Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(C(C)C)CC)(C)C.[C:10]([O:14][C:15](=[O:23])[NH:16][CH:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1)([CH3:13])([CH3:12])[CH3:11].Cl[S:25]([C:28]1[CH:36]=[CH:35][C:31]([C:32]([OH:34])=[O:33])=[CH:30][CH:29]=1)(=[O:27])=[O:26]>C1COCC1>[C:10]([O:14][C:15]([NH:16][CH:17]1[CH2:22][CH2:21][N:20]([S:25]([C:28]2[CH:29]=[CH:30][C:31]([C:32]([OH:34])=[O:33])=[CH:35][CH:36]=2)(=[O:27])=[O:26])[CH2:19][CH2:18]1)=[O:23])([CH3:13])([CH3:11])[CH3:12]
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: O=C(O)c1ccc(S(=O)(=O)Cl)cc1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NC1CCN(S(=O)(=O)c2ccc(C(=O)O)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 119.7 %

Procedure:
Diisopropylethylamine (10.9 ml, 62.4 mmol) was added in one portion to a stirred solution of piperidin-4-yl-carbamic acid tert-butyl ester (5.0 g, 20.0 mmol) in THF (150 ml) at room temperature. To this mixture was added 4-(chlorosulfonyl)benzoic acid (5.52 g, 25.0 mmol) portion wise and the mixture was stirred at room temperature under a nitrogen atmosphere for 1 hour. After this time the mixture was concentrated and the resulting residue suspended in HCl (1M solution, 100 ml), the resulting solid precipitate was collected by filtration, washed with water and dried under vacuum give the title compound (9.2 g, 96% yield) as a white solid. Tr=1.28 min m/z (ES+) (M+Na+) 407.
Reaction SMILES: C1CCC(N=C=NC2CCCCC2)CC1.[OH:16][N:17]1[C:21](=[O:22])[CH2:20][CH2:19][C:18]1=[O:23].[CH3:24][C:25]1[CH:30]=[CH:29][N:28]=[C:27]([C:31]2[CH:36]=[C:35]([CH2:37][CH2:38][CH2:39][C:40](O)=[O:41])[CH:34]=[CH:33][N:32]=2)[CH:26]=1>ClCCl>[C:21]1(=[O:22])[N:17]([O:16][C:40](=[O:41])[CH2:39][CH2:38][CH2:37][C:35]2[CH:34]=[CH:33][N:32]=[C:31]([C:27]3[CH:26]=[C:25]([CH3:24])[CH:30]=[CH:29][N:28]=3)[CH:36]=2)[C:18](=[O:23])[CH2:19][CH2:20]1
Reactant: Cc1ccnc(-c2cc(CCCC(=O)O)ccn2)c1
Reactant: O=C1CCC(=O)N1O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: Cc1ccnc(-c2cc(CCCC(=O)ON3C(=O)CCC3=O)ccn2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
More specifically, with reference to the reaction scheme I ,4-(4′-methyl-[2,2′]bipyridinyl-4-yl)-butyric acid succinimidyl ester was obtained according to step (5) as follows. 27 mg of DCC (0.129 mmol) and 14 mg N-hydroxysuccinimide (0.129 mmol) were added to 30 mg (0.117 mmol) of 4-(4′-methyl-[2,2′]bipyridinyl-4-yl)-butyric acid (prepared as schematically illustrated by steps (1)-(4) of the reaction scheme I, according to the published procedure in Della Ciana et al., JOC 1989, 54, 1731-1725) in dichloromethane and stirred at room temperature for 2 hours. After 2 hours, the reaction mixture was filtered and concentrated in vacuo. The pure final 4-(4′-methyl-[2,2′]bipyridinyl-4-yl)-butyric acid succinimidyl ester was obtained as a clear oil after column chromatography (SiO2, EtOAc, Hex). 1H NMR: 8.55 (dd, 4H), 8.26 (d, 2H), 7.21 (d, 2H), 2.86 (m, 6H), 2.68 (t, 2H), 2.46 (s, 3H), 2.171 (t, 2H). ESI-MS: m/z=354.
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:18])([F:17])[C:5]1[CH:10]=[CH:9][N:8]=[C:7]([C:11]2[NH:12][O:13][C:14](=[O:16])[N:15]=2)[CH:6]=1.[CH:19]1([C:22](Cl)=[O:23])[CH2:21][CH2:20]1.[Cl-].[NH4+]>CN(C)C=O>[CH:19]1([C:22]([N:15]2[C:14](=[O:16])[O:13][N:12]=[C:11]2[C:7]2[CH:6]=[C:5]([C:4]([F:3])([F:17])[F:18])[CH:10]=[CH:9][N:8]=2)=[O:23])[CH2:21][CH2:20]1
Reactant: O=c1nc(-c2cc(C(F)(F)F)ccn2)[nH]o1
Reactant: O=C(Cl)C1CC1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: O=C(C1CC1)n1c(-c2cc(C(F)(F)F)ccn2)noc1=O
Reaction time: 0.17 h
Yield: 30.9 %

