Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[C@@H:13]([CH2:14][O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17])[O:12][C@@H:11]([N:23]2[C:37]3[N:36]=[C:30]([NH:31][C:32](=[O:35])[NH:33][CH3:34])[NH:29][C:27](=[O:28])[C:26]=3[N:25]=[CH:24]2)[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(N(C(C)C)CC)(C)C.[C:47]1([N:53]([C:57]2[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=2)[C:54](Cl)=[O:55])[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1.C(OCC)(=O)C>N1C=CC=CC=1>[Si:1]([O:8][C@@H:9]1[C@@H:13]([CH2:14][O:15][Si:16]([C:19]([CH3:20])([CH3:21])[CH3:22])([CH3:17])[CH3:18])[O:12][C@@H:11]([N:23]2[C:37]3[N:36]=[C:30]([NH:31][C:32](=[O:35])[NH:33][CH3:34])[N:29]=[C:27]([O:28][C:54](=[O:55])[N:53]([C:57]4[CH:58]=[CH:59][CH:60]=[CH:61][CH:62]=4)[C:47]4[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=4)[C:26]=3[N:25]=[CH:24]2)[CH2:10]1)([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:2])[CH3:3]
Reactant: CNC(=O)Nc1nc2c(ncn2[C@H]2C[C@H](O[Si](C)(C)C(C)(C)C)[C@@H](CO[Si](C)(C)C(C)(C)C)O2)c(=O)[nH]1
Reactant: O=C(Cl)N(c1ccccc1)c1ccccc1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)Nc1nc(OC(=O)N(c2ccccc2)c2ccccc2)c2ncn([C@H]3C[C@H](O[Si](C)(C)C(C)(C)C)[C@@H](CO[Si](C)(C)C(C)(C)C)O3)c2n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93.8 %

Procedure:
The above-obtained 3′,5′-bis-O-(tert-butyldimethylsilyl)-2-N-methylcarbamoyldeoxyguanosine (889 mg, 1.61 mmol) was azeotroped with anhydrous pyridine three times and then dissolved in anhydrous pyridine (16 mL), and diisopropylethylamine (421 μL, 2.41 mmol) and then diphenylcarbamoyl chloride (424 mg, 1.93 mmol) were added thereto. The mixture was stirred at room temperature for 0.5 hours. Then, after addition of ethyl acetate (10 mL), the reaction was terminated by adding sodium bicarbonate water (10 mL) thereto. The reaction solution was extracted with ethyl acetate (150 mL)/sodium bicarbonate water (150 mL) once and then with ethyl acetate (150 mL)/brine (100 mL) twice. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (C200) with ethyl acetate/40% to 50% hexane to give 3′,5′-bis-O-(tert-butyldimethylsilyl)-6-O-diphenylcarbamoyl-2-N-methylcarbamoyldeoxyguanosine (1.13 g, 94%).
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[CH:10]=[CH:9][N:8]([S:11]([C:14]3[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:5]2=[N:6][CH:7]=1.[CH3:21][OH:22].[C]=O.CN([CH:28]=[O:29])C>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[S:11]([N:8]1[C:5]2=[N:6][CH:7]=[C:2]([C:21]([O:29][CH3:28])=[O:22])[N:3]=[C:4]2[CH:10]=[CH:9]1)([C:14]1[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=1)(=[O:13])=[O:12]
Reactant: Cc1ccc(S(=O)(=O)n2ccc3nc(Br)cnc32)cc1
Reactant: CN(C)C=O
Reactant: CO
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [C]=O
Product: COC(=O)c1cnc2c(ccn2S(=O)(=O)c2ccc(C)cc2)n1
Temperature: 65 °C
Reaction time: 0.17 h

