Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.C[O:3][C:4]1[C:16]2[CH2:15][CH2:14][C@H:13]3[C@H:9]([CH2:10][CH2:11][N:12]3[CH2:17][CH2:18][CH2:19][CH2:20][N:21]3[C:26](=[O:27])[CH2:25][C:24]([CH3:29])([CH3:28])[CH2:23][C:22]3=[O:30])[C:8]=2[CH:7]=[CH:6][CH:5]=1.Cl.N1C=CC=CC=1.[OH-].[NH4+]>C(Cl)Cl.C(OCC)(=O)C>[OH:3][C:4]1[C:16]2[CH2:15][CH2:14][C@H:13]3[C@H:9]([CH2:10][CH2:11][N:12]3[CH2:17][CH2:18][CH2:19][CH2:20][N:21]3[C:22](=[O:30])[CH2:23][C:24]([CH3:28])([CH3:29])[CH2:25][C:26]3=[O:27])[C:8]=2[CH:7]=[CH:6][CH:5]=1
Reactant: COc1cccc2c1CC[C@H]1[C@@H]2CCN1CCCCN1C(=O)CC(C)(C)CC1=O
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CC1(C)CC(=O)N(CCCCN2CC[C@@H]3c4cccc(O)c4CC[C@@H]32)C(=O)C1
Temperature: 0 °C
Reaction time: 4 h
Yield: 64.7 %

Procedure:
8.8 g (22.1 mmol) of rac-cis-1-[4-(6-methoxy-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]indol-3-yl)-butyl]-4,4-dimethyl-piperidine-2,6-dione hydrochloride were mixed well with 100 g of pyridine hydrochloride and stirred under an argon atmosphere in an oil bath for 4 hours at an oil bath temperature of 180°. After cooling the mixture was treated with ice-water, whereupon the brown solution was made alkaline with ammonium hydroxide solution and then extracted with methylene chloride. The organic phase was washed with water, dried over magnesium sulphate and evaporated. The brown oily product obtained (9.8 g) was chromatographed on a 30-fold amount of silica gel. The uniform eluates obtained in a thinlayer chromatogram using methylene chloride/ethyl acetate 1:1 were pooled and evaporated. The oil obtained crystallized after treatment with hexane. There were obtained 5.5 g (65%) of rac-cis-1-[4-(6-hydroxy-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]indol-3-yl)-butyl]-4,4-dimethyl-piperidine-2,6-dione in the form of yellowish crystals of m.p. 131°-132°.
Reaction SMILES: Cl[C:2]1[N:23]=[C:5]2[C:6]([NH:10][C:11]3[C:12]([N:17]([CH3:22])[S:18]([CH3:21])(=[O:20])=[O:19])=[N:13][CH:14]=[CH:15][CH:16]=3)=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.[CH3:24][N:25]1[CH2:30][CH2:29][N:28]([C:31]2[CH:32]=[C:33]([CH:35]=[CH:36][CH:37]=2)[NH2:34])[CH2:27][CH2:26]1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)CCCCC1>>[CH3:22][N:17]([C:12]1[C:11]([NH:10][C:6]2[C:5]3[N:4]([N:3]=[C:2]([NH:34][C:33]4[CH:35]=[CH:36][CH:37]=[C:31]([N:28]5[CH2:27][CH2:26][N:25]([CH3:24])[CH2:30][CH2:29]5)[CH:32]=4)[N:23]=3)[CH:9]=[CH:8][CH:7]=2)=[CH:16][CH:15]=[CH:14][N:13]=1)[S:18]([CH3:21])(=[O:20])=[O:19]
Reactant: CN(c1ncccc1Nc1cccn2nc(Cl)nc12)S(C)(=O)=O
Reactant: CN1CCN(c2cccc(N)c2)CC1
Agent: c1ccc(P(C2CCCCC2)C2CCCCC2)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c1
Product: CN1CCN(c2cccc(Nc3nc4c(Nc5cccnc5N(C)S(C)(=O)=O)cccn4n3)c2)CC1

