Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].Cl.[OH:4][C@@H:5]1[CH2:10][CH2:9][CH2:8][CH2:7][C@H:6]1[NH2:11].[CH3:12][O:13][C:14]1[CH:15]=[C:16]([CH:20]=[CH:21][C:22]=1[O:23][CH2:24][C:25]#[CH:26])[C:17](Cl)=[O:18]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1>[OH:4][C@@H:5]1[CH2:10][CH2:9][CH2:8][CH2:7][C@H:6]1[NH:11][C:17](=[O:18])[C:16]1[CH:20]=[CH:21][C:22]([O:23][CH2:24][C:25]#[CH:26])=[C:14]([O:13][CH3:12])[CH:15]=1
Reactant: C#CCOc1ccc(C(=O)Cl)cc1OC
Reactant: N[C@@H]1CCCC[C@H]1O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [Br-]
Solvent: Cc1ccccc1
Product: C#CCOc1ccc(C(=O)N[C@@H]2CCCC[C@H]2O)cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 101.8 %

Procedure:
To a mixture of 10 ml of a 15% aqueous sodium hydroxide solution and 20 ml of toluene were added 1.08 g of trans-2-hydroxycyclohexylamine hydrochloride, 0.05 g of tetrabutylammonium bromide and 0.80 g of 3-methoxy-4-(2-propynyloxy)benzoyl chloride, and the mixture was stirred at room temperature for 2 hours. After the reaction mixture was extracted with ethyl acetate, the organic layer was washed successively with water and an aqueous saturated sodium chloride solution, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and 1.1 g of N-(trans-2-hydroxycyclohexyl)-3-methoxy-4-(2-propynyloxy)benzamide was obtained.
Reaction SMILES: [CH3:1][C:2]([CH3:15])([CH3:14])[CH2:3][C:4]([C:6]1[CH:13]=[CH:12][C:9]([CH:10]=[O:11])=[CH:8][CH:7]=1)=[O:5].[CH3:16][Mg]Br.O>C1COCC1.CCOC(C)=O>[OH:11][CH:10]([C:9]1[CH:8]=[CH:7][C:6]([C:4](=[O:5])[CH2:3][C:2]([CH3:15])([CH3:14])[CH3:1])=[CH:13][CH:12]=1)[CH3:16]
Reactant: C[Mg]Br
Reactant: CC(C)(C)CC(=O)c1ccc(C=O)cc1
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(O)c1ccc(C(=O)CC(C)(C)C)cc1
Temperature: -10 °C
Yield: 84.2 %

Procedure:
Dissolve 4-(3,3-dimethyl-butyryl)-benzaldehyde (1.67 g, 8.186 mmol) in anhydrous THF (20 mL) and cool the solution at −10° C. Add methyl magnesium bromide (2.7 mL, 8.186 mmol, 3M solution in diethyl ether) and stir the mixture for 30 min. Add water at 0° C., dilute with EtOAc and extract the aqueous layer three times with EtOAc. Dry the combined organic extracts over Na2SO4, filter through a short pad of silica gel and concentrate in vacuo to give the desired intermediate as yellow oil (1.519 g, 84%).
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][C:9]([O:11]CC2C=CC=CC=2)=[O:10])[CH:5]=[N:4][CH:3]=[N:2]1.[H][H]>C(O)C.[C].[Pd]>[N:1]1([CH2:6][CH2:7][CH2:8][C:9]([OH:11])=[O:10])[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: [H][H]
Reactant: O=C(CCCn1cncn1)OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: O=C(O)CCCn1cncn1
Yield: 89.1 %

