Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([N:8]([CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[CH:9]2[CH2:13][N:12]([CH2:14][CH3:15])[CH2:11][CH:10]2[OH:16])=[O:7])=[CH:4][CH:3]=1.[OH-].[K+].O>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([N:8]([CH:17]2[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]2)[C@@H:9]2[CH2:13][N:12]([CH2:14][CH3:15])[CH2:11][C@H:10]2[OH:16])=[O:7])=[CH:23][CH:24]=1
Reactant: CCN1CC(O)C(N(C(=O)c2ccc(Cl)cc2)C2CCCCC2)C1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCN1C[C@@H](O)[C@H](N(C(=O)c2ccc(Cl)cc2)C2CCCCC2)C1

Procedure:
A mixture of 6.9 g (0.014 mole) of trans-4-chlorobenzoic acid ester with 4-[(4-chlorobenzoyl)(cyclohexyl)amino]-1-ethyl-3-pyrrolidinol, 0.9 g (0.016 mole) of potassium hydroxide, 10 ml of water and 40 ml of methanol was heated on a steam bath for 1 hr. then concentrated to 10 ml volume under reduced pressure. The residue was partitioned between water and methylene chloride and the organic layer was dried and conentrated under reduced pressure. After recrystallization from 60% aqueous methanol, 3.5 g (72%) of white powder, m.p. 111°-116° C. was obtained.
Reaction SMILES: S(=O)(=O)(O)O.[O:6]=[C:7]([CH:11]=[CH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:8]([O-:10])=[O:9].[Na+].[CH3:20]O>>[O:6]=[C:7]([CH:11]=[CH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:8]([O:10][CH3:20])=[O:9]
Reactant: CO
Reactant: O=C([O-])C(=O)C=Cc1ccccc1
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: COC(=O)C(=O)C=Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2 ml of concentrated sulfuric acid are added dropwise to a suspension of 5.9 g (30 mmol) sodium 2-oxo-4-phenylbut-3-enoate (1) (Synth. Commun., (1996), 26(11), 2231) in 100 ml of methanol. The mixture is refluxed for 8 hours and stirred overnight at room temperature. A light insoluble material is filtered off and the filtrate is concentrated to half its volume and poured into 300 ml of water. The pasty solid obtained is extracted with dichloromethane and washed with aqueous 5% sodium hydrogen carbonate solution and then with water. The resulting solution is dried over sodium sulfate. The solvent is evaporated off under vacuum. The residue (4.2 g) is purified by flash chromatography (SiO2, 70/30 CH2Cl2/heptane).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:15]=[CH:16][CH:17]=[C:18]3[C:23]=2[CH2:22][C@H:21]([NH:24][C:25]([C:27]2[CH:32]=[CH:31][C:30]([N:33]4[CH2:38][CH2:37][O:36][CH2:35][CH2:34]4)=[CH:29][CH:28]=2)=[O:26])[CH2:20][CH2:19]3)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[N:11]1([C:14]2[CH:15]=[CH:16][CH:17]=[C:18]3[C:23]=2[CH2:22][C@H:21]([NH:24][C:25](=[O:26])[C:27]2[CH:32]=[CH:31][C:30]([N:33]4[CH2:34][CH2:35][O:36][CH2:37][CH2:38]4)=[CH:29][CH:28]=2)[CH2:20][CH2:19]3)[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2cccc3c2C[C@H](NC(=O)c2ccc(N4CCOCC4)cc2)CC3)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(N[C@@H]1CCc2cccc(N3CCNCC3)c2C1)c1ccc(N2CCOCC2)cc1
Temperature: 25 °C
Reaction time: 7 h
Yield: 69 %