Procedure:
N-(3-Amino-pyridin-2-yl)-N-methyl-methanesulfonamide was prepared from N-methyl-N-(3-nitro-pyridin-2-yl)-methanesulfonamide (6.20 g, 26.8 mmol)(prepared as described in J. Med. Chem., 2007, 50, 3431) via hydrogenation using a Paar apparatus with 10% Palladium on Carbon (50% Wet)(5:45:50, Palladium:carbon black:Water, 5.71 g, 2.68 mmol) and Hydrogen (50 psi) in 2:1 ethyl acetate:methanol (150 mL). The mixture was shaken on a Paar apparatus until adsorption of hydrogen ceased. The mixture was degassed, backflushed with nitrogen, filtered through a plug of diatomaceous earth and rinsed with dichloromethane. The filtrate was evaporated under reduced pressure. Product isolated as brown solid (5.15 g, 95%). 1H NMR (400 MHz, CDCl3, δ, ppm): 7.85 (dd, J=3.7, 2.5 Hz, 1H), 7.10-7.08 (m, 2H), 4.24 (br s, 2H), 3.23 (s, 3H), 3.08 (s, 3H). MS=202 (MH)+. 111b) N-[3-(2-Chloro-[1,2,4]triazolo[1,5-a]pyridin-8-ylamino)-pyridin-2-yl]-N-methyl-methanesulfonamide was prepared from N-(3-amino-pyridin-2-yl)-N-methyl-methanesulfonamide (238.0 mg, 1.183 mmol) and 8-bromo-2-chloro-[1,2,4]triazolo[1,5-a]pyridine (250.0 mg, 1.075 mmol) in a manner analogous to Example 2d. Product isolated as a pale yellow foam (0.185 g, 48%). 1H NMR (400 MHz, CDCl3, δ, ppm): 8.18-8.15 (m, 1H), 8.11 (d, J=6.8 Hz, 1H), 7.81 (d, J=8.0 Hz, 1H), 7.50 (s, 1H), 7.32-7.25 (m, 1H), 7.17 (d, J=7.5 Hz, 1H), 6.93 (t, J=7.3 Hz, 1H), 3.31 (s, 3H), 3.07 (s, 3H). MS=353, 355 (MH)+. 111c) N-Methyl-N-(3-{2-[3-(4-methyl-piperazin-1-yl)-phenylamino]-[1,2,4]triazolo[1,5-a]pyridin-8-ylamino}-pyridin-2-yl)-methanesulfonamide was prepared from N-[3-(2-chloro-[1,2,4]triazolo[1,5-a]pyridin-8-ylamino)-pyridin-2-yl]-N-methyl-methanesulfonamide (75.0 mg, 0.212 mmol) and 3-(4-methylpiperazin-1-yl)aniline (45.0 mg, 0.235 mmol) with 2,2′-bis-dicyclohexylphosphanyl-biphenyl (23.0 mg, 0.0421 mmol) as the ligand in a manner analogous to Example 2d. Product isolated as a brown foam (0.017 g, 16%). 1H NMR (400 MHz, CDCl3, δ, ppm): 8.11-8.06 (m, 2H), 7.78 (d, J=7.5 Hz, 1H), 7.52 (s, 1H), 7.28-7.19 (m, 3H), 7.12 (d, J=7.5 Hz, 1H), 7.06 (d, J=7.9 Hz, 1H), 6.84 (s, 1H), 6.78-6.73 (m, 1H), 6.57 (d, J=8.0 Hz, 1H), 3.32 (s, 3H), 3.29-3.24 (m, 4H), 3.09 (s, 3H), 2.62-2.57 (m, 4H), 2.36 (s, 3H). MS=518 (MH)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][NH:10][C:11]([C:13]1[C:14](=[O:31])[C:15]([OH:30])=[C:16]2[C:27](=[O:28])[N:20]3[C@@H:21]([CH3:26])[CH2:22][CH2:23][N:24]([CH3:25])[C@@H:19]3[CH2:18][N:17]2[CH:29]=1)=[O:12].N[C@@H:33]([CH3:38])[CH2:34][CH2:35]NC.[C:39]([OH:42])(=O)[CH3:40].[Cl:43][CH2:44]Cl>>[ClH:43].[ClH:43].[NH2:20][C@@H:21]([CH3:26])[CH2:22][CH2:23][NH:24][CH3:19].[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][NH:10][C:11]([C:13]1[C:14](=[O:31])[C:15]([OH:30])=[C:16]2[C:27](=[O:28])[N:20]3[C@@H:21]([CH3:26])[CH2:22][CH2:23][N:24]([CH3:25])[C@@H:19]3[CH2:18][N:17]2[CH:29]=1)=[O:12].[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][NH:10][C:11]([C:13]1[C:14](=[O:31])[C:15]([O:42][CH2:39][C:40]2[CH:44]=[CH:35][CH:34]=[CH:33][CH:38]=2)=[C:16]2[C:27](=[O:28])[N:20]3[C@@H:21]([CH3:26])[CH2:22][CH2:23][N:24]([CH3:25])[C@@H:19]3[CH2:18][N:17]2[CH:29]=1)=[O:12]
Reactant: CC(=O)O
Reactant: ClCCl
Agent: CNCC[C@H](C)N
Agent: C[C@H]1CCN(C)[C@@H]2Cn3cc(C(=O)NCc4ccc(F)cc4F)c(=O)c(O)c3C(=O)N12
Product: C[C@H]1CCN(C)[C@@H]2Cn3cc(C(=O)NCc4ccc(F)cc4F)c(=O)c(OCc4ccccc4)c3C(=O)N12
Product: Cl
Yield: 89 %