Procedure:
Into 2 ml of N,N-dimethylformamide was suspended 0.04 g of sodium hydride (60% oily), and 0.2 g of 3-(4-trifluoromethylpyridin-2-yl)-1,2,4-oxadiazol-5-one was added at 0° C. After stirring for 10 minutes, 0.12 g of cyclopropanecarbonyl chloride was added, and the mixture was stirred at 50° C. for 4 hours. Thereafter, the reaction solution was poured into an aqueous saturated ammonium chloride solution, followed by extraction with ethyl acetate three times. The organic layers were combined, washed with an aqueous saturated sodium chloride solution, dried with anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography to obtain 0.08 g of 4-cyclopropanecarbonyl-3-(4-trifluoromethylpyridin-2-yl)-1,2,4-oxadiazol-5-one (present compound (4)).
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:10][CH:11]([CH2:26][OH:27])[CH2:12][N:13]1[C:25]2[C:24]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[N:18]=[CH:17][C:16]=2[N:15]=[CH:14]1>>[C:1]([O:10][CH:11]([CH2:26][O:27][C:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:12][N:13]1[C:25]2[C:24]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[N:18]=[CH:17][C:16]=2[N:15]=[CH:14]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCC(O)Cn1cnc2cnc3ccccc3c21
Reactant: O=C(Cl)c1ccccc1
Product: O=C(OCC(Cn1cnc2cnc3ccccc3c21)OC(=O)c1ccccc1)c1ccccc1

Procedure:
Using the method of Example 115, benzoyl chloride was reacted with 1-(2,3-dihydroxypropyl)-1H-imidazo[4,5-c]-quinoline (from Example 51) to provide 1-(2,3-dibenzoyloxypropyl)-1H-imidazo[4,5-c]quinoline.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]([N:12]2[CH2:17][CH2:16][C:15]3[CH:18]=[C:19]([C:21]4[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=4)[S:20][C:14]=3[C:13]2=[O:29])[CH:9]=[CH:8][C:4]=1[C:5](O)=[O:6].[N:30]1([CH2:35][CH2:36][NH2:37])[CH2:34][CH2:33][CH2:32][CH2:31]1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(CC)CC>CN(C=O)C.CCOC(C)=O>[CH3:1][O:2][C:3]1[CH:11]=[C:10]([N:12]2[CH2:17][CH2:16][C:15]3[CH:18]=[C:19]([C:21]4[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=4)[S:20][C:14]=3[C:13]2=[O:29])[CH:9]=[CH:8][C:4]=1[C:5]([NH:37][CH2:36][CH2:35][N:30]1[CH2:34][CH2:33][CH2:32][CH2:31]1)=[O:6]
Reactant: COc1ccc(-c2cc3c(s2)C(=O)N(c2ccc(C(=O)O)c(OC)c2)CC3)cc1
Reactant: NCCN1CCCC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1ccc(-c2cc3c(s2)C(=O)N(c2ccc(C(=O)NCCN4CCCC4)c(OC)c2)CC3)cc1
Yield: 5.1 %

