e (%): 511 (M+H+, 100).
Reaction SMILES: [ClH:1].[N:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][Cl:9])[CH:3]=1.Cl.[C:11]1([C:17]2[CH2:18][CH2:19][N:20]([CH2:23][CH2:24][SH:25])[CH2:21][CH:22]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(N(CC)CC)C>CN(C)C=O>[ClH:9].[ClH:1].[C:11]1([C:17]2[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][S:25][CH2:8][C:4]3[CH:3]=[N:2][CH:7]=[CH:6][CH:5]=3)[CH2:19][CH:18]=2)[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: ClCc1cccnc1
Reactant: SCCN1CC=C(c2ccccc2)CC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C1=C(c2ccccc2)CCN(CCSCc2cccnc2)C1
Temperature: 80 °C
Yield: 29.1 %

Procedure:
A solution of 3-picolyl chloride hydrochloride (2.50 g) and 3,6-dihydro-4-phenyl-1(2H)-pyridineethanethiol hydrochloride (3.90 g) (Example A) in 100 mL of dimethylformamide is treated with triethylamine (7.4 ml) and the mixture is heated at 80° C. for 8 hours. The solvent is evaporated in vacuo, and the residue is partitioned into chloroform/sodium bicarbonate solution. The organic extract is dried over magnesium sulfate, filtered and concentrated. The crude product is purified by column chromatography (silica gel; 2% methanol in chloroform) to yield 1.7 g of the title compound as an oil, which is converted into its hydrochloride salt (hydrogen chloride gas in diethyl ether) and recrystallized from ethanol/acetonitrile; mp 218°-220° C. (dec).
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(C(C)C)C(C)C)C.[CH:42]([N:45]1[CH2:50][CH2:49][CH:48]([NH2:51])[CH2:47][CH2:46]1)([CH3:44])[CH3:43]>CN(C)C=O>[CH:1]1([N:6]2[CH2:12][C:11]([F:13])([F:14])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([NH:51][CH:48]5[CH2:49][CH2:50][N:45]([CH:42]([CH3:44])[CH3:43])[CH2:46][CH2:47]5)=[O:27])=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CC(C)N1CCC(N)CC1
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cc(C(=O)NC2CCN(C(C)C)CC2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Temperature: 25 °C
Reaction time: 1 h
Yield: 15.9 %

Procedure:
To a mixture of 0.050 g (0.11 mmole) of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-benzoic acid (I-22), 0.08 mL (0.44 mmole) of ethyldiisopropyl amine and 0.018 g (0.12 mmole) of 1-isopropyl-piperidin-4-ylamine in 1.5 mL of dimethylformamide was added 0.053 g (0.12 mmole) of 1-(di-1-pyrrolidinylmethylene)-1H-benzotriazolium 3-oxide hexafluorophosphate. The mixture was stirred at room temperature for 1 hour, then diluted with 10 mL of ice water. The resulting solid was collected by filtration, washed with saturated sodium carbonate and water, and dried under vacuum. Purification by silica gel chromatography, eluting with dichloromethane-methanol (gradient, 100:0-85:15) gave 0.010 g of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-N-(1-isopropyl-piperidin-4-yl)-3-methoxy-benzamide (I-64) as a white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8](O)=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].S(Cl)([Cl:15])=O>>[N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([Cl:15])=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Reactant: O=S(Cl)Cl
Product: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Yield: 95.2 %

Procedure:
A mixture of p-nitrobenzoic acid (500 g, 3.0 moles, 1 equiv) and thionyl chloride (600 mL, 8.2 moles, 2.73 equiv) was heated to reflux for 6-7 hours until a clear solution was obtained. Excess of thionyl chloride was removed by distillation followed by co-distillation with toluene (300 mL). The reaction mass was cooled to room temperature, and hexane (1.5 L) was added, forming a precipitate, which was then filtered and dried under vacuum, yielding 4-nitrobenzoyl chloride as a yellow solid (530 g, approximately 100% yield), which was used without any further purification.
Reaction SMILES: Cl.[CH3:2][CH:3]1[CH2:6][NH:5][CH2:4]1.Cl.Cl[C:9]1[N:14]=[CH:13][N:12]=[C:11]([N:15]2[C:19](=[O:20])[C:18]([N:21]3[CH:25]=[CH:24][N:23]=[CH:22]3)=[CH:17][NH:16]2)[CH:10]=1.C(N(C(C)C)C(C)C)C>O1CCCC1>[N:21]1([C:18]2[C:19](=[O:20])[N:15]([C:11]3[CH:10]=[C:9]([N:5]4[CH2:6][CH:3]([CH3:2])[CH2:4]4)[N:14]=[CH:13][N:12]=3)[NH:16][CH:17]=2)[CH:25]=[CH:24][N:23]=[CH:22]1
Reactant: O=c1c(-n2ccnc2)c[nH]n1-c1cc(Cl)ncn1
Reactant: CC1CNC1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC1CN(c2cc(-n3[nH]cc(-n4ccnc4)c3=O)ncn2)C1