Procedure:
To an ice-cooled solution of (R)-N-[8-(4-tert-butyloxycarbonylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphthyl]-4-morpholinophenylcarboxamide (1.0 g, 2 mmol) in methylene chloride (100 mL) was added trifluoroacetic acid (3 mL). The reaction was stirred at ambient temperature for 7 h. The solvent was evaporated in vacuo and the residue was dissolved in water (20 mL), alkalized with a 2 M aqueous sodium hydroxide solution and extracted, twice, with methylene chloride. The phases were separated, the combined organic phases were dried (Na2SO4), filtered and evaporated in vacuo. Purification on a silica gel column using chloroform/methanol/concentrated ammonium hydroxide (95:5:0.5) as the eluent gave 580 mg (70% yield) of the title compound as white crystals: mp 202-203° C.; [α]21D -56° (c 1.0, chloroform); EIMS (70 eV) m/z (relative intensity) 420 (5, M+).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[C:15]([S:20]([NH:23]C(C)(C)C)(=[O:22])=[O:21])=[CH:16][CH:17]=[CH:18][CH:19]=3)=[CH:10][C:9]=2[F:28])=[N:6][CH:7]=1.C1(OC)C=CC=CC=1.C(O)(C(F)(F)F)=O>>[NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[C:15]([S:20]([NH2:23])(=[O:22])=[O:21])=[CH:16][CH:17]=[CH:18][CH:19]=3)=[CH:10][C:9]=2[F:28])=[N:6][CH:7]=1
Reactant: CC(C)(C)NS(=O)(=O)c1ccccc1-c1ccc(-c2cnc(N)cn2)c(F)c1
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: Nc1cnc(-c2ccc(-c3ccccc3S(N)(=O)=O)cc2F)cn1
Temperature: 25 °C
Yield: 72.4 %

Procedure:
A solution of 4′-(5-aminopyrazin-2-yl)-N-(tert-butyl)-3′-fluoro-[1,1′-biphenyl]-2-sulfonamide (130.0 g, 298.0 mmol), anisole (97.4 mL, 894.0 mmol), and TFA (228.0 mL, 2.98 mol) was stirred at 60° Celsius for 16 hours. The reaction was cooled to rt, concentrated to dryness, and partitioned between 600 mL H2O and 600 mL acetone. 750 mL sat. NaHCO3 (aq), was added over 30 min. The resulting precipitate was isolated via filtration and rinsed with 300 mL H2O then 300 mL acetone. The precipitate was triturated with 1.5 L acetone at 50° Celsius for 16 hours. After cooling to room temperature the solid was collected by filtration and rinsed twice with 250 mL acetone then dried in a vacuum oven at 50° Celsius for 16 hours yielding the title compound (74.3 g, 72.4%). MS (ESI): mass calcd. for C16H13FN4O2S, 344.07; m/z found, 345.1 [M+H]+. 1H NMR (600 MHz, DMSO-d6) δ 8.44-8.36 (s, 1H), 8.10-8.02 (m, 2H), 7.92-7.85 (m, 1H), 7.69-7.59 (m, 2H), 7.43-7.35 (m, 3H), 7.35-7.27 (m, 2H), 6.77-6.69 (s, 2H). Elemental analysis: calcd. for C16H13FN4O2S, C, 55.80; H, 3.81; N, 16.27; measured: C, 55.43; H, 3.54; N, 16.22.
Reaction SMILES: Cl.[C:2]1([NH:8][NH2:9])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:10]([C:13]1[Se:14][CH:15]=[CH:16][CH:17]=1)(=O)[CH3:11]>>[C:2]1([NH:8][N:9]=[C:10]([C:13]2[Se:14][CH:15]=[CH:16][CH:17]=2)[CH3:11])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NNc1ccccc1
Reactant: CC(=O)c1ccc[se]1
Agent: Cl
Product: CC(=NNc1ccccc1)c1ccc[se]1

Procedure:
This compound is prepared from commercial phenylhydrazine hydrochloride (Aldrich) and 2-acetylselenophene, which is itself obtained according to the procedure described by S. Umezawa (reference 18).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([C:15]([N:17]1[CH2:23][CH2:22][CH2:21][N:20]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:19][CH2:18]1)=[O:16])=[CH:10][CH:9]=2)=[O:5])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].[CH:37](CS([O-])(=O)=O)([CH3:39])[CH3:38]>C(#N)C>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH:37]([CH3:39])[CH3:38])[C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([C:15]([N:17]1[CH2:23][CH2:22][CH2:21][N:20]([C:24]([O:26][C:27]([CH3:29])([CH3:28])[CH3:30])=[O:25])[CH2:19][CH2:18]1)=[O:16])=[CH:10][CH:9]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc2cc(C(=O)N3CCCN(C(=O)OC(C)(C)C)CC3)ccc2[nH]1
Reactant: CC(C)CS(=O)(=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CCOC(=O)c1cc2cc(C(=O)N3CCCN(C(=O)OC(C)(C)C)CC3)ccc2n1C(C)C
Temperature: 95 °C
Yield: 99.9 %