Procedure:
Suspend 2-methoxy-4-[2-(4-methoxy-phenyl)-7-oxo-4,7-dihydro-5H-thieno[2,3-c]pyridin-6-yl]-benzoic acid (0.1451 g, 0.35 mmol) in DMF (5 mL) and add 2-pyrrolidin-1-yl-ethylamine (45 mg, 0.39 mmol), EDCI (81 mg, 0.42 mmol), HOBt (57 mg, 0.42 mmol) and Et3N (0.15 mL, 1.06 mmol). Stir the reaction at RT overnight. Dilute with EtOAc (100 mL), wash with water (2×30 mL), and dry over Na2SO4. Purify the crude material by silica gel chromatography, eluting with 2% NH3—H2O, 50% CH3OH/EtOAc to give 9 mg (5%) of the title compound. LC-MS/ES m/z 506.2 [M+H]+.
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([Cl:8])[N:3]=1.[OH:9][C:10]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:11]=1[CH:12]=[CH:13][CH:14]=[N:15]2>CCOC(C)=O.C1CCCCC1>[Cl:8][C:4]1[CH:5]=[N:6][CH:7]=[C:2]([O:9][C:10]2[C:11]3[CH:12]=[CH:13][CH:14]=[N:15][C:16]=3[CH:17]=[CH:18][CH:19]=2)[N:3]=1
Reactant: Clc1cncc(Cl)n1
Reactant: Oc1cccc2ncccc12
Solvent: CCOC(C)=O
Solvent: C1CCCCC1
Product: Clc1cncc(Oc2cccc3ncccc23)n1
Yield: 61 %

Procedure:
Using Method DD with 2,6-dichloropyrazine (250 mg, 1.69 mmol) and 5-hydroxyquinoline (270 mg, 1.49 mmol), and purification by column chromatography (AcOEt:cyclohexane, 1:1), the title compound was obtained (264 mg). Yield: 61%. 1H NMR (250 MHz, DMSO-d6) δ 7.54-7.58 (m, 2H, Harom 3+8), 7.84 (t, 1H, Harom 7, J=8.1 Hz), 8.01 (d, 1H, Harom 6, J=8.5 Hz), 8.37 (d, 1H, Harom 4, J=8.0 Hz), 8.55 (s, 1H, HPz 5), 8.73 (s, 1H, HPz 3), 8.98 (dd, 1H, Harom 2, J=1.4 Hz, J=4.0 Hz). m/z: 258.0 [(M+H)+, calcd for C13H8ClN3O 257.0].
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[N:11][C:12]([N:15]3[CH2:19][CH2:18][CH2:17][C@H:16]3[C:20]([F:23])([F:22])[F:21])=[N:13][CH:14]=2)O1.Br[C:26]1[N:31]=[C:30]([NH2:32])[CH:29]=[CH:28][CH:27]=1.C(=O)([O-])[O-].[Na+].[Na+]>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.O1CCOCC1>[F:23][C:20]([F:21])([F:22])[C@@H:16]1[CH2:17][CH2:18][CH2:19][N:15]1[C:12]1[N:13]=[CH:14][C:9]([C:26]2[N:31]=[C:30]([NH2:32])[CH:29]=[CH:28][CH:27]=2)=[CH:10][N:11]=1
Reactant: CC1(C)OB(c2cnc(N3CCC[C@H]3C(F)(F)F)nc2)OC1(C)C
Reactant: Nc1cccc(Br)n1
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: C1COCCO1
Product: Nc1cccc(-c2cnc(N3CCC[C@H]3C(F)(F)F)nc2)n1
Temperature: 90 °C
Yield: 83.3 %