Procedure:
[(3S)-3-Aminobutyl]methylamine dihydrochloride was prepared in a similar manner as described in example Z-47. 1H NMR (400 MHz, CDCl3) δ 1.18 (d, J=6.8 Hz, 3H), 1.82-1.91 (m, 1H), 1.94-2.03 (m, 1H), 2.53 (s, 3H), 2.89-2.93 (m, 2H), 3.22-3.30 (m, 1H), 8.02 (br, <1H), 8.81 (br, <1H). b) (4S,12aS)—N-[(2,4-Difluorophenyl)methyl]-7-hydroxy-1,4-dimethyl-6,8-dioxo-1,2,3,4,6,8,12,12a-octahydropyrido[1′,2′:4,5]pyrazino[1,2-a]pyrimidine-9-carboxamide. The title compound was made in two steps using a similar process to that described in example Z-2, 16a (4.0 mg, 0.085 mmol) and free based [(3S)-3-aminobutyl]methylamine (24 mg, 0.23 mmol) were reacted in dichloromethane (2 mL) with acetic acid to give (4S,12aS)—N-[(2,4-difluorophenyl)methyl]-1,4-dimethyl-6,8-dioxo-7-[(phenylmethyl)oxy]-1,2,3,4,6,8,12,12a-octahydropyrido[1′,2′:4,5]pyrazino[1,2-a]pyrimidine-9-carboxamide (39 mg, 89%) as a film. This material was hydrogenated in a second step as described in example 22 to give (4S,12aS)—N-[(2,4-difluorophenyl)methyl]-7-hydroxy-1,4-dimethyl-6,8-dioxo-1,2,3,4,6,8,12,12a-octahydropyrido[1′,2′:4,5]pyrazino[1,2-a]pyrimidine-9-carboxamide (32 mg, 97%) as an off-white solid. 1H NMR (400 MHz, CDCl3) δ 1.33 (d, J=6.4 Hz, 3H), 1.46-1.50 (m, 1H), 2.12-2.14 (m, 1H), 2.32 (s, 3H), 2.83 (m, 2H), 4.24 (m, 3H), 4.62 (m, 2H), 5.02 (m, 1H), 6.77-6.79 (m, 2H), 7.33 (m, 1H), 8.30 (s, 1H), 10.43 (s, 1H), 12.50 (br, 1H); ES+ MS: 4.33 (M+1),
Reaction SMILES: [OH-].[Na+].[SH:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.Cl.Cl[CH2:15][C:16]1[CH:21]=[C:20]([N:22]([CH3:24])[CH3:23])[CH:19]=[CH:18][N:17]=1>C(O)C.O>[CH3:23][N:22]([CH3:24])[C:20]1[CH:19]=[CH:18][N:17]=[C:16]([CH2:15][S:3][C:4]2[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[NH:6][CH:5]=2)[CH:21]=1
Reactant: Sc1c[nH]c2ccccc12
Reactant: CN(C)c1ccnc(CCl)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CN(C)c1ccnc(CSc2c[nH]c3ccccc23)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 47 %