Procedure:
0.5 g of 5% palladium carbon was added to a solution of 11 g of benzyl 4-(1,2,4-triazol-1-yl)butyrate in 150 ml of ethanol. The mixture was stirred at a hydrogen pressure of 1 atm. at room temperature for 1 hour. Thereto was added 100 ml of ethanol. The mixture was heated and made uniform. Palladium carbon was collected by filtration and washed with ethanol. The filtrate and the washings were combined and concentrated under reduced pressure. To the residue was added a small amount of ethanol. The resulting insolubles were collected by filtration to obtain 6.2 g of 4-(1,2,4-triazol-1-yl)butyric acid as a white powder.
Reaction SMILES: [CH:1]([C:4]1[CH:23]=[C:22]([C:24](=[O:30])[CH:25]=[CH:26][C:27]([OH:29])=O)[CH:21]=[CH:20][C:5]=1[O:6][CH2:7][C:8]([NH:10][C:11]1[S:12][C:13]2[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=2[N:15]=1)=[O:9])([CH3:3])[CH3:2].C(N(CC)CC)C.ClC(OCC(C)C)=O.[CH3:46][N:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1>ClCCl>[CH:1]([C:4]1[CH:23]=[C:22]([C:24](=[O:30])[CH:25]=[CH:26][C:27]([N:50]2[CH2:51][CH2:52][N:47]([CH3:46])[CH2:48][CH2:49]2)=[O:29])[CH:21]=[CH:20][C:5]=1[O:6][CH2:7][C:8]([NH:10][C:11]1[S:12][C:13]2[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=2[N:15]=1)=[O:9])([CH3:3])[CH3:2]
Reactant: CN1CCNCC1
Reactant: CC(C)c1cc(C(=O)C=CC(=O)O)ccc1OCC(=O)Nc1nc2ccccc2s1
Agent: CC(C)COC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)c1cc(C(=O)C=CC(=O)N2CCN(C)CC2)ccc1OCC(=O)Nc1nc2ccccc2s1
Reaction time: 2.5 h

Procedure:
To a solution of 2-[2-isopropyl-4-(3-carboxyacryloyl)phenoxymethylcarbonylamino]benzothiazole (1.0 g) and triethylamine (0.4 ml) in dichloromethane (20 ml) is added dropwise isobutyl chloroformate (0.32 ml) under ice-cooling. To the mixture is added N-methylpiperazine (0.27 ml) at the same temperature, and the mixture is stirred for 2.5 hours. The reaction solution is washed with water, dried and concentrated under reduced pressure. The residue is purified by silica gel column chromatography (solvent; dichloromethane→dichloromethane:methanol=30:1), and recrystallized from ethanol to give 2-{2-isopropyl-4-[3-(4-methyl-1-piperazinylcarbonyl)acryloyl]phenoxymethylcarbonylamino}benzothiazole (0.80 g).
Reaction SMILES: [CH3:1][C:2]1([CH3:29])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([C:14]([NH:16][C:17]3[CH:18]=[C:19]([CH:23]=[CH:24][C:25]([O:27]C)=[O:26])[CH:20]=[CH:21][CH:22]=3)=[O:15])[CH:5]=[CH:4][C:3]1=2.C1COCC1.[OH-].[Li+].Cl>O>[CH3:1][C:2]1([CH3:29])[CH2:11][CH2:10][C:9]([CH3:12])([CH3:13])[C:8]2[CH:7]=[C:6]([C:14]([NH:16][C:17]3[CH:18]=[C:19]([CH:23]=[CH:24][C:25]([OH:27])=[O:26])[CH:20]=[CH:21][CH:22]=3)=[O:15])[CH:5]=[CH:4][C:3]1=2
Reactant: COC(=O)C=Cc1cccc(NC(=O)c2ccc3c(c2)C(C)(C)CCC3(C)C)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC1(C)CCC(C)(C)c2cc(C(=O)Nc3cccc(C=CC(=O)O)c3)ccc21