Procedure:
To a solution of 5-(4-tert-butoxycarbonyl-[1,4]diazepane-1-carbonyl)-1H-indole-2-carboxylic acid ethyl ester (1.55 g, 3.5 mmol) in acetonitrile (25 ml) under an argon atmosphere were added caesium carbonate (2 eq., 2.44 g) and isopropylmethanesulfonate (2 eq., 1.03 g). The mixture was heated at 95° C. (oil-bath temperature) overnight. The mixture was cooled to room temperature and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel (3:1 heptane/ethyl acetate eluant) to afford the product as a light-brown oil (1.6 g, 93%). MS (m/z): 458.3 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[Cl:12][C:13]1[CH:18]=[CH:17][C:16](/[CH:19]=[C:20](\[CH2:26][OH:27])/[CH2:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[CH:15][CH:14]=1.C(N(CC)CC)C>C(Cl)Cl>[Cl:12][C:13]1[CH:14]=[CH:15][C:16](/[CH:19]=[C:20](\[CH2:26][O:27][S:8]([C:5]2[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=2)(=[O:10])=[O:9])/[CH2:21][C:22]([CH3:23])([CH3:24])[CH3:25])=[CH:17][CH:18]=1
Reactant: CC(C)(C)C/C(=C/c1ccc(Cl)cc1)CO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)OC/C(=C\c2ccc(Cl)cc2)CC(C)(C)C)cc1
Reaction time: 24 h
Yield: 97 %

Procedure:
42 g of 4-methylbenzenesulfonyl chloride are added to a solution of 45.8 g of Z-1-(4-chlorophenyl)-2-hydroxymethyl-4,4-dimethylpent-1-ene in 200 ml of methylene chloride and 59 g of triethylamine at room temperature. After 24 hours, the reaction mixture is washed with aqueous sodium bicarbonate solution and water, dried over sodium sulfate and evaporated down under reduced pressure. The residue gives 73.1 g (98%) of Z-1-(4-chlorophenyl)-2-(4-methylphenylsulfonyloxymethyl)-4,4-dimethylpent-1-ene.
Reaction SMILES: [NH2:1][C@H:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH2:3][OH:4].[Cl:11][C:12]1[CH:17]=[N:16][CH:15]=[C:14](Cl)[N:13]=1>>[Cl:11][C:12]1[N:13]=[C:14]([NH:1][C@H:2]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH2:3][OH:4])[CH:15]=[N:16][CH:17]=1
Reactant: Clc1cncc(Cl)n1
Reactant: N[C@@H](CO)c1ccccc1
Product: OC[C@H](Nc1cncc(Cl)n1)c1ccccc1
Yield: 37.5 %

Procedure:
In a procedure analogous to Example 1, reaction of (2R)-2-amino-2-phenylethanol (420 mg, 3.1 mmol) and 2,6-dichloropyrazine (415 mg, 2.79 mmol) furnished the product (261 mg, 37%).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:12]3[N:13]=[C:14]4[C:20]([C:21](O)=[O:22])=[CH:19][N:18]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:15]4=[N:16][CH:17]=3)=[N:7][N:8]2[CH3:11])=[CH:4][CH:3]=1.[NH2:32][C@@H:33]([CH2:36][CH:37]([CH3:39])[CH3:38])[CH2:34][OH:35].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>C(#N)C>[OH:35][CH2:34][C@@H:33]([NH:32][C:21]([C:20]1[C:14]2[C:15](=[N:16][CH:17]=[C:12]([C:6]3[C:5]4[C:9](=[CH:10][C:2]([F:1])=[CH:3][CH:4]=4)[N:8]([CH3:11])[N:7]=3)[N:13]=2)[N:18]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:29])([CH3:31])[CH3:30])[CH:19]=1)=[O:22])[CH2:36][CH:37]([CH3:39])[CH3:38]
Reactant: CC(C)C[C@H](N)CO
Reactant: Cn1nc(-c2cnc3c(n2)c(C(=O)O)cn3COCC[Si](C)(C)C)c2ccc(F)cc21
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: CC#N
Product: CC(C)C[C@@H](CO)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4cc(F)ccc34)nc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 59.7 %