Procedure:
To a solution of 2-bromo-5-tosyl-5H-pyrrolo[2,3-b]pyrazine (5.00 g, 14.2 mmol) in DMF (64 mL) were added dichlorobis(triphenylphosphine)palladium (0.60 g, 0.86 mmol), TEA (5.9 mL, 43 mmol), and MeOH (17 mL, 420 mmol). The reaction flask was fitted with a balloon filled with carbon monoxide. The flask was evacuated and back-filled with carbon monoxide twice and the mixture was heated at about 65° C. for about 3 h. Additional dichlorobis(triphenylphosphine) palladium (0.60 g, 0.86 mmol) was added and the flask was re-evacuated and back-filled with carbon monoxide twice. The reaction mixture was heated at about 95° C. for about 16 h under an atmosphere of carbon monoxide. The mixture was cooled to room temperature and poured into ice water (350 mL). The resulting suspension was stirred for about 10 min and filtered. The filter cake was washed with water and the solid was lyophilized for about 48 h to give methyl 5-tosyl-5H-pyrrolo[2,3-b]pyrazine-2-carboxylate (5.0 g, 90% UV purity, 95%) as a light brown solid:
Reaction SMILES: C1(C)C=C[C:4]([S:7]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)(=[O:9])=[O:8])=CC=1.[C:18]([N:21]1[CH2:29][CH2:28][CH:24]([C:25](Cl)=[O:26])[CH2:23][CH2:22]1)(=[O:20])[CH3:19].C(N1CCCC(C(Cl)=O)C1)(=O)C1C=CC=CC=1>>[C:18]([N:21]1[CH2:22][CH2:23][CH:24]([C:25](=[O:26])[C:14]2[CH:13]=[CH:12][C:11]([NH:10][S:7]([CH3:4])(=[O:8])=[O:9])=[CH:16][CH:15]=2)[CH2:28][CH2:29]1)(=[O:20])[CH3:19]
Reactant: Cc1ccc(S(=O)(=O)Nc2ccccc2)cc1
Reactant: CC(=O)N1CCC(C(=O)Cl)CC1
Agent: O=C(Cl)C1CCCN(C(=O)c2ccccc2)C1
Product: CC(=O)N1CCC(C(=O)c2ccc(NS(C)(=O)=O)cc2)CC1

Procedure:
The same procedure as above was repeated except that methanesulfonamilide was replaced with p-toluenesulfonanilide or 1-acetylisonipecotoyl chloride was replaced with (±)-N-benzoylnipecotoyl chloride or (±)-N-benzoyl-β-prolyl chloride prepared in Referential Example 2 to obtain the following compounds:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=1.Cl[CH:10]([O:12][CH3:13])Cl>ClCCl.[Ti](Cl)(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[CH:10]=[O:12].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:8])=[C:6]([CH:7]=1)[CH:13]=[O:12]
Reactant: COC(Cl)Cl
Reactant: Cc1ccc(Cl)cc1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: Cc1ccc(Cl)c(C=O)c1
Product: Cc1ccc(Cl)cc1C=O
Reaction time: 15 h

Procedure:
To a solution of 4-chlorotoluene (25.0 g) and dichloromethylmethylether (45.4 g) in dichloromethane (160 ml) was added dropwise at room temperature a solution of titanium tetrachloride (74.9 g) in dichloromethane (40 ml), and the mixture was stirred at the same temperature for 15 hours. The reaction solution was poured into ice, and the organic layer was washed with water, sodium hydrogen carbonate solution, water and saturated brine, and dried with magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was subjected to silica gel column chromatography (ethyl acetate-hexane) to give oil of crude 2-chloro-5-methylbenzaldehyde (18.3 g) and 5-chloro-2-methylbenzaldehyde (4.1 g), respectively.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([N:14]2[CH2:19][CH2:18][CH:17]([N:20]3[CH2:25][CH2:24][N:23]([C:26]([OH:28])=[O:27])[CH2:22][CH2:21]3)[CH2:16][CH2:15]2)=[C:6]2[C:11]=1[C:10](=[O:12])[N:9]([CH3:13])[CH2:8][CH2:7]2.[Cl:29][C:30]1[N:35]=[C:34](Cl)[C:33]([Cl:37])=[CH:32][N:31]=1.C([O-])([O-])=O.[K+].[K+].O>CS(C)=O>[C:6]([O:27][C:26]([N:23]1[CH2:22][CH2:21][N:20]([CH:17]2[CH2:18][CH2:19][N:14]([C:5]3[CH:4]=[CH:3][C:2]([NH:1][C:32]4[C:33]([Cl:37])=[CH:34][N:35]=[C:30]([Cl:29])[N:31]=4)=[C:11]4[C:6]=3[CH2:7][CH2:8][N:9]([CH3:13])[C:10]4=[O:12])[CH2:15][CH2:16]2)[CH2:25][CH2:24]1)=[O:28])([CH3:11])([CH3:7])[CH3:5]
Reactant: CN1CCc2c(N3CCC(N4CCN(C(=O)O)CC4)CC3)ccc(N)c2C1=O
Reactant: Clc1ncc(Cl)c(Cl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CN1CCc2c(N3CCC(N4CCN(C(=O)OC(C)(C)C)CC4)CC3)ccc(Nc3nc(Cl)ncc3Cl)c2C1=O
Temperature: 25 °C
Yield: 72 %