Procedure:
To a solution of S-(3-indolyl)isothioronium iodide (180 mg, 0.75 mmol) of the formula ##STR37## in ethanol (5 ml) was added a 2N aqueous sodium hydroxide solution (0.86 ml) under ice-cooling, and the mixture obtained was stirred at room temperature for 1 hour. The resultant reaction solution containing 3-mercapto-indole so formed was then admixed with 2-chloromethyl-4-dimethylaminopyridine hydrochloride (118 mg, 0.75 mmol), followed by stirring the mixture at room temperature for 1 hour. The resulting reaction was made strongly alkaline with a 2N aqueous sodium hydroxide solution (1.0 ml) and then diluted with water (20 ml) to precipitate crystals, affording the titled compound (130 mg) after filtration.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2([C:19]3[CH:24]=[CH:23][N:22]=[C:21]([O:25][CH3:26])[CH:20]=3)[C:16]3[C:11](=[C:12]([F:17])[CH:13]=[CH:14][CH:15]=3)[C:10]([NH2:18])=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[C:27]([C:29]1[CH:30]=[N:31][CH:32]=[C:33](B2OC(C)(C)C(C)(C)[O:36]2)[CH:34]=1)#[N:28]>>[C:21]([OH:25])(=[O:36])[CH3:20].[NH2:18][C:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][C:12]=2[F:17])[C:8]([C:4]2[CH:3]=[C:2]([C:33]3[CH:32]=[N:31][CH:30]=[C:29]([CH:34]=3)[C:27]#[N:28])[CH:7]=[CH:6][CH:5]=2)([C:19]2[CH:24]=[CH:23][N:22]=[C:21]([O:25][CH3:26])[CH:20]=2)[N:9]=1
Reactant: COc1cc(C2(c3cccc(Br)c3)N=C(N)c3c(F)cccc32)ccn1
Reactant: CC1(C)OB(c2cncc(C#N)c2)OC1(C)C
Product: CC(=O)O
Product: COc1cc(C2(c3cccc(-c4cncc(C#N)c4)c3)N=C(N)c3c(F)cccc32)ccn1
Yield: 52 %

Procedure:
The title compound was synthesized as described for example 27 in 52% yield, starting from 1-(3-bromophenyl)-4-fluoro-1-(2-methoxypyridin-4-yl)-1H-isoindol-3-amine (100 mg, 0.24 mmol) and 3-cyanopyridine-5-boronic acid pinacol ester (58.6 mg, 0.25 mmol). 1H NMR (400 MHz, DMSO-d6) δ ppm 9.06 (d, 1 H) 9.00 (d, 1 H) 8.56 (s, 1 H) 8.04 (d, 1 H) 7.79 (d, 1 H) 7.63-7.73 (m, 2 H) 7.51-7.60 (m, 1 H) 7.41-7.51 (m, 2 H) 7.28 (t, 1 H) 6.90 (d, 1 H) 6.64 (s, 1 H) 3.78 (s, 3 H) 1.89 (s, 3 H); MS (ES+) m/z 436 [M+H]+.
Reaction SMILES: [OH:1][CH2:2][C:3]([CH3:23])([CH3:22])[CH2:4][NH:5][C:6]1[C:19]2[C:18](=[O:20])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11](=[O:21])[C:10]=2[CH:9]=[CH:8][CH:7]=1.[Br:24]Br.CO.O>N1C=CC=CC=1>[Br:24][C:9]1[C:10]2[C:11](=[O:21])[C:12]3[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:18](=[O:20])[C:19]=2[C:6]([NH:5][CH2:4][C:3]([CH3:23])([CH3:22])[CH2:2][OH:1])=[CH:7][CH:8]=1
Reactant: CC(C)(CO)CNc1cccc2c1C(=O)c1ccccc1C2=O
Reactant: BrBr
Solvent: O
Solvent: c1ccncc1
Solvent: CO
Product: CC(C)(CO)CNc1ccc(Br)c2c1C(=O)c1ccccc1C2=O
Temperature: 92.5 °C
Reaction time: 2 h
Yield: 93.2 %