Procedure:
A 25 mL round-bottomed flask was charged with 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (100 mg, 0.226 mmol), (S)-2-amino-4-methylpentan-1-ol (28 mg, 0.24 mmol), and HATU (90 mg, 0.24 mmol). Then added acetonitrile (2 mL) followed by N,N-diisopropylethylamine (0.13 mL, 0.77 mmol). The reaction mixture was stirred at room temperature overnight then quenched with water. The mixture was extracted with ethyl acetate (3×). The organic layers were combined, dried over Na2SO4, and concentrated to afford 73 mg (59%) of 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((S)-1-hydroxymethyl-3-methyl-butyl)-amide as a white solid. MS: [M+H]+=541.
Reaction SMILES: O.[C:2]1([CH3:12])[CH:7]=[CH:6][C:5](S(O)(=O)=O)=[CH:4][CH:3]=1.[NH2:13][C@@H:14]1[C:32](=[O:33])[N:16]2[C:17]([C:29]([OH:31])=[O:30])=[C:18]([CH:21]([S:23][C:24]3[NH:28][N:27]=[N:26][N:25]=3)[CH3:22])[CH2:19][S:20][C@H:15]12>CO>[C:2]1([CH:12]([O:30][C:29]([C:17]2[N:16]3[C:32](=[O:33])[C@@H:14]([NH2:13])[C@H:15]3[S:20][CH2:19][C:18]=2[CH:21]([S:23][C:24]2[NH:25][N:26]=[N:27][N:28]=2)[CH3:22])=[O:31])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CC(Sc1nnn[nH]1)C1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Solvent: CO
Solvent: O
Product: CC(Sc1nnn[nH]1)C1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@@H](N)[C@H]2SC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
2.09 g of p-toluenesulphonic acid monohydrate are added to a suspension of 5.0 g of 7β-amino-3-(1-methyl-5-tetrazolylthiomethyl)-3-cephem-4-carboxylic acid (U.S. Pat. No. 3,516,997) in 200 ml of methanol, whilst stirring; this slowly produces a clear solution, which is concentrated under reduced pressure. Diethyl ether is added and the p-toluenesulphonic acid salt of 7β-amino-3-(1-methyl-5-tetrazolylthiomethyl)-3-cephem-4carboxylic acid is filtered off. The salt is dissolved in 100 ml of dioxane and 2.5 g of diphenyldiazomethane are added in portions to the solution. The mixture is stirred for 18 hours at room temperature and concentrated under reduced pressure; 100 ml of an 0.1 N aqueous sodium bicarbonate solution are added to the residue and the mixture is extracted with twice 100 ml of ethyl acetate. The organic extracts are washed successively with water and with a saturated aqueous sodium chloride solution, dried over magnesium sulphate and concentrated. The crystallisation from diethyl ether gives 7β-amino-3-(1-methyl-5-tetrazolylthiomethyl)-3-cephem-4-carboxylic acid diphenylmethyl ester, thin layer chromatogram (silica gel): Rf=0.21 (system: chloroform/ethyl acetate/acetic acid, 80:19:1); ultraviolet absorption spectrum (ethanol): λmax =269 mμ (ε=6,400); infrared absorption spectrum (in methylene chloride); characteristic bands at 2.93μ, 5.60μ and 6.15μ.
Reaction SMILES: [C:1]1([C:7]2[C:8]3[CH:17]=[CH:16][S:15][C:9]=3[NH:10][C:11](=O)[CH2:12][N:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:19]>N1C=CC=CC=1>[C:1]1([C:7]2[C:8]3[CH:17]=[CH:16][S:15][C:9]=3[NH:10][C:11](=[S:19])[CH2:12][N:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C1CN=C(c2ccccc2)c2ccsc2N1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Solvent: c1ccncc1
Product: S=C1CN=C(c2ccccc2)c2ccsc2N1