Procedure:
A mixture 4-[1-(8-amino-2-methyl-1-oxo-1,2,3,4-tetrahydro-isoquinolin-5-yl)-piperidin-4-yl]-piperazine-1-carboxylic acid #tert!-butyl ester (9.20 g, 20.7 mmol), 2,4,5-trichloropyrimidine (5.96 mL, 51.8 mmol), K2CO3 (7.17 g, 51.8 mmol) in DMSO (200 mL) was stirred at 60° C. for 12 hours. After cooling to room temperature, 700 mL of water was added with stirring. The mixture was filtrated. The resulting brown solids were suspended in CH3CN (ca. 200 mL), stirred for a while and filtrated. The residue was further washed with CH3CN and dried under reduced pressure to give 8.75 g of 4-{1-[8-(2,5-dichloro-pyrimidin-4-ylamino)-2-methyl-1-oxo-1,2,3,4-tetrahydro-isoquinolin-5-yl]-piperidin-4-yl}-piperazine-1-carboxylic acid tert-butyl ester as pale beige solids in 72% yield.
Reaction SMILES: I[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)[N:5]=[N:4][C:3]=1[O:14][CH3:15].[C:16]([O:20][C:21]([N:23]1[C:31]2[C:26](=[CH:27][CH:28]=[C:29]([Br:32])[CH:30]=2)[CH:25]=[C:24]1B1OC(C)(C)C(C)(C)O1)=[O:22])([CH3:19])([CH3:18])[CH3:17].C(=O)([O-])[O-].[Cs+].[Cs+].ClCCl>O1CCOCC1.O>[C:16]([O:20][C:21]([N:23]1[C:31]2[C:26](=[CH:27][CH:28]=[C:29]([Br:32])[CH:30]=2)[CH:25]=[C:24]1[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)[N:5]=[N:4][C:3]=1[O:14][CH3:15])=[O:22])([CH3:19])([CH3:17])[CH3:18]
Reactant: CC(C)(C)OC(=O)n1c(B2OC(C)(C)C(C)(C)O2)cc2ccc(Br)cc21
Reactant: COc1nnc(-c2ccncc2)cc1I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Solvent: O
Solvent: C1COCCO1
Product: COc1nnc(-c2ccncc2)cc1-c1cc2ccc(Br)cc2n1C(=O)OC(C)(C)C
Yield: 96.2 %