Procedure:
To a solution of 1-[(3-hydroxy-2,2-dimethylpropyl)amino]anthraquinone (88.0 g, 0.28 mol) in pyridine (400 mL) is added bromine (48.0 g, 0.30 mol) with vigorous agitation, allowing the temperature to rise to about 40° C. The reaction is completed by heating at 90 to 95° C. for 6 hours and then allowed to cool. Methanol (200 mL) is added, stirring continued for about 2 hours at room temperature and the product is then drowned into water with thorough stirring. The solids are collected by filtration, washed with water and dried in air to give 101.3 g of 4-bromo-l-[(3-hydroxy-2,2-dimethyl-propyl) amino]anthraquinone. The identity of the product is confirmed by mass spectrometry analysis.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:11]2[CH:19]=[CH:18][C:14]([C:15](Cl)=[O:16])=[CH:13][CH:12]=2)=[O:10])=[CH:5][CH:4]=1.[CH3:22][C@H:23]1[CH2:28][N:27]([CH2:29][C:30]2[CH:35]=[CH:34][C:33]([NH:36][CH3:37])=[CH:32][CH:31]=2)[CH2:26][CH2:25][N:24]1[C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39].C(N(CC)CC)C>C(Cl)Cl.O>[CH3:22][C@H:23]1[CH2:28][N:27]([CH2:29][C:30]2[CH:35]=[CH:34][C:33]([N:36]([CH3:37])[C:15]([C:14]3[CH:18]=[CH:19][C:11]([C:9]([C:6]4[CH:7]=[CH:8][C:3]([C:2]([F:21])([F:20])[F:1])=[CH:4][CH:5]=4)=[O:10])=[CH:12][CH:13]=3)=[O:16])=[CH:32][CH:31]=2)[CH2:26][CH2:25][N:24]1[C:38]([O:40][C:41]([CH3:42])([CH3:44])[CH3:43])=[O:39]
Reactant: CNc1ccc(CN2CCN(C(=O)OC(C)(C)C)[C@@H](C)C2)cc1
Reactant: O=C(Cl)c1ccc(C(=O)c2ccc(C(F)(F)F)cc2)cc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@H]1CN(Cc2ccc(N(C)C(=O)c3ccc(C(=O)c4ccc(C(F)(F)F)cc4)cc3)cc2)CCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The acid chloride from step 1 was taken up in DCM (2 mL) and added drop-wise to a mixture of 1,1-dimethylethyl (2S)-2-methyl-4-{[4-(methylamino)phenyl]methyl}-1-piperazinecarboxylate (D3) (0.170 g, 0.53 mmol) and triethylamine (0.11 mL) in DCM (2 mL). The reaction mixture was stirred at room temperature under argon overnight then diluted with water (20 mL) and DCM (20 mL). The aqueous layer was extracted with DCM (20 mL) and the combined organic layers were dried, concentrated and purified by column chromatography. Elution with 0-30% EtOAc/pentane gave the title compound as a colourless oil (0.244 g). MS (ES): MH+ 596.2.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](B2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:6][C:7]=1[C:8]([F:11])([F:10])[F:9].Br[C:22]1[O:26][N:25]=[C:24]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[C:23]=1[CH3:32].C(=O)([O-])[O-].[K+].[K+]>COCCOC.O.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:1][C:2]1[CH:3]=[C:4]([C:22]2[O:26][N:25]=[C:24]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[C:23]=2[CH3:32])[CH:5]=[CH:6][C:7]=1[C:8]([F:9])([F:10])[F:11]
Reactant: CCOC(=O)c1noc(Br)c1C
Reactant: CC1(C)OB(c2ccc(C(F)(F)F)c(F)c2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Solvent: O
Product: CCOC(=O)c1noc(-c2ccc(C(F)(F)F)c(F)c2)c1C
Temperature: 100 °C
Yield: 51.2 %

Procedure:
Tetrakis(triphenylphosphine)palladium(0) (139 mg, 0.121 mmol) was added to a suspension of 2-(3-fluoro-4-(trifluoromethyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (350 mg, 1.21 mmol), ethyl 5-bromo-4-methylisoxazole-3-carboxylate (282 mg, 1.21 mmol) and potassium carbonate (334 mg, 2.413 mmol) in DME and water mix. The reaction mixture was sealed in a microwave vial and heated at 100° C. for 2 hours, after which time, the reaction was allowed to cool. The reaction mixture was then diluted with ethyl acetate and washed with water. The aqueous layer was then extracted with ethyl acetate, the organics combined, washed with brine and dried over magnesium sulfate, filtered and concentrated in vacuo. the resulting residue was purified by silica gel chromatography, eluting with heptane to 40% ethylacetate in heptane, to afford ethyl 5-(3-fluoro-4-(trifluoromethyl)phenyl)-4-methylisoxazole-3-carboxylate (196 mg, 0.62 mmol).
Reaction SMILES: [C:1]([O:4][C:5]1[CH:15]=[CH:14][C:8]([CH:9]=[CH:10][C:11]([OH:13])=O)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[CH3:16][NH:17][CH2:18][C:19]1[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=1.C(P(C#N)(CC)=O)C.C(N(CC)CC)C>CN(C)C=O.O>[C:1]([O:4][C:5]1[CH:6]=[CH:7][C:8](/[CH:9]=[CH:10]/[C:11](=[O:13])[N:17]([CH3:16])[CH2:18][C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)=[CH:14][CH:15]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1ccc(C=CC(=O)O)cc1
Reactant: CNCc1cccnc1
Agent: CCP(=O)(C#N)CC
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(=O)Oc1ccc(/C=C/C(=O)N(C)Cc2cccnc2)cc1
Yield: 96.8 %