Procedure:
12.1 g (0.05 mol) of 1,3-dihydro-5-phenyl-2H-thieno[2,3-e]-1,4-diazepin-2-one are heated to reflux for 35 minutes with 12.2 g (0.055 mol) of phosphorus pentasulphide in 400 ml of absolute pyridine, dry nitrogen being conducted through the solution. The solution is concentrated to 200 ml and the mixture separated on a 70 cm long column (φ3.5 cm) filled with 250 g of Silica gel [0.05 to 0.2 mm (Merck)]. The solution is concentrated under a vacuum and yields 1,3-dihydro-5-phenyl-2H-thieno[2,3-e]-1,4-diazepine-2-thione in the form of yellow crystals, melting point 208°-210° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:24]2[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:25]=2[O:31][CH3:32])=[C:4]2[CH:10]=[C:9]([C:11]3[CH2:16][CH2:15][N:14]([C:17](OC(C)(C)C)=O)[CH2:13][CH:12]=3)[NH:8][C:5]2=[N:6][CH:7]=1.F[C:34](F)(F)C(O)=O>ClCCl>[Cl:1][C:2]1[C:3]([C:24]2[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:25]=2[O:31][CH3:32])=[C:4]2[CH:10]=[C:9]([C:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH3:34])[CH2:13][CH:12]=3)[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: O=C(O)C(F)(F)F
Reactant: COc1ccc(F)cc1-c1c(Cl)cnc2[nH]c(C3=CCN(C(=O)OC(C)(C)C)CC3)cc12
Solvent: ClCCl
Product: CCN1CC=C(c2cc3c(-c4cc(F)ccc4OC)c(Cl)cnc3[nH]2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of Example 229E (0.072 g, 0.157 mmol) in dichloromethane (1.429 mL) was treated with 2,2,2-trifluoroacetic acid (0.121 mL, 1.572 mmol) and the mixture was stirred at room temperature for 8 hours. The mixture was concentrated and the residue was partitioned in ethyl acetate and saturated aqueous sodium bicarbonate. The aqueous layer was back-extracted with additional ethyl acetate and the combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated to provide the title compound. MS (ESI+) m/z 358.1 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([O:23][CH2:24][CH:25]=[CH2:26])=[O:22])=[CH:17][C:16]=2[NH2:27])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(C(C)C)C(C)C)C.Cl[C:38](Cl)([O:40]C(=O)OC(Cl)(Cl)Cl)Cl>C1(C)C=CC=CC=1>[CH2:24]([O:23][C:21]([C:18]1[CH:19]=[CH:20][C:15]2[N:14]([CH:11]3[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9][CH2:10]3)[C:38](=[O:40])[NH:27][C:16]=2[CH:17]=1)=[O:22])[CH:25]=[CH2:26]
Reactant: C=CCOC(=O)c1ccc(NC2CCN(C(=O)OC(C)(C)C)CC2)c(N)c1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: C=CCOC(=O)c1ccc2c(c1)[nH]c(=O)n2C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 70 °C
Reaction time: 1.5 h
Yield: 72.5 %

Procedure:
To a stirred solution of 4-(4-allyloxycarbonyl-2-amino-phenylamino)-piperidine-1-carboxylic acid tert-butyl ester (20.0 g, 53.27 mmol, 1.0 equiv; example 1/step 4) in toluene (200 mL) and N-ethyldiisopropylamine (17.21 g, 133.17 mol, 2.5 equiv) was added a solution of triphosgene (18.97 g, 63.92 mmol, 1.2 equiv) in toluene (200 mL) and the reaction mixture stirred at 70° C. for 1.5 h. The solvent was evaporated, the residue diluted with water and extracted with ethyl acetate. The combined organic fractions were washed with water and a sat. solution of NaCl, dried over Na2SO4 and concentrated by evaporation under reduced pressure. The crude material was further washed with a mixture of hexane/ethyl acetate (95:5) to yield 15.5 g (73%) of the title product as wvhite solid. 1H NMR (400 MHz, DMSO): δ 1.43 (s, 9H), 1.72 (d, J=10.8, 2H), 2.17-2.23 (m, 2H), 2.88 (br s, 2H), 4.09 (d, J=8.6 Hz, 2H), 4.38 (t, J=12.2 Hz, 1H), 4.77 (d, J=5.3 Hz, 2H), 5.26 (d, J=10.4 Hz, 1H), 5.40 (dd, J=17.2 Hz, J=1.4 Hz, 1H), 5.99-6.09 (m, 1H), 7.35 (d, J=8.4 Hz, 1H), 7.53 (d, J=1.3 Hz, 1H), 7.69-7.71 (m, 1H), 11.17 (s, 1H). 13C-NMR (100 MHz, DMSO): δ 28.04, 28.43, 50.32, 64.78, 78.79, 108.13, 109.18, 117.70, 121.69, 121.71, 122.67, 128.20, 132.81, 133.39, 153.78, 153.82, 165.36. MS (ISP): 402.2 [M+H]+.
Reaction SMILES: [NH2:1][C@H:2]([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][C@@H:14]([CH3:17])[CH2:15][CH3:16])=[CH:8][CH:7]=1)[C@H:3]([OH:5])[CH3:4].Cl.C(N([CH2:24][CH3:25])CC)C>ClCCl>[OH:5][C@H:3]([CH3:4])[C@H:2]([NH:1][C:3](=[O:5])[C@H:2]([C:25]1[CH:24]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH3:6])[C:6]1[CH:7]=[CH:8][C:9]([O:12][CH2:13][C@@H:14]([CH3:17])[CH2:15][CH3:16])=[CH:10][CH:11]=1
Reactant: CCN(CC)CC
Reactant: CC[C@H](C)COc1ccc([C@@H](N)[C@@H](C)O)cc1
Agent: Cl
Solvent: ClCCl
Product: CC[C@H](C)COc1ccc([C@@H](NC(=O)[C@@H](C)c2ccccc2)[C@@H](C)O)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 10 %