Procedure:
1.075 g 4-Iodo-3-methoxy-6-pyridin-4-yl-pyridazine, 1.45 g 6-bromo-2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-indole-1-carboxylic acid tert-butyl ester, 4.48 g cesium carbonate, and 140 mg [1,1′-bis(diphenylphosphino)ferrocene]dichloro-palladium(II) complex with dichloromethane (1:1) are dissolved in a mixture of 30 mL dioxane and 8.8 mL water. Argon is bubbled through the solution for 5 minutes. The mixture is heated to reflux for 2 hours. After diluting with EtOAc, the organic phase is washed with water and brine, dried with MgSO4 and concentrated in vacuo. Purification on silica (Flashmaster, methylenechloride/MeOH) gives 1.59 g (96%) 6-bromo-2-(3-methoxy-6-pyridin-4-yl-pyridazin-4-yl)-indole-1-carboxylic acid tert-butyl ester.
Reaction SMILES: [CH3:1]S(OCC1CCN(C(OC(C)(C)C)=O)CC1)(=O)=O.C([S-])CC.[Na+].F[C:26](F)(F)[CH2:27][S:28][CH2:29][CH:30]1[CH2:35][CH2:34][N:33]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:32][CH2:31]1>>[CH3:26][CH:27]([S:28][CH2:29][CH:30]1[CH2:35][CH2:34][N:33]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:32][CH2:31]1)[CH3:1]
Reactant: CC(C)(C)OC(=O)N1CCC(CSCC(F)(F)F)CC1
Reactant: CC(C)(C)OC(=O)N1CCC(COS(C)(=O)=O)CC1
Agent: CCC[S-]
Agent: [Na+]
Product: CC(C)SCC1CCN(C(=O)OC(C)(C)C)CC1
Yield: 60 %

Procedure:
tert-Butyl 4-[(propan-2-ylsulfanyl)methyl]piperidine-1-carboxylate was prepared from tert-butyl 4-(hydroxymethyl)piperidine-1-carboxylate (Intermediate 181, 0.320 g, 1.091 mmol) and sodium propanethiolate (0.161 g, 1.636 mmol) according to the method described for Intermediate 183 to afford the title compound (0.180 g, 60%). Method B HPLC-MS: MH+ requires m/z=274 Found: m/z=218 (M-tert-Bu), Rt=2.51 min.
Reaction SMILES: BrBr.[C:3](=[S:6])([S-:5])[S-:4].[Na+:7].[Na+].O.[CH2:10]([O:18][C:19](=[O:22])CCl)[CH2:11][CH2:12][CH2:13][CH2:14][CH:15]([CH3:17])[CH3:16].[CH3:23]O>>[CH2:10]([O:18][C:19]([SH:6]([CH3:23])[C:3]([S-:5])=[S:4])=[O:22])[CH2:11][CH2:12][CH2:13][CH2:14][CH:15]([CH3:16])[CH3:17].[Na+:7]
Reactant: CC(C)CCCCCOC(=O)CCl
Reactant: S=C([S-])[S-]
Reactant: CO
Agent: BrBr
Agent: [Na+]
Solvent: O
Product: CC(C)CCCCCOC(=O)[SH](C)C(=S)[S-]
Reaction time: 1 h

Procedure:
In a double-walled glass reactor equipped with a stirring system, a thermometer, an equilibrated bromine ampoule and a condenser surmounted with a gas-lock, 108.2 g of a 35.26% aqueous solution of sodium trithiocarbonate (0.25 mole), 50 ml of methanol and 25.3 g of water were placed. 51.5 g of isooctylchloroacetate (0.25 mole) diluted in 25 ml of methanol was then added dropwise, while maintaining the temperature of the reaction mixture from 15° to 20° C. At the end of the addition, the mixture was stirred for 1 hour at the same temperature. A two-phase mixture was obtained.
Reaction SMILES: [C:1]1(O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:8][CH:9]([OH:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.S(=O)(=O)(O)O>C(C1C=CC=CC=1)C>[C:1]1([CH2:8][CH:9]([O:16][CH:8]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(O)c1ccccc1
Reactant: Oc1ccccc1
Agent: O=S(=O)(O)O
Solvent: CCc1ccccc1
Product: c1ccc(CC(OC(Cc2ccccc2)c2ccccc2)c2ccccc2)cc1