Procedure:
1.03 g of 4-acetoxycinnamic acid and 0.61 g of 3-(methylaminomethyl)pyridine were dissolved in 5 ml dimethylformamide, and then stirred with 0.90 ml diethylphosphoryl cyanide and subsequently with 0.75 ml triethylamine on ice for 2 hours. After addition of water, the reaction mixture was extracted with ethyl acetate, washed with brine, and then dried over magnesium sulfate. The solvent was evaporated under reduced pressure to give a residue, which was then purified via column chromatography on silica gel (dichloromethane:methanol=30:1) to provide 4[(E)-2-[N-methyl-N-(3-pyridylmethyl)carbamoyl]ethenyl]phenyl acetate (1.50 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:12][CH3:13])=[C:6]([CH2:8][CH2:9][CH2:10]O)[CH:7]=1.S(Cl)([Cl:16])=O>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:12][CH3:13])=[C:6]([CH2:8][CH2:9][CH2:10][Cl:16])[CH:7]=1
Reactant: COc1ccc(Cl)cc1CCCO
Reactant: O=S(Cl)Cl
Product: COc1ccc(Cl)cc1CCCCl

Procedure:
58.2 g of 3-(5-chloro-2-methoxyphenyl)propan-1-ol and 50 ml of thionyl chloride are stirred at 50° for 8 hours; the excess thionyl chloride is distilled off in vacuo and the residue is distilled under a high vacuum. 50.9 g of 3-(5-chloro-2-methoxyphenyl)propyl chloride of b.p. 87° to 95° under 0.005 mm Hg are obtained.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[C:10]([O-])([O-])=O.[K+].[K+].[CH3:16][N:17]([CH:19]=O)[CH3:18]>O>[CH3:16][N:17]([CH2:19][CH2:10][O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1)[CH3:18]
Reactant: CN(C)C=O
Reactant: O=C([O-])[O-]
Reactant: O=Cc1ccc(O)cc1
Agent: [K+]
Solvent: O
Product: CN(C)CCOc1ccc(C=O)cc1
Yield: 49 %

Procedure:
To a solution of 4-hydroxybenzaldehyde (500 mg, 4 mmol) and K2CO3 (662 mg, 4.8 mmol) in anhydrous DMF, N,N-dimethyl-2-metilsulphonilethylamine (775 mg, 4.4 mmol) was added. The reaction mixture was heated to reflux, under magnetic stirring, for 4 hours, then poured in water to obtain a suspension from which the solid was isolated by filtration. The crude product was purified by chromatography on silica gel (ethyl acetate), to give 379 mg of pure product of the title (yield 49%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:12][C:11]([CH3:14])([CH3:13])[C@H:10]([OH:15])[CH2:9]2)[C:5]([F:16])=[C:4]([NH:17][NH2:18])[N:3]=1.[CH:19]1([CH2:24][C@H:25]([CH2:29][N:30]([CH:38]=[O:39])[O:31][CH:32]2[CH2:37][CH2:36][CH2:35][CH2:34][O:33]2)[C:26](O)=[O:27])[CH2:23][CH2:22][CH2:21][CH2:20]1.CN1CCOCC1.ON1C2N=CC=CC=2N=N1.C(Cl)CCl>CN(C=O)C>[Cl:1][C:2]1[N:3]=[C:4]([NH:17][NH:18][C:26](=[O:27])[C@H:25]([CH2:24][CH:19]2[CH2:20][CH2:21][CH2:22][CH2:23]2)[CH2:29][N:30]([O:31][CH:32]2[CH2:37][CH2:36][CH2:35][CH2:34][O:33]2)[CH:38]=[O:39])[C:5]([F:16])=[C:6]([N:8]2[CH2:9][C@@H:10]([OH:15])[C:11]([CH3:14])([CH3:13])[CH2:12]2)[N:7]=1
Reactant: CC1(C)CN(c2nc(Cl)nc(NN)c2F)C[C@H]1O
Reactant: O=CN(C[C@@H](CC1CCCC1)C(=O)O)OC1CCCCO1
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Solvent: ClCCCl
Product: CC1(C)CN(c2nc(Cl)nc(NNC(=O)[C@H](CC3CCCC3)CN(C=O)OC3CCCCO3)c2F)C[C@H]1O
Reaction time: 8 h
Yield: 58.8 %