Procedure:
2.9 g (7.4 mmol) of methyl 3-{3-[(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthalenecarbonyl)-amino]phenyl}acrylate obtained in Example 18, 50 ml of THF and 3.1 g (74 mmol) of lithium hydroxide are introduced into a round-bottomed flask. The reaction medium is refluxed for 24 h ours and then poured into water, acidified to pH 1 with concentrated hydrochloric acid and extracted with ethyl acetate, and the organic phase is separated out after settling has taken place, washed with water, dried over magnesium sulphate and evaporated. The residue obtained is triturated from heptane, filtered off and dried. 2.8 g (100%) of 3-{3-[(5,5,8,8- tetramethyl-5,6,7,8-tetrahydro-2-naphthalenecarbonyl) amino]phenyl}acrylic acid, with a melting point of 215-6° C., are collected.
Reaction SMILES: [CH3:1][C:2]1([C:11]([OH:13])=[O:12])[CH2:7][C:6]([CH3:9])([CH3:8])[CH2:5][C:4](=[O:10])[CH2:3]1.[CH3:14][C:15]([CH3:21])([CH2:19]C)[CH2:16][CH2:17]O.C(N=C=NC(C)C)(C)C>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH3:14][C:15]([CH3:21])([CH3:19])[CH2:16][CH2:17][O:12][C:11]([C:2]1([CH3:1])[CH2:7][C:6]([CH3:8])([CH3:9])[CH2:5][C:4](=[O:10])[CH2:3]1)=[O:13]
Reactant: CCC(C)(C)CCO
Reactant: CC1(C)CC(=O)CC(C)(C(=O)O)C1
Agent: CC(C)N=C=NC(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)CCOC(=O)C1(C)CC(=O)CC(C)(C)C1
Yield: 56.7 %

Procedure:
1,5,5-trimethyl-3-oxo-1-cyclohexylcarboxylic acid (3.0 g) (M. S. Ziegler and R. M. Herbst, J. Org. Chem. 1951, 16, 920) was treated with 3,3-dimethylpentanol (1.84 g), DMAP (2.21 g) and 1,3-diisopropylcarbodiimide (2.17 g) in CH2Cl2 (80 mL) under standard coupling conditions to give 2.41 g (55% yield) of 3-(3,3-dimethylbutoxycarbonyl)-3,5,5-trimethylcyclohexanone. Mass spectrum (EI) indicated parent ion at m/e 268.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[NH:19][C:20](=[O:37])[CH2:21][C:22]([C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([C:30]2[CH:31]=[N:32][C:33]([CH3:36])=[CH:34][CH:35]=2)[CH:25]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:14][C:12]1[C:11]([C:15]([F:16])([F:18])[F:17])=[CH:10][C:9]2[NH:19][C:20](=[O:37])[CH2:21][C:22]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:30]4[CH:31]=[N:32][C:33]([CH3:36])=[CH:34][CH:35]=4)[CH:25]=3)=[N:7][C:8]=2[CH:13]=1
Reactant: Cc1ccc(-c2cccc(C(=O)CC(=O)Nc3cc(C(F)(F)F)c(C)cc3NC(=O)OC(C)(C)C)c2)cn1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(-c2cccc(C3=Nc4cc(C)c(C(F)(F)F)cc4NC(=O)C3)c2)cn1

Procedure:
The title compound was prepared from (5-methyl-2-{3-[3-(6-methyl-pyridin-3-yl)-phenyl]-3-oxo-propionylamino}-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example M217) (299 mg, 0.57 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light yellow solid (194 mg, 83%).
Reaction SMILES: Cl.[O:2]1[CH2:7][CH2:6][N:5]([CH:8]2[CH2:13][CH2:12][N:11]([CH2:14][C:15]([OH:17])=O)[CH2:10][CH2:9]2)[CH2:4][CH2:3]1.[NH2:18][C@@H:19]([CH2:37][O:38][CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[C:20]([NH:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=2)=[CH:25][CH:24]=1)=[O:21]>>[CH2:39]([O:38][CH2:37][C@H:19]([NH:18][C:15](=[O:17])[CH2:14][N:11]1[CH2:10][CH2:9][CH:8]([N:5]2[CH2:4][CH2:3][O:2][CH2:7][CH2:6]2)[CH2:13][CH2:12]1)[C:20]([NH:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=2)=[CH:25][CH:24]=1)=[O:21])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1
Reactant: N[C@@H](COCc1ccccc1)C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1
Reactant: O=C(O)CN1CCC(N2CCOCC2)CC1
Agent: Cl
Product: O=C(CN1CCC(N2CCOCC2)CC1)N[C@@H](COCc1ccccc1)C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1
Yield: 47.4 %