Procedure:
Phenol (21.21 grams; 0.25 mole) and methylbenzyl alcohol (30.5 grams; 0.25 mole) in 100.00 grams of ethylbenzene were refluxed at a temperature of from about 135° to 140° C. for about four hours with 0.500 grams (0.33 weight percent) concentrated sulfuric acid. Water was removed overhead as a azeotrope and was collected in a Dean-Stark trap. Methylbenzyl alcohol conversion was quantitative but only 8% selectivity to α-phenylmethylbenzyl ether was obtained. The remaining product was styrene (74.8% selectivity) and styrene polymer.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.[F:26][C:27]1[CH:28]=[C:29]([NH:40][C:41]([C@H:43]2[C:52]3[C:47](=[CH:48][C:49]([O:53][CH3:54])=[CH:50][CH:51]=3)[CH2:46][CH2:45][NH:44]2)=[O:42])[CH:30]=[C:31]([F:39])[C:32]=1[C:33]([CH3:38])([CH3:37])[CH2:34][O:35][CH3:36].[C:55]([O:59][C:60](=[O:69])[CH2:61][C@@H:62]1[CH2:65][C@H:64]([C:66](O)=[O:67])[CH2:63]1)([CH3:58])([CH3:57])[CH3:56].CCN(C(C)C)C(C)C>CN(C=O)C.O>[F:26][C:27]1[CH:28]=[C:29]([NH:40][C:41]([C@H:43]2[C:52]3[C:47](=[CH:48][C:49]([O:53][CH3:54])=[CH:50][CH:51]=3)[CH2:46][CH2:45][N:44]2[C:66]([C@@H:64]2[CH2:63][C@H:62]([CH2:61][C:60]([O:59][C:55]([CH3:58])([CH3:57])[CH3:56])=[O:69])[CH2:65]2)=[O:67])=[O:42])[CH:30]=[C:31]([F:39])[C:32]=1[C:33]([CH3:37])([CH3:38])[CH2:34][O:35][CH3:36]
Reactant: CC(C)(C)OC(=O)C[C@H]1C[C@@H](C(=O)O)C1
Reactant: COCC(C)(C)c1c(F)cc(NC(=O)[C@@H]2NCCc3cc(OC)ccc32)cc1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: COCC(C)(C)c1c(F)cc(NC(=O)[C@H]2c3ccc(OC)cc3CCN2C(=O)[C@H]2C[C@@H](CC(=O)OC(C)(C)C)C2)cc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
HATU (114 mg, 0.30 mmol) was added to a solution of (R)—N-(3,5-difluoro-4-(1-methoxy-2-methylpropan-2-yl)phenyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxamide hydrochloride (120 mg, 0.27 mmol), cis-3-(2-(tert-butoxy)-2-oxoethyl)cyclobutanecarboxylic acid (61.2 mg, 0.29 mmol) and DIEA (0.107 mL, 0.60 mmol) in DMF (2 mL) at room temperature, and the mixture was stirred overnight at room temperature. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent gradient; 3→50% ethyl acetate/hexane) to give tert-butyl 2-(cis-3-((R)-1-((3,5-difluoro-4-(1-methoxy-2-methylpropan-2-yl)phenyl)carbamoyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclobutyl)acetate (120 mg, 0.200 mmol, 73.4%) as a colorless oil.
Reaction SMILES: O[C:2]1[N:7]=[CH:6][N:5]=[C:4]2[NH:8][N:9]=[CH:10][C:3]=12.CN(C)C1C=CC=CC=1.O=P(Cl)(Cl)[Cl:22]>>[Cl:22][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[NH:8][N:9]=[CH:10][C:3]=12
Reactant: O=P(Cl)(Cl)Cl
Reactant: Oc1ncnc2[nH]ncc12
Solvent: CN(C)c1ccccc1
Product: Clc1ncnc2[nH]ncc12