Procedure:
To a solution of (3S)-1-(2-chloro-5-fluoro-6-hydrazino-4-pyrimidinyl)-4,4-dimethyl-3-pyrrolidinol (0.131 g, 0.475 mmol) in DMF (3 mL) was added added (2R)-3-cyclopentyl-2-{[formyl(tetrahydro-2H-pyran-2-yloxy)amino]methyl}propanoic acid (0.1181 g, 0.395 mmol), N-methylmorpholine (0.220 ml, 2.001 mmol), 1-hydroxy-7-azabenzotriazole (64 mg, 0.470 mmol), and EDC (91 mg, 0.475 mmol). The solution was stirred overnight and then purified directly by Gilson RPLC to afford [(2R)-3-(2-{2-chloro-5-fluoro-6-[(4S)-4-hydroxy-3,3-dimethyl-1-pyrrolidinyl]-4-pyrimidinyl}hydrazino)-2-(cyclopentylmethyl)-3-oxopropyl](tetrahydro-2H-pyran-2-yloxy)formamide (0.1294 g, 59% yield) as an orange oil. LCMS: (M+H)+: 557.3.
Reaction SMILES: [CH2:1]([Cl:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:9]12[CH2:16][CH2:15][CH:12]([CH2:13][CH2:14]1)[C:11](=[O:17])[CH2:10]2>C(#N)C>[Cl-:8].[CH2:1]([N+:9]12[CH2:16][CH2:15][CH:12]([CH2:13][CH2:14]1)[C:11](=[O:17])[CH2:10]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CN2CCC1CC2
Reactant: ClCc1ccccc1
Solvent: CC#N
Product: O=C1C[N+]2(Cc3ccccc3)CCC1CC2
Product: [Cl-]
Yield: 92.8 %

Procedure:
62.3 g (492 mmol) of benzyl chloride was added dropwise over 30 minutes to 61.6 g (492 mmol) of 3-quinuclidinone in 250 ml of acetonitrile and the suspension formed was filtered through a frit after 2 hours at 25° C. Washing with acetonitrile (2×100 ml) and drying gave 115.0 g (93 percent) of 1-benzyl-3-oxoquinuclidinium chloride in the form of white crystalline solid. Other data concerning the product was: ##EQU3##
Reaction SMILES: [C:1]([C:3]1[C:4]([F:14])=[C:5]([CH:9]=[C:10]([F:13])[C:11]=1[F:12])[C:6](Cl)=[O:7])#[N:2].[CH3:15][N:16]([CH3:24])[CH:17]=[CH:18][C:19]([O:21][CH2:22][CH3:23])=[O:20].C(N(CC)CC)C>C1(C)C=CC=CC=1>[C:1]([C:3]1[C:4]([F:14])=[C:5]([CH:9]=[C:10]([F:13])[C:11]=1[F:12])[C:6]([C:18](=[CH:17][N:16]([CH3:24])[CH3:15])[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[O:7])#[N:2]
Reactant: CCOC(=O)C=CN(C)C
Reactant: N#Cc1c(F)c(F)cc(C(=O)Cl)c1F
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCOC(=O)C(=CN(C)C)C(=O)c1cc(F)c(F)c(C#N)c1F
Temperature: 50 °C
Reaction time: 2 h