Procedure:
Proceeding as in Example 1, but substituting 2-(4-morpholinopiperidin-1-yl)acetic acid hydrochloride and (S)-2-amino-3-(benzyloxy)-N-(4-(4-fluorophenoxy)phenyl)propanamide, gave Compound 105, (S)-3-(benzyloxy)-N-(4-(4-fluorophenoxy)phenyl)-2-(2-(4-morpholinopiperidin-1-yl)acetamido)propanamide (22.4 mg, 47.4%). Major isomer: 1H-NMR (400 MHz, DMSO-D6): σ 10.21 (s, 1H), 7.94 (d, 1H), 7.60 (d, 2H), 7.30 (m, 5H), 7.22 (t, 2H), 7.03-6.98 (m, 4H), 4.69 (m, 1H), 4.52 (s, 2H), 3.78 (m, 1H), 3.70 (m, 1H), 3.56 (t, 4H), 2.96-2.83 (m, 4H), 2.41 (m, 4H), 2.05 (m, 3H), 1.73 (m, 2H), 1.39 (m, 2H). MS (EI) for C33H39FN4O5. found 591.7 (MH+).
Reaction SMILES: [Cl:1]C1C=CC(C(O)=O)=C(OCC2C3C(OC(C)(C)O3)C(N3C=NC4C3=NC=NC=4NC(NC3C=CC=CC=3)=O)O2)N=1.Cl[C:43]1[N:51]=[C:50]([O:52][CH2:53][CH:54]2[CH:61]3[CH:57]([O:58][C:59]([CH3:63])([CH3:62])[O:60]3)[CH:56]([N:64]3[CH:72]=[N:71][C:70]4[C:65]3=[N:66][CH:67]=[N:68][C:69]=4[NH:73][C:74]([NH:76][C:77]3[CH:82]=[CH:81][CH:80]=[CH:79][CH:78]=3)=[O:75])[O:55]2)[CH:49]=[CH:48][C:44]=1[C:45]([OH:47])=[O:46]>>[Cl:1][C:49]1[C:50]([O:52][CH2:53][CH:54]2[CH:61]3[CH:57]([O:58][C:59]([CH3:63])([CH3:62])[O:60]3)[CH:56]([N:64]3[CH:72]=[N:71][C:70]4[C:65]3=[N:66][CH:67]=[N:68][C:69]=4[NH:73][C:74]([NH:76][C:77]3[CH:78]=[CH:79][CH:80]=[CH:81][CH:82]=3)=[O:75])[O:55]2)=[N:51][CH:43]=[C:44]([CH:48]=1)[C:45]([OH:47])=[O:46]
Reactant: CC1(C)OC2C(COc3nc(Cl)ccc3C(=O)O)OC(n3cnc4c(NC(=O)Nc5ccccc5)ncnc43)C2O1
Reactant: CC1(C)OC2C(COc3ccc(C(=O)O)c(Cl)n3)OC(n3cnc4c(NC(=O)Nc5ccccc5)ncnc43)C2O1
Product: CC1(C)OC2C(COc3ncc(C(=O)O)cc3Cl)OC(n3cnc4c(NC(=O)Nc5ccccc5)ncnc43)C2O1

Procedure:
6-Chloro-2-{2,2-dimethyl-6-[6-(3-phenyl-ureido)-purin-9-yl]-tetrahydro-furo[3,4-d][1,3]dioxol-4-ylmethoxy}-nicotinic acid (isomer A) & 2-Chloro-6-{2,2-dimethyl-6-[6-(3-phenyl-ureido)-purin-9-yl]-tetrahydro-furo[3,4-d][1,3]dioxol-4-ylmethoxy}-nicotinic acid (isomer B):
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH:16]([CH2:17][CH:18]([O:21][CH3:22])[O:19][CH3:20])[CH2:15][CH2:14][CH2:13][CH:12]1[C:23](O)=[O:24])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:26]([NH2:34])[CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH2:1]([O:8][C:9]([N:11]1[CH:12]([C:23](=[O:24])[NH:34][CH2:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:13][CH2:14][CH2:15][CH:16]1[CH2:17][CH:18]([O:21][CH3:22])[O:19][CH3:20])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCCc1ccccc1
Reactant: COC(CC1CCCC(C(=O)O)N1C(=O)OCc1ccccc1)OC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: ClCCl
Product: COC(CC1CCCC(C(=O)NCCc2ccccc2)N1C(=O)OCc1ccccc1)OC
Temperature: 25 °C
Reaction time: 18 h
Yield: 85.7 %