Procedure:
43 mg (0.4 mmol) of 3-methylazetidine hydrochloride, 100 mg (0.3 mmol) of the compound from Example 13A and 174 μl (130 mg, 1.0 mmol) of N-ethyl-N-(propan-2-yl)propane-2-amine are suspended in 2 ml of tetrahydrofuran and reacted in a single mode microwave (Emrys Optimizer) at 120° C. for 4.5 h. The reaction mixture is concentrated under reduced pressure, taken up in water with addition of aqueous 1 N sodium hydroxide solution (pH=9-10) and purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient). Yield: 30 mg (30% of theory)
Reaction SMILES: Cl[C:2]([O:4][CH:5]([Cl:7])[CH3:6])=[O:3].[CH3:8][O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17][OH:18].N1C=CC=CC=1>C(Cl)Cl>[C:2](=[O:3])([O:18][CH2:17][CH2:16][O:15][CH2:14][CH2:13][O:12][CH2:11][CH2:10][O:9][CH3:8])[O:4][CH:5]([Cl:7])[CH3:6]
Reactant: CC(Cl)OC(=O)Cl
Reactant: COCCOCCOCCO
Solvent: ClCCl
Solvent: c1ccncc1
Product: COCCOCCOCCOC(=O)OC(C)Cl

Procedure:
In a manner similar to the method described in Example 3, 1-chloroethyl chloroformate was reacted with 2-(2-(2-methoxyethoxy)ethoxy)ethanol (TCI) and pyridine in methylene chloride at −78° C. for 3 h to give 1-chloroethyl 2-(2-(2-methoxyethoxy)ethoxy)ethyl carbonate. This was then reacted with chiral 4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoic acid in the presence of cesium carbonate in dimethylformamide overnight to give, after flash chromatography purification (hexane/ethyl acetate, 80/20 to 20/80), 4-{[(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-3-methoxy-benzoic acid 1-{2-[2-(2-methoxy-ethoxy)-ethoxy]-ethoxycarbonyloxy}-ethyl ester as a white solid. LCMS (ES+) m/z calcd. for C41H48Cl2F2N3O10 [(M+H)+]: 850, found: 850.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:14])=[C:6]([CH:13]=1)[C:7]([O:9][CH2:10][CH2:11][CH3:12])=[O:8].C(N(CC)CC)C.[C:22]1([CH3:31])[C:23]([C:28](Cl)=[O:29])=[CH:24][CH:25]=[CH:26][CH:27]=1>C(Cl)Cl>[Cl:14][C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:28](=[O:29])[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[CH3:31])=[CH:13][C:6]=1[C:7]([O:9][CH2:10][CH2:11][CH3:12])=[O:8]
Reactant: Cc1ccccc1C(=O)Cl
Reactant: CCCOC(=O)c1cc(N)ccc1Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCOC(=O)c1cc(NC(=O)c2ccccc2C)ccc1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 45 %

Procedure:
A solution of propyl 5-amino-2-chlorobenzoate (10.7 g, 0.050 mole) and triethylamine (6 g, 0.059 mole) in methylene chloride (50 ml) was added dropwise over 1 hour to an ice-cooled solution of o-toluoyl chloride (7.8 g, 0.50 mole) in methylene chloride (50 ml). The mixture was then stirred at room temperature for 3 hours and worked up by washing sequentially with water, dilute hydrochloric acid, water, 2% aqueous sodium hydroxide and water. The residue from evaporation of the methylene chloride was recrystallized from ethanol (100 ml) to give the title compound, m.p. 103°-105° C. (7.5 g, 45% yield).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[N:11][CH:12]=[C:13](Br)[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li]C(C)(C)C.Cl([O-])(=O)(=O)=O.[CH2:26]1[C:33]2[CH2:32][CH2:31][CH2:30][N+:29]=2[CH2:28][CH2:27]1>CCOCC.CCCCC>[CH2:1]([O:8][C:9]1[CH:10]=[N:11][CH:12]=[C:13]([C:33]23[CH2:32][CH2:31][CH2:30][N:29]2[CH2:28][CH2:27][CH2:26]3)[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1CC2=[N+](C1)CCC2
Reactant: Brc1cncc(OCc2ccccc2)c1
Agent: [Li]C(C)(C)C
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: CCCCC
Solvent: CCOCC
Product: c1ccc(COc2cncc(C34CCCN3CCC4)c2)cc1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 21.7 %