Procedure:
To a mixture of commercially available 4-hydroxypyrazolo[3,4-d]pyrimidine (78) (Acros, 14.5 g, 106.5 mmol) stirred in POCl3 (375 mL) was added N,N-dimethylaniline (21 mL). The mixture was refluxed for 1.5 h. After cooling, excess POCl3 was removed by rotarty evaporation and pumped on high vacuum before pouring over 500 mL ice while stirring. The mixture was stirred for 10 min before extracting with ethyl ether (6×250 mL). The combined organic layer was washed with ice water (3×100 mL) and dried over MgSO4 and filtered. The ethyl ether was stripped and the resulting pale yellow solid (10 g, 61%) was pumped on high vacuum overnight. Compound 79: mp>300° C., dec. 125° C.; MS (ES+ calculated: 154.56; found: 156.21 M+H). HPLC (98% purity, retention time 6.033 minutes—method D) 1H NMR (400 MHz, DMSO-d6) δ 14.55 (bs, 1H), 8.84 (s, 1H), 8.46 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C@H:12]2[CH2:17][CH2:16][N:15]([C:18]3[S:19][C:20]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[C:21]([C:23](O)=[O:24])[N:22]=3)[CH2:14][C@H:13]2[O:31][CH2:32][CH3:33])=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8].[CH3:34][O:35][CH2:36][CH2:37][NH2:38].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>>[Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C@H:12]2[CH2:17][CH2:16][N:15]([C:18]3[S:19][C:20]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[C:21]([C:23](=[O:24])[NH:38][CH2:37][CH2:36][O:35][CH3:34])[N:22]=3)[CH2:14][C@H:13]2[O:31][CH2:32][CH3:33])=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8]
Reactant: COCCN
Reactant: CCOC(=O)c1sc(N2CC[C@H](NC(=O)c3nc(Cl)c(CC)[nH]3)[C@H](OCC)C2)nc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Product: CCOC(=O)c1sc(N2CC[C@H](NC(=O)c3nc(Cl)c(CC)[nH]3)[C@H](OCC)C2)nc1C(=O)NCCOC
Yield: 72.5 %

Procedure:
The same operation as in Example (1g) was performed using cis(±)-2-(4-{[(4-chloro-5-ethyl-1H-imidazol-2-yl)carbonyl]amino}-3-ethoxypiperidin-1-yl)-5-(ethoxycarbonyl)-1,3-thiazole-4-carboxylic acid obtained in Example (68c) (112 mg, 0.22 mmol), methoxyethylamine (40 μL, 0.46 mmol), WSC hydrochloride (130 mg, 0.68 mmol) and HOBT (30 mg, 0.22 mmol), to obtain 88.8 mg of the title compound as a white solid (71%).
Reaction SMILES: Cl[C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1.[NH2:16][CH:17]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=1)[C:18]([OH:20])=[O:19]>CS(C)=O>[C:18]([CH:17]([NH:16][C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1)[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=1)([OH:20])=[O:19]
Reactant: NC(Cc1ccccn1)C(=O)O
Reactant: O=C(O)c1cc2cc(Cl)ccc2nc1Cl
Solvent: CS(C)=O
Product: O=C(O)c1cc2cc(Cl)ccc2nc1NC(Cc1ccccn1)C(=O)O

Procedure:
In close analogy to the procedure described in Example 1, 2,6-dichloroquinoline-3-carboxylic acid is reacted with 2-amino-3-pyridin-2-yl-propionic acid in DMSO to provide the title compound in good yield.
Reaction SMILES: Cl.[O:2]1[C:6]2[CH2:7][NH:8][CH2:9][CH2:10][C:5]=2[CH:4]=[CH:3]1.[C:11](=O)([O:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[OH-].[Na+]>N1C=CC=CC=1>[C:24]1([CH2:23][CH2:22][CH2:21][CH2:20][O:19][C:11]([N:8]2[CH2:9][CH2:10][C:5]3[CH:4]=[CH:3][O:2][C:6]=3[CH2:7]2)=[O:12])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.[C:13]1([OH:12])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: c1cc2c(o1)CNCC2
Reactant: O=C(OCCCCc1ccccc1)Oc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Product: O=C(OCCCCc1ccccc1)N1CCc2ccoc2C1
Product: Oc1ccccc1