Procedure:
6-(2,2-Dimethoxy-ethyl)-piperidine-1,2-dicarboxylic acid 1-benzyl ester (Compound 238, 0.335 g, 0.96 mmol) and phenethyl amine (0.14 g, 1.15 mmol) were dissolved CH2Cl2 (20 mL). HOBt (0.156 g, 1.15 mmol) was added followed by EDC.HCl (0.221 g, 1.15 mmol). The reaction was stirred at room temperature for 18 hours. Saturated NaHCO3 solution (25 mL) was added and then extracted with CHCl3 (2×50 mL). The combined organic layers were dried over Na2SO4, and then concentrated. Flash chromatographic purification of the residue (1:1 EtOAc/hexanes) gave Compound 239 (0.374 g, 86%). Rf=0.47 (1:1 EtOAC/hexanes).
Reaction SMILES: C(O[C:5](=[O:7])C)(=O)C.[NH2:8][CH2:9][C:10]1([N:16]2[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]2)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1>C(O)=O>[CH:5]([NH:8][CH2:9][C:10]1([N:16]2[CH2:17][CH2:18][N:19]([CH3:22])[CH2:20][CH2:21]2)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1)=[O:7]
Reactant: CC(=O)OC(C)=O
Reactant: CN1CCN(C2(CN)CCCCC2)CC1
Solvent: O=CO
Product: CN1CCN(C2(CNC=O)CCCCC2)CC1
Reaction time: 1 h
Yield: 62.7 %

Procedure:
Formic acid (6.9 g, 0.15 mole) and acetic anhydride (15.3 g, 0.15 mole) were mixed without cooling and kept at room temperature for 1 hr. 1-(1-aminomethylcyclohexyl)-4-methylpiperazine (8.4 g, 0.04 mole) was dissolved in formic acid (12 ml) and the formylating mixture (16 ml) added. This produced vigorous effervescence and a rise in temperature to 70°. The mixture was left at room temperature for 2 hr. and then heated on a water bath at 55° for 0.75 hr. The solvents were removed under reduced pressure yielding a viscous brown oil (6.0 g, 66.3%) which crystallised as colourless plates of 1-(1-formylaminomethylcyclohexyl)-4-methylpiperazine from light petroleum (b.p. 80°-100°), m.p. 97°-98°.
Reaction SMILES: C[O:2][C:3](=[O:15])[CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:13]=[C:12]([NH2:14])[CH:11]=[CH:10][CH:9]=1.[NH:16]([C:23]1[S:24][C:25]2[CH:31]=[C:30]([CH2:32][C:33](O)=[O:34])[CH:29]=[CH:28][C:26]=2[N:27]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[NH:16]([C:23]1[S:24][C:25]2[CH:31]=[C:30]([CH2:32][C:33]([NH:14][C:12]3[CH:11]=[CH:10][CH:9]=[C:8]([O:7][CH2:6][CH2:5][CH2:4][C:3]([OH:2])=[O:15])[CH:13]=3)=[O:34])[CH:29]=[CH:28][C:26]=2[N:27]=1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: COC(=O)CCCOc1cccc(N)c1
Reactant: O=C(O)Cc1ccc2nc(Nc3ccccc3)sc2c1
Product: O=C(O)CCCOc1cccc(NC(=O)Cc2ccc3nc(Nc4ccccc4)sc3c2)c1