Procedure:
3-Benzyloxy-5-bromopyridine (1.18 g, 4.47 mmol) was dissolved in Et2O and cooled to -78° C. A solution of 2.5M t-BuLi (5.8 mL, 9.83 mmol) in pentane was added, and the reaction was stirred for 10 minutes. 1,2,3,5,6,7-hexahydropyrrolizinium perchlorate (1.4 g, 6.70 mmol) was added, and the reaction mixture was allowed to stir for 3 hours at -78° C. then allowed to warm to -20° C. and stir for 2 hours. The cold bath was removed, 2N HCl was added, and the mixture was extracted with Et2O. The phases were separated, and the aqueous phase was basified with 15% NaOH and extracted with CH2Cl2 (2×). The CH2Cl2 fractions were combined, dried (MgSO4) and concentrated, and the residue was chromatographed (silica gel; CHCl3 /MeOH, 98:2) to afford a clear oil (286 mg, 22%): mp 45°-49° C. 1H NMR (CDCl3, 300 MHz) δ1.58-1.69 (m, 2H), 1.78-1.83 (m, 2H), 1.89-2.03 (m, 4H), 2.63-2.72 (m, 2H), 3.05-3.18 (m, 2H), 5.12 (s, 2H), 7.31-7.54 (m, 6H), 8.17 (d, J=3.0 Hz, 1H), 8.29 (d, J=1.7 Hz, 1H); MS (CI/NH3) m/z: 295 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:11]([CH3:19])([CH3:18])[O:12][SiH2:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH2:10][CH2:9][NH:8][CH2:7]1)=[O:5])[CH3:2].C(N(CC)CC)C.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:34][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36]>C(#N)C>[CH2:1]([O:3][C:4]([C:6]1([C:11]([CH3:18])([CH3:19])[O:12][SiH2:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH2:10][CH2:9][N:8]([CH2:34][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:7]1)=[O:5])[CH3:2]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: CCOC(=O)C1(C(C)(C)O[SiH2]C(C)(C)C)CCNC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCOC(=O)C1(C(C)(C)O[SiH2]C(C)(C)C)CCN(CC(=O)OC(C)(C)C)C1
Reaction time: 1 h
Yield: 93.8 %

Procedure:
To a stirred mixture of 3-(tert-butyl-dimethyl-silanyloxymethyl)-pyrrolidine-3-carboxylic acid ethyl ester (444 mg, 1.54 mmol), triethylamine (214 μl, 1.54 mmol) and cesium carbonate (251 mg, 0.77 mmol) in acetonitrile (5 ml) was added tert-butyl bromoacetate (351 μl, 2.38 mmol) slowly. The mixture was stirred for 1 hour, filtered and concentrated. The residue was diluted with ethyl acetate, washed with water and dried over MgSO4. Solvent was removed under reduced pressure to give a crude product that was purified by column chromatography on silica gel. Elution with a solution of ethyl acetate in hexanes (1:4) provided 580 mg (94%) of the title compound.
Reaction SMILES: [CH3:1][N:2]([CH3:31])[C:3]1[N:8]=[C:7]([O:9][CH3:10])[C:6]([C:11]2[C:24]3[C:19](=[CH:20][C:21]([O:27][CH2:28][CH3:29])=[C:22]([O:25][CH3:26])[CH:23]=3)[C@@H:18]3[C@@H:13]([CH2:14][CH2:15][C@@H:16]([OH:30])[CH2:17]3)[N:12]=2)=[CH:5][N:4]=1.[O:32]=[C:33]([CH2:37][CH2:38][C:39]([OH:41])=[O:40])[C:34](O)=[O:35]>CC(C)=O>[O:32]=[C:33]([CH2:37][CH2:38][C:39]([OH:41])=[O:40])[C:34]([O:30][C@@H:16]1[CH2:15][CH2:14][C@@H:13]2[C@@H:18]([C:19]3[C:24]([C:11]([C:6]4[C:7]([O:9][CH3:10])=[N:8][C:3]([N:2]([CH3:1])[CH3:31])=[N:4][CH:5]=4)=[N:12]2)=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH2:28][CH3:29])[CH:20]=3)[CH2:17]1)=[O:35]
Reactant: CCOc1cc2c(cc1OC)C(c1cnc(N(C)C)nc1OC)=N[C@@H]1CC[C@@H](O)C[C@H]21
Reactant: O=C(O)CCC(=O)C(=O)O
Solvent: CC(C)=O
Product: CCOc1cc2c(cc1OC)C(c1cnc(N(C)C)nc1OC)=N[C@@H]1CC[C@@H](OC(=O)C(=O)CCC(=O)O)C[C@H]21
Yield: 71 %

Procedure:
(2R,4aR,10bR)-6-(2-Dimethylamino-4-methoxy-pyrimidin-5-yl)-9-ethoxy-8-methoxy-1,2,3,4,4a,10b-hexahydro-phenanthridin-2-ol ((42.7 mg, 0.1 mmol) are dissolved in 0.5 ml of acetone. 16.1 mg (0.11 mmol) of 2-oxo-pentanedioic acid (dissolved in 0.5 ml of acetone) are added. The crystals are filtered off and dried to obtain 40.6 mg (71%) of the title compound (m.p.: 124° C.).