Procedure:
A solution of 0.226 g (1.416 mmol) of 4,5,6,7-tetrahydrofuro[2,3-c]pyridine hydrochloride and 0.57 g (2.1 mmol) of phenyl 4-phenylbutyl carbonate in 10 ml of pyridine was stirred at 100° C. overnight. The reaction mixture was poured into aqueous sodium hydroxide and extracted with ethyl acetate 3 times. The combined organic layer was dried over anhydrous magnesium sulfate; the solvent was distilled off under reduced pressure. The resulting crude product was purified by silica gel column chromatography (hexane/ethyl acetate=15/1 to 9/1) to yield 6-(4-phenylbutoxycarbonyl)-4,5,6,7-tetrahydrofuro[2,3-c]pyridine as a mixture with phenol.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C@H:9]2[C@:13]3([N:17]([CH3:18])[C:16](=[O:19])[N:15]([C:20]4[CH:25]=[C:24]([Cl:26])[CH:23]=[C:22]([Cl:27])[CH:21]=4)[C:14]3=[O:28])[CH2:12][N:11]([CH2:29][C:30]3[S:34][CH:33]=[C:32]([C:35]([OH:37])=[O:36])[CH:31]=3)[CH2:10]2)=[CH:5][CH:4]=1)#[N:2].[CH3:38][Si](C=[N+]=[N-])(C)C.OP(O)(O)=O>C(Cl)Cl.CO.O.CO>[CH3:38][O:36][C:35]([C:32]1[CH:31]=[C:30]([CH2:29][N:11]2[CH2:10][C@@H:9]([C:6]3[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=3)[C@:13]3([N:17]([CH3:18])[C:16](=[O:19])[N:15]([C:20]4[CH:21]=[C:22]([Cl:27])[CH:23]=[C:24]([Cl:26])[CH:25]=4)[C:14]3=[O:28])[CH2:12]2)[S:34][CH:33]=1)=[O:37]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: CN1C(=O)N(c2cc(Cl)cc(Cl)c2)C(=O)[C@]12CN(Cc1cc(C(=O)O)cs1)C[C@H]2c1ccc(C#N)cc1
Agent: O=P(O)(O)O
Solvent: CO
Solvent: ClCCl
Solvent: O
Product: COC(=O)c1csc(CN2C[C@@H](c3ccc(C#N)cc3)[C@]3(C2)C(=O)N(c2cc(Cl)cc(Cl)c2)C(=O)N3C)c1
Temperature: 25 °C

Procedure:
To a solution of 5-[(5S*,9R*)-9-(4-Cyanophenyl)-3-(3,5-dichlorophenyl)-1-methyl-2,4-dioxo-1,3,7-triazaspiro[4.4]non-7-ylmethyl]-thiophene-3-carboxylic acid (example 37) (0.150 g, 0.27 mmol) in DCM/MeOH (5:1 mL) was added trimethylsilyldiazomethane (2.0 M solution in hexane, 0.33 mL, 0.67 mmol) over a period of three minutes at RT. The reaction mixture was stirred at RT for twenty minutes, quenched by the slow addition of acetic acid (approximatly ten drops) and partitioned between DCM (20 mL) and saturated aqueous sodium bicarbonate (15 mL). The DCM layer was washed with brine (20 mL), dried over sodium sulfate and concentrated to yield a thick oil. LC retention time=3.34 min. Column used: YMC S5 combiscreen ODS 4.6×50 mm (4 min. gradient); Solvent A=10% MeOH, 90% H2O and 0.2% H3PO4; solvent B=90% MeOH, 10% H2O, 0.2% H3PO4.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[CH2:9][C:7](=[O:8])[CH2:6][C:4](=[O:5])[CH2:3]1.[CH3:11]C(C)([O-])C.[K+].CI>C(O)(C)(C)C>[CH3:11][CH:6]1[C:4](=[O:5])[CH2:3][C:2]([CH3:10])([CH3:1])[CH2:9][C:7]1=[O:8]
Reactant: CC(C)(C)[O-]
Reactant: CC1(C)CC(=O)CC(=O)C1
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: CI
Product: CC1C(=O)CC(C)(C)CC1=O
Reaction time: 2 h