Procedure:
Methyl4-(5-aminophenoxy)butyrate was made as described in example 7 above and coupled with 2-anilino-6-carboxymethylbenzothiazole according to the method described in example 7 to produce the methyl ester of 2-anilino-6-{3-[3-carboxypropoxy]anilino carbonyl methyl}benzothiazole
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][C:9]1[C:14]([C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[O:23][CH3:24])=[O:16])=[CH:13][N:12]=[C:11]([NH:25][CH:26]2[CH2:31][CH2:30][CH2:29][NH:28][CH2:27]2)[N:10]=1.Cl[C:33]([O:35][CH2:36][CH3:37])=[O:34]>>[CH2:36]([O:35][C:33]([N:28]1[CH2:29][CH2:30][CH2:31][CH:26]([NH:25][C:11]2[N:10]=[C:9]([NH2:8])[C:14]([C:15](=[O:16])[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[O:23][CH3:24])=[CH:13][N:12]=2)[CH2:27]1)=[O:34])[CH3:37]
Reactant: CCOC(=O)Cl
Reactant: COc1ccccc1C(=O)c1cnc(NC2CCCNC2)nc1N
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)N1CCCC(Nc2ncc(C(=O)c3ccccc3OC)c(N)n2)C1

Procedure:
The same procedure as described in Example 54 was used, starting with [4-amino-2-(piperidin-3-ylamino)-pyrimidin-5-yl]-(2-methoxy-phenyl)-methanone trifluoroacetic acid salt, Example 53, and ethyl chloroformate (Aldrich) to give 3-[4-amino-5-(2-methoxy-benzoyl)-pyrimidin-2-ylamino]-piperidine-1-carboxylic acid ethyl ester. MS (M+H)+, 400.
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:18]2[NH:28][C:21]3=[N:22][CH:23]=[C:24]([CH2:26]O)[CH:25]=[C:20]3[CH:19]=2)[C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][CH:9]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.S(Cl)([Cl:31])=O>ClCCl>[Cl:31][CH2:26][C:24]1[CH:25]=[C:20]2[CH:19]=[C:18]([CH:7]([C:8]3[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][CH:9]=3)[CH2:6][CH:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)[NH:28][C:21]2=[N:22][CH:23]=1
Reactant: CS(=O)(=O)c1ccc(C(CC2CCCC2)c2cc3cc(CO)cnc3[nH]2)cc1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc(C(CC2CCCC2)c2cc3cc(CCl)cnc3[nH]2)cc1
Reaction time: 2 h
Yield: 99.7 %

Procedure:
To a stirred solution of {2-[2-cyclopentyl-1-(4-methanesulfonyl-phenyl)-ethyl]-1H-pyrrolo[2,3-b]pyridin-5-yl}-methanol (prepared as in Example 8, 800 mg, 1.92 mmol) in dichloromethane (20 mL) at 0° C. was added a solution of thionyl chloride (0.36 mL, 4.89 mmol) in dichloromethane (2 mL) and the mixture was stirred for 2 h. The resulting mixture was concentrated in vacuo and the residue was extracted with ethyl acetate, washed with a saturated aqueous sodium bicarbonate solution (2×50 mL), brine, dried over anhydrous sodium sulfate and then concentrated in vacuo to afford 5-chloromethyl-2-[2-cyclopentyl-1-(4-methanesulfonyl-phenyl)-ethyl]-1H-pyrrolo[2,3-b]pyridine (798 mg, quant.) as a light yellow solid which was used in the next step without further purification: LC/MS m/e calcd for C22H25ClN2O2S [M+H]+ 417.97, observed 417.0.
Reaction SMILES: [OH-].[Na+].C([O:5][C:6]([CH2:8][C:9]1[S:13][C:12]([N:14]=[C:15]2[N:19]3[CH2:20][C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][C:26]=4[CH2:27][C@H:18]3[CH2:17][S:16]2)=[N:11][CH:10]=1)=[O:7])C.[ClH:28]>C(O)C>[ClH:28].[C:6]([CH2:8][C:9]1[S:13][C:12]([N:14]=[C:15]2[N:19]3[CH2:20][C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][C:26]=4[CH2:27][C@H:18]3[CH2:17][S:16]2)=[N:11][CH:10]=1)([OH:7])=[O:5]
Reactant: CCOC(=O)Cc1cnc(N=C2SC[C@@H]3Cc4ccccc4CN23)s1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)Cc1cnc(N=C2SC[C@@H]3Cc4ccccc4CN23)s1
Temperature: 20 °C