Procedure:
A solution of 55 g of 3-cyano-2,4,5-trifluoro-benzoyl chloride in 50 ml of toluene is added dropwise to a solution of 36,5 g of ethyl 3-dimethylamino-acrylate and 26,5 g of triethylamine in 140 ml of toluene at a temperature between 50 and 55° C. After stirring at 50° C. for 2 hours the reaction mixture is concentrated in vacuo. The crude product is used for the next step without further purification.
Reaction SMILES: FC1C=C(C(N[C:14]([CH:16]2[CH2:20][C:19](=[O:21])[N:18]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([NH:28][C:29]([NH:31][CH2:32][C:33]4C=C[CH:36]=[CH:35][CH:34]=4)=[O:30])[CH:23]=3)[CH2:17]2)=[O:15])CC(O)=O)C=CC=1.[NH2:39][CH:40]([C:47]1[CH:52]=[C:51]([Cl:53])[CH:50]=[C:49]([Cl:54])[C:48]=1[OH:55])[CH2:41][C:42]([O:44]CC)=[O:43].[S:56]1C=CC=C1CN>>[Cl:54][C:49]1[C:48]([OH:55])=[C:47]([CH:40]([NH:39][C:14]([CH:16]2[CH2:20][C:19](=[O:21])[N:18]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([NH:28][C:29]([NH:31][CH2:32][C:33]4[S:56][CH:36]=[CH:35][CH:34]=4)=[O:30])[CH:23]=3)[CH2:17]2)=[O:15])[CH2:41][C:42]([OH:44])=[O:43])[CH:52]=[C:51]([Cl:53])[CH:50]=1
Reactant: CCOC(=O)CC(N)c1cc(Cl)cc(Cl)c1O
Reactant: NCc1cccs1
Reactant: O=C(O)CC(NC(=O)C1CC(=O)N(c2cccc(NC(=O)NCc3ccccc3)c2)C1)c1cccc(F)c1
Product: O=C(O)CC(NC(=O)C1CC(=O)N(c2cccc(NC(=O)NCc3cccs3)c2)C1)c1cc(Cl)cc(Cl)c1O

Procedure:
The title compound was analogously synthesized to the preparation of 3-(3-fluorophenyl)-3-{(5-oxo-1-(3-{(benzylamino)carbonylamino}phenyl)pyrrolidin-3-yl)carbonylamino}propanoic acid from ethyl 3-amino-3-(3,5-dichloro-2-hydroxyphenyl)propanoate and 2-thienylmethyl amine. MS (ES+): 591 (M+H)+; (ES−): 589 (M−H)−.
Reaction SMILES: Cl[CH2:2][CH:3]([NH:8][C:9]([C:11]1[C:19]2[N:18]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[C:33]4[NH:37][N:36]=[N:35][N:34]=4)=[CH:23][CH:22]=3)[C:17]([O:38][CH2:39][CH3:40])=[N:16][C:15]=2[CH:14]=[CH:13][CH:12]=1)=[O:10])[CH2:4][CH:5]([CH3:7])[CH3:6].[C:41]([O-:44])(=[S:43])[CH3:42].[K+]>CC#N>[CH2:39]([O:38][C:17]1[N:18]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[C:33]3[NH:37][N:36]=[N:35][N:34]=3)=[CH:23][CH:22]=2)[C:19]2[C:11]([C:9]([NH:8][CH:3]([CH2:4][CH:5]([CH3:7])[CH3:6])[CH2:2][S:43][C:41](=[O:44])[CH3:42])=[O:10])=[CH:12][CH:13]=[CH:14][C:15]=2[N:16]=1)[CH3:40]
Reactant: CC([O-])=S
Reactant: CCOc1nc2cccc(C(=O)NC(CCl)CC(C)C)c2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Agent: [K+]
Solvent: CC#N
Product: CCOc1nc2cccc(C(=O)NC(CSC(C)=O)CC(C)C)c2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Temperature: 90 °C

Procedure:
2-Ethoxy-3-[2′-(1H-tetrazol-5-yl)-biphenyl-4-ylmethyl]-3H-benzoimidazole-4-carboxylic acid (1-chloromethyl-3-methylbutyl)amide (100 mg, 180 μmol) and potassium thioacetate (31 mg, 15 equiv) were dissolved in MeCN (5 mL) and heated at 90° C. overnight. The solvent was evaporated and the residue partitioned between water (10 mL) and EtOAc (10 mL). The aqueous phase was discarded, the organic layer washed with saturated aqueous NaCl, dried over NaSO4, decanted, and the solvent evaporated. The crude product (80 mg, 70%) was used without further purification. ESMS [M+H]+ calcd for C32H35N7O3S, 597.3. found 598.3.