Procedure:
28.0 g (0.2 mol) of dimedone were dissolved in 150 ml of absolute t-butanol and, at 40° C., 22.4 g (0.2 mol) of potassium t-butoxide were added a little at a time. After 2 hours, an equimolar amount of methyl iodide was added. After a further 2 hours, the solvent was removed under reduced pressure and the residue which remained was extracted 3 times with diethyl ether. The combined ether extracts were evaporated to dryness. Yield: 26.2 g (85%). The crude product was not purified further.
Reaction SMILES: [BH4-].[Na+].[Br:3][C:4]1[CH:11]=[C:10]([O:12][CH3:13])[C:9]([O:14][CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])=[CH:8][C:5]=1[CH:6]=[O:7]>CO.O>[Br:3][C:4]1[CH:11]=[C:10]([O:12][CH3:13])[C:9]([O:14][CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:21])([CH3:20])[CH3:22])=[CH:8][C:5]=1[CH2:6][OH:7]
Reactant: COc1cc(Br)c(C=O)cc1OCOCC[Si](C)(C)C
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1cc(Br)c(CO)cc1OCOCC[Si](C)(C)C
Reaction time: 0.5 h
Yield: 100.2 %

Procedure:
Sodium borohydride (275 mg, 7.2 mmol) was added in portions over 10 min to a solution of 2-bromo-4-methoxy-5-(2-trimethylsilanyl-ethoxymethoxy)-benzaldehyde (1.3 g, 3.6 mmol) in MeOH (20 mL) at 0° C. After 30 min, the reaction was diluted with H2O (40 mL) and extracted with EtOAc (2×30 mL). Organics were washed with brine (30 mL), dried (Na2SO4) and concentrated in vacuo to give 1.31 g of (2-bromo-4-methoxy-5-(2-trimethylsilanyl-ethoxymethoxy)-phenyl]-methanol as a clear oil. 1H NMR (300 MHz, CDCl3) δ 7.29 (s, 1H), 7.05 (s, 1H), 5.27 (s, 2H), 4.66 (d, 2H, J=6.6 Hz), 3.87 (s, 3H), 3.79 (t, 2H, J=8.4 Hz), 1.92 (t, 1H, J=6.6 Hz), 0.96 (t, 2H, J=8.4 Hz), 0.01 (s, 9H).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:14]=[CH:13][C:12]2[NH:11][CH:10]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[C:17]([Cl:22])[CH:16]=3)[CH2:9][C:8]([CH3:25])([CH:23]=[CH2:24])[C:7]=2[N:6]=1)=[O:4].[OH-].[Na+]>O1CCCC1.CO.O>[Cl:22][C:17]1[CH:16]=[C:15]([CH:10]2[CH2:9][C:8]([CH3:25])([CH:23]=[CH2:24])[C:7]3[N:6]=[C:5]([C:3]([OH:4])=[O:2])[CH:14]=[CH:13][C:12]=3[NH:11]2)[CH:20]=[CH:19][C:18]=1[F:21]
Reactant: C=CC1(C)CC(c2ccc(F)c(Cl)c2)Nc2ccc(C(=O)OC)nc21
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: C=CC1(C)CC(c2ccc(F)c(Cl)c2)Nc2ccc(C(=O)O)nc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 64.9 %

Procedure:
To a solution of 6-(3-chloro-4-fluoro-phenyl)-8-methyl-8-vinyl-5,6,7,8-tetrahydro-[1,5]naphthyridine-2-carboxylic acid methyl ester (300 mg, 0.8 mmol) in tetrahydrofuran (2 mL) and methanol (2 mL) was added 3 N sodium hydroxide (1 mL). The reaction mixture was stirred at room temperature for 16 hours, and then diluted with water (10 mL), extracted with diethyl ether (20 mL). The organic layer was discarded. The aqueous layer was acidified with concentrated hydrochloric acid to pH 4 and extracted with ethyl acetate (40 mL×3), and the combined organics were dried over anhydrous Na2SO4. The solvent was removed in vacuo and purified by preparative HPLC to afford 6-(3-chloro-4-fluoro-phenyl)-8-methyl-8-vinyl-5,6,7,8-tetrahydro-[1,5]naphthyridine-2-carboxylic acid (180 mg, 62.7%) as a yellow oil. MS (ESI+) [(M+H)+] 347.2.