Procedure:
To a solution of (S)-(+)-2-phenylpropionic acid (0.067 g, 0.449 mmol) in dichloromethane (5 mL) in an ice-bath was added oxalyl chloride (0.39 mL, 4.49 mmol), then DMF (0.02 mL) under nitrogen. The reaction mixture was stirred for 30 minutes at 0° C. The excessive solvent was removed on ratovapor and dried under high vacuum for 2 hrs to give the corresponding acid chloride. A separate 50 mL round-bottom flask was charged with (1R,2R)-1-amino-1-[4-((S)-2-methyl-butoxy)phenyl]-propan-2-ol.HCl salt (0.37 mmol), dichloromethane (6 mL) and triethylamine (0.3 mL, 1.85 mmol) in an ice cold bath under nitrogen. The acid chloride mentioned above, in dichloromethane (2 mL) was added into the reaction mixture dropwise. The final reaction mixture was stirred for 1.5 hrs at room temperature. The finished reaction was quenched with water. The organic phase was washed with brine (3×10 mL), dried over MgSO4, filtrated, concentrated in vacuum and purified via column chromatography on silica gel with a gradient of 0%→100% of ethyl acetate in hexane to give a white solid (0.013 g, 10% yield). 1H NMR (400 MHz, CDCl3) δ 7.33 (m, 5H), 6.93 (d, J=8.8 Hz, 2H), 6.80 (m, 2H), 6.05 (d, J=8.3 Hz, 1H), 4.82 (dd, J=8.2, 3.7 Hz, 1H), 4.00 (br. s., 1H), 3.74 (m, 3H), 1.96 (d, J=3.0 Hz, 1H), 1.85 (d, J=6.6 Hz, 1H), 1.54 (m, 3H), 1.27 (m, 2H), 1.16 (d, J=6.3 Hz, 3H), 1.02 (m, 3H), 0.96 (t, J=7.5 Hz, 3H); LCMS (ESI) m/e 370.4 [(M+H), calcd. for C23H32NO3 370.5].
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][O:11][C:12]([NH:14][CH2:15][C:16]([OH:18])=[O:17])=[O:13])=[CH:6][CH:5]=1)([O-:3])=[O:2].O[N:20]1[C:24](=[O:25])[CH2:23][CH2:22][C:21]1=[O:26].C1(N=C=NC2CCCCC2)CCCCC1>O1CCOCC1.C(Cl)Cl>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:10][O:11][C:12](=[O:13])[NH:14][CH2:15][C:16]([O:18][N:20]2[C:24](=[O:25])[CH2:23][CH2:22][C:21]2=[O:26])=[O:17])=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=C(O)CNC(=O)OCc1ccc([N+](=O)[O-])cc1
Reactant: O=C1CCC(=O)N1O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Solvent: C1COCCO1
Product: O=C(CNC(=O)OCc1ccc([N+](=O)[O-])cc1)ON1C(=O)CCC1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 47.9 %