Procedure:
5 N Aqueous sodium hydroxide (20 cc) is added to a solution of (S)-3-[(5-ethoxycarbonylmethylthiazol-2-yl)imino]-1,5,10,10a-tetrahydrothiazolo[3,4-b]-isoquinoline (7.9 g) in ethanol (60 cc). The mixture is heated under reflux for two hours. After cooling to 20° C., it is acidified by adding 12 N hydrochloric acid (d=1.19; 10 cc). The resulting precipitate is filtered off and washed with water (3×50 cc) and then with ethanol (50 cc) and diethyl ether (20 cc). The product is recrystallised by dissolving it in dimethylformamide (15 cc) at 70° C., adding ethanol (80 cc) and cooling to 0° C. The resulting crystals are filtered off, washed with ethanol (50 cc) and then with diethyl ether (20 cc) and dried at 50° C. under reduced pressure (0.1 mm Hg; 0.013 kPa) to yield (S)-3-[(5-carboxymethylthiazol-2-yl)imino]-1,5,10,10a-tetrahydrothiazolo[3,4-b]isoquinoline hydrochloride (6.8 g), melting at about 240° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]2[O:13][CH:12](Br)[CH:11](Br)[N:10]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:9]=2[CH:23]=1)=[O:4].[Na+].[I-]>CC(C)=O>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]2[O:13][CH:12]=[CH:11][N:10]([C:16]([O:18][C:19]([CH3:21])([CH3:20])[CH3:22])=[O:17])[C:9]=2[CH:23]=1)=[O:4]
Reactant: COC(=O)c1ccc2c(c1)N(C(=O)OC(C)(C)C)C(Br)C(Br)O2
Agent: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: COC(=O)c1ccc2c(c1)N(C(=O)OC(C)(C)C)C=CO2
Yield: 92.1 %

Procedure:
2,3-Dibromo-2,3-dihydro-benzo[1,4]oxazine-4,6-dicarboxylic acid 4-tert-butyl ester 6-methyl ester (767 mg, 1.7 mmol) from proceeding step was stirred in acetone (14 ml) at RT for 2 h with NaI (1.27 g, 8.5 mmol). The solvent was removed, EtOAc, water and 1 M sodium thiosulfate were added. After separating phases the organic layer was washed with brine. The solvent was concentrated and the crude was purified on silica gel using CH/EtOAc 7:3 to obtain a colorless oil (456 mg, 92%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:18]([N:19]2[CH2:24][CH2:23][CH2:22][CH2:21][C@@H:20]2[CH3:25])=[N:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:26]([O:28]C)=[O:27])[CH:15]=2)[N:10]=1.[OH-].[Na+]>CO.O>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:18]([N:19]2[CH2:24][CH2:23][CH2:22][CH2:21][C@@H:20]2[CH3:25])=[N:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:26]([OH:28])=[O:27])[CH:15]=2)[N:10]=1
Reactant: COC(=O)c1ccc2nc(-c3ccc(F)cc3F)c(N3CCCC[C@@H]3C)nc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: C[C@H]1CCCCN1c1nc2cc(C(=O)O)ccc2nc1-c1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 57.9 %