Procedure:
A flask was charged with (S)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(2-(trifluoromethyl)pyrrolidin-1-yl)pyrimidine (Intermediate 2, 5 g, 14.57 mmol), 6-bromopyridin-2-amine (3.03 g, 17.48 mmol), Pd(PPh3)4 (1.684 g, 1.457 mmol) and 1,4-dioxane (36 mL). The reaction mixture was purged with nitrogen for several minutes before aqueous 2M sodium carbonate (14.57 mL, 29.1 mmol) solution was added. The reaction mixture was then purged with nitrogen for another 10 minutes at 25° C. before it was heated to 90° C. under nitrogen overnight. 1,4-Dioxane was removed in vacuo and the crude mixture was diluted with EtOAc. The product was washed with water (3×) and brine. The combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure. The crude material was purified on silica gel chromatography eluting with MeOH:CH2Cl2 (2:98) to yield 3.75 g (12.13 mmol, 83%) of the title product as an off white solid; 1H NMR (300 MHz, DMSO-d6) δ 8.99 (s, 2H), 7.44 (dd, J=8.1, 7.5 Hz, 1H), 7.13-6.93 (m, 1H), 6.47-6.34 (m, 1H), 6.04 (s, 2H), 5.22-4.90 (m, 1H), 3.67 (t, J=6.1 Hz, 2H), 2.32-1.95 (m, 4H); m/z found [M+H]+=310.45.
Reaction SMILES: [F:1][C:2]1([C:21]([O:23]C)=[O:22])[CH2:7][CH2:6][N:5]([CH:8]2[CH2:11][C:10]3([CH2:15][CH2:14][N:13]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:12]3)[CH2:9]2)[CH2:4][CH2:3]1.[Li+].[OH-].Cl>C1COCC1>[CH2:19]([O:18][C:16]([N:13]1[CH2:14][CH2:15][C:10]2([CH2:11][CH:8]([N:5]3[CH2:6][CH2:7][C:2]([F:1])([C:21]([OH:23])=[O:22])[CH2:3][CH2:4]3)[CH2:9]2)[CH2:12]1)=[O:17])[CH3:20]
Reactant: CCOC(=O)N1CCC2(CC(N3CCC(F)(C(=O)OC)CC3)C2)C1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCOC(=O)N1CCC2(CC(N3CCC(F)(C(=O)O)CC3)C2)C1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Ethyl 2-[4-fluoro-4-(methoxycarbonyl) piperidin-1-yl]-6-azaspiro[3.4]octane-6-carboxylate (assumed 0.81 mmol) was dissolved in THF (5 mL) at rt and 1 M LiOH sol. (0.81 mL) was added. The reaction mixture was stirred at rt for 2 days. The pH was carefully adjusted to pH 6 by addition of concentrated hydrochloric acid, the solvents were removed in vacuo, to give 1-[6-(ethoxycarbonyl)-6-azaspiro[3.4]oct-2-yl]-4-fluoropiperidine-4-carboxylic acid as an off white solid, which was used directly without further purification.
Reaction SMILES: C(Cl)CCl.[C:5]([O:9][C:10]([NH:12][CH:13]([CH:17]([OH:26])[C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1)[C:14]([OH:16])=O)=[O:11])([CH3:8])([CH3:7])[CH3:6].FC(F)(F)C(O)=O.[CH2:34]([O:38][C:39]1([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=2[CH3:49])[CH2:42][NH:41][CH2:40]1)[CH2:35][CH2:36][CH3:37].C1C=NC2N(O)N=NC=2C=1.[OH-].[Na+]>CN(C)C1C=CN=CC=1.ClCCl>[C:5]([O:9][C:10](=[O:11])[NH:12][CH:13]([C:14]([N:41]1[CH2:40][C:39]([O:38][CH2:34][CH2:35][CH2:36][CH3:37])([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=2[CH3:49])[CH2:42]1)=[O:16])[CH:17]([OH:26])[C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1)([CH3:6])([CH3:7])[CH3:8]
Reactant: COc1ccc(C(O)C(NC(=O)OC(C)(C)C)C(=O)O)cc1
Reactant: CCCCOC1(c2ccccc2C)CNC1
Agent: CN(C)c1ccncc1
Agent: On1nnc2cccnc21
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCCl
Solvent: ClCCl
Product: CCCCOC1(c2ccccc2C)CN(C(=O)C(NC(=O)OC(C)(C)C)C(O)c2ccc(OC)cc2)C1
Temperature: 0 °C
Reaction time: 24 h
Yield: 85.3 %