Procedure:
To a solution of 2.83 g of product from Example 255 in 43 ml of dioxane is added 1.28 g of N-hydroxysuccinimide and 2.30 g of 1,3-dicyclohexylcarbodiimide, hereinafter called DCC, in 13 ml of dioxane. The formed suspension is stirred at room temperature overnight. The urea by-product is collected and the filtrate is concentrated in vacuo to give an oil. The oil is dissolved in methylene chloride, washed with water, the layers are separated and the organic phase is cooled. The formed crystals are collected and dried to give 1.87 g of the desired product.
Reaction SMILES: [CH3:1][N:2]([CH3:29])[C:3]([C:5]1[NH:27][C:8]2[CH2:9][C@@:10]3([C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([O:25]C)[CH:20]=4)[C@H:15]([CH2:16][C:7]=2[C:6]=1[CH3:28])[CH2:14][N:13]([CH2:17][CH3:18])[CH2:12][CH2:11]3)=[O:4].B(Br)(Br)Br.[ClH:34].CCOCC>CO>[ClH:34].[CH3:29][N:2]([CH3:1])[C:3]([C:5]1[NH:27][C:8]2[CH2:9][C@@:10]3([C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([OH:25])[CH:20]=4)[C@H:15]([CH2:16][C:7]=2[C:6]=1[CH3:28])[CH2:14][N:13]([CH2:17][CH3:18])[CH2:12][CH2:11]3)=[O:4]
Reactant: CCN1CC[C@@]2(c3cccc(OC)c3)Cc3[nH]c(C(=O)N(C)C)c(C)c3C[C@@H]2C1
Agent: BrB(Br)Br
Agent: Cl
Solvent: CO
Solvent: CCOCC
Product: CCN1CC[C@@]2(c3cccc(O)c3)Cc3[nH]c(C(=O)N(C)C)c(C)c3C[C@@H]2C1

Procedure:
0.5 g (1.25 mmol) of (±)trans-2-dimethylaminocarbonyl-6-ethyl-8a-(3-methoxyphenyl)-3-methyl-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrrolo[2,3-g] isoquinoline were treated with 0.725 ml (7.5 mmol) of boron tribromide as described in example 2. The etude product was dissolved in MeOH and the solution brought to acidic pH with HCl/Et2O. The solvent was evaporated in vacuo and the solid crystallized from EtOH, yielding 0.15 g of the title compound. M.p.=305° C. dec.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:17][C:16]2[C:11](=[N:12][C:13](S(C)(=O)=O)=[N:14][CH:15]=2)[NH:10][C:9]1=[O:22].[NH2:23][C@H:24]1[CH2:29][CH2:28][C@H:27]([OH:30])[CH2:26][CH2:25]1.Cl>COCCOCCOC>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:17][C:16]2[C:11](=[N:12][C:13]([NH:23][C@H:24]3[CH2:29][CH2:28][C@H:27]([OH:30])[CH2:26][CH2:25]3)=[N:14][CH:15]=2)[NH:10][C:9]1=[O:22]
Reactant: N[C@H]1CC[C@H](O)CC1
Reactant: CS(=O)(=O)c1ncc2c(n1)NC(=O)N(c1ccccc1Cl)C2
Agent: Cl
Solvent: COCCOCCOC
Product: O=C1Nc2nc(N[C@H]3CC[C@H](O)CC3)ncc2CN1c1ccccc1Cl
Temperature: 102.5 °C

Procedure:
Sulfone 11.1 (0.400 g, 1.18 mmol) was combined with trans-4-aminocyclohexanol (0.272 g, 2.36 mmol) and 2-methoxyethyl ether (0.4 mL). The mixture was heated to 100-105° C. for 1 hour at which time it was cooled to room temperature and concentrated in vacuo. The residue was purified by column chromatography on silica gel using 9:1 dichloromethane/methanol. The column fractions containing product were combined and concentrated in vacuo to an oil which was re-dissolved in ethyl acetate and methanol. Addition of hydrochloric acid (1.0M/Et2O, 1.0 equivalent) gave the salt which dissolved in the solvents. The solution was concentrated in vacuo to a solid which was triturated in ether, filtered and dried to give 0.220 g of 3-(2-chlorophenyl)-7-(trans-4-hydroxycyclohexylamino)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one.