Procedure:
To a solution of (S)-methyl 2-(2,4-difluorophenyl)-3-(2-methylpiperidin-1-yl)quinoxaline-6-carboxylate (100 mg, 0.25 mmol) in methanol (30 mL) and water (1.0 mL) was added sodium hydroxide (40 mg, 1.00 mmol) with stirring overnight at room temperature. The reaction mixture was concentrated in vacuo, dissolved in water (10 mL) and adjusted to pH 5 with HCl (3N). The solids were collected by filtration to afford (S)-2-(2,4-difluorophenyl)-3-(2-methylpiperidin-1-yl)quinoxaline-6-carboxylic acid as a light yellow solid (55.5 mg, 57.5%).
Reaction SMILES: [OH:1][C@H:2]([CH2:15][CH2:16][C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1)[C@H:3]([CH3:14])[O:4][C:5]1[CH:10]=[CH:9][C:8](B(O)O)=[CH:7][CH:6]=1.Br[C:24]1[CH:25]=[C:26]([CH:32]=[CH:33][CH:34]=1)[O:27][CH2:28][C:29]([NH2:31])=[O:30].C(=O)([O-])[O-].[Na+].[Na+]>C(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>[OH:1][C@H:2]([CH2:15][CH2:16][C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1)[C@@H:3]([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:24]2[CH:25]=[C:26]([O:27][CH2:28][C:29]([NH2:31])=[O:30])[CH:32]=[CH:33][CH:34]=2)=[CH:7][CH:6]=1)[CH3:14]
Reactant: C[C@H](Oc1ccc(B(O)O)cc1)[C@H](O)CCc1cccnc1
Reactant: NC(=O)COc1cccc(Br)c1
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: [Na+]
Solvent: CCO
Product: C[C@H](Oc1ccc(-c2cccc(OCC(N)=O)c2)cc1)[C@H](O)CCc1cccnc1
Temperature: 90 °C
Yield: 68.2 %

Procedure:
Prepared according to the method described in Example 12b) from (1S,2R)-4-(2-hydroxy-1-methyl-4-pyridin-3-ylbutoxy)benzeneboronic acid (0.150 g, Example 33), 2-(3-bromophenoxy)acetamide (0.230 g), 2M aqueous sodium carbonate (0.50 ml) and tetrakis(triphenylphosphine)palladium(0) (0.025 g) in ethanol (3 ml). The reaction mixture was heated at 90° C. for 4 hours. After cooling, the solution was concentrated under reduced pressure, taken up in ethanol and concentrated again (twice). The residue was triturated with acetone and then filtered through silica gel. The filtrate was concentrated under reduced pressure, dissolved in dichloromethane, filtered and purified by normal-phase HPLC eluting with a gradient of 0-25% ethanol in dichloromethane to give a colourless solid, which was recrystallised from boiling ethyl acetate:isohexane (1:1) to give the title compound as a solid (0.138 g).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:9]=[C:8]([C:10]([O:12]C)=[O:11])[N:7]([CH2:14][C:15]2[CH:19]=[C:18]([C:20]3[S:21][C:22]([Cl:25])=[CH:23][CH:24]=3)[O:17][N:16]=2)[N:6]=1)=[O:4].[OH-].[Na+].Cl>O.C1COCC1>[CH3:1][O:2][C:3]([C:5]1[CH:9]=[C:8]([C:10]([OH:12])=[O:11])[N:7]([CH2:14][C:15]2[CH:19]=[C:18]([C:20]3[S:21][C:22]([Cl:25])=[CH:23][CH:24]=3)[O:17][N:16]=2)[N:6]=1)=[O:4]
Reactant: COC(=O)c1cc(C(=O)OC)n(Cc2cc(-c3ccc(Cl)s3)on2)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1cc(C(=O)O)n(Cc2cc(-c3ccc(Cl)s3)on2)n1
Reaction time: 3 h

Procedure:
To a solution of 1.7 g 1-[5-(5-Chloro-thiophen-2-yl)-isoxazol-3-ylmethyl]-1H-pyrazole-3,5-dicarboxylic acid dimethyl ester in 10 ml water/THF 1:1, 4 ml of a 1M aqueous NaOH were added at RT and the mixture was stirred for 3 h with LCMS reaction control. Then the reaction mixture was acidified to pH 3 with half concentrated HCl and extracted with DCM (3×50 ml). The organic phase was dried over MgSO4, filtered and the solvent removed under reduced pressure. The residue was subjected to the next reaction step without further purification.