Procedure:
740 mg (3.5 mmol) of EDC and 1.2 g (9.6 mmol) of 4-dimethylaminopyridine are added to a solution of 1 g (3.2 mmol) of 2-tert-butoxycarbonylamino-3-hydroxy-3-(4-methoxyphenyl)propanoic acid, 1.1 g (3.5 mmol) of 3-butoxy-3-o-tolylazetidine trifluoroacetate and 480 mg (3.5 mmol) of HOAT in 10 ml of dichloromethane cooled to 0° C. After stirring for 24 hours at ambient temperature, the reaction medium is treated with a 1N aqueous solution of sodium hydroxide and then extracted with ethyl acetate. The organic phase is washed successively with a 1N aqueous solution of hydrochloric acid and water, and then dried over magnesium sulphate, filtered and concentrated. The residue obtained is purified by silica gel chromatography (eluent: 60/40 heptane/ethyl acetate). 1.4 g of tert-butyl[1-(3-butoxy-3-o-tolylazetidine-1-carbonyl)-2-hydroxy-2-(4-methoxyphenyl)ethyl]carbamate are obtained in the form of a colourless oil with a yield of 87%.
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20](SCC)=[N:19][C:18]4=[O:25])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:28]([F:31])([F:30])[F:29])[CH:3]=1.[C:32]([O:36][C:37]([N:39]1[CH2:43][CH:42]([OH:44])[CH:41]([NH2:45])[CH2:40]1)=[O:38])([CH3:35])([CH3:34])[CH3:33]>>[C:32]([O:36][C:37]([N:39]1[CH2:43][CH:42]([OH:44])[CH:41]([NH:45][C:20]2[S:21][C:17](=[CH:16][C:12]3[CH:11]=[C:10]4[C:15](=[CH:14][CH:13]=3)[N:7]([CH2:6][C:5]3[CH:26]=[CH:27][C:2]([Cl:1])=[CH:3][C:4]=3[C:28]([F:31])([F:29])[F:30])[N:8]=[CH:9]4)[C:18](=[O:25])[N:19]=2)[CH2:40]1)=[O:38])([CH3:35])([CH3:33])[CH3:34]
Reactant: CCSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Reactant: CC(C)(C)OC(=O)N1CC(N)C(O)C1
Product: CC(C)(C)OC(=O)N1CC(O)C(NC2=NC(=O)C(=Cc3ccc4c(cnn4Cc4ccc(Cl)cc4C(F)(F)F)c3)S2)C1

Procedure:
3-{5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-ylamino}-4-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester was prepared from 5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazol-4-one and 3-Amino-4-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester following General Procedure C.
Reaction SMILES: [C:1]1([CH:7]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:8][NH:9][C:10]2[N:18]=[C:17]([C:19]#[N:20])[N:16]=[C:15]3[C:11]=2[N:12]=[CH:13][N:14]3[CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][O:22]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>N.C(O)C.[Pd]>[NH2:20][CH2:19][C:17]1[N:16]=[C:15]2[C:11]([N:12]=[CH:13][N:14]2[CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][O:22]2)=[C:10]([NH:9][CH2:8][CH:7]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:18]=1
Reactant: N#Cc1nc(NCC(c2ccccc2)c2ccccc2)c2ncn(C3CCCCO3)c2n1
Agent: [Pd]
Agent: N
Solvent: CCO
Product: NCc1nc(NCC(c2ccccc2)c2ccccc2)c2ncn(C3CCCCO3)c2n1
Reaction time: 36 h
Yield: 89.8 %

Procedure:
6-[(2,2-Diphenylethyl)amino]-9-(tetrahydro-2H-pyran-2-yl)-9H-purine-2-carbonitrile (19.7 g, 0.046 mol) (Preparation 23) was dissolved in a saturated solution of ammonia in ethanol (500 ml). 10% Palladium on carbon (2 g) was added and the suspension was stirred under an atmosphere of hydrogen (414 kPa, 60 psi) for 36 hours. The suspension was filtered through Arbocel (Trade Mark) and the solvent was removed under reduced pressure. This gave the title compound as a foam (17.7 g).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([CH2:12][N:13]([CH3:30])[C:14]([C:16]1[CH:17]=[N:18][N:19]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:20]=1[CH2:21][CH2:22][CH3:23])=[O:15])[CH:6]=[CH:5]2.[Br:31]Br>C(O)(=O)C>[Br:31][C:3]1[C:2]([OH:1])=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][C:7]([CH2:12][N:13]([CH3:30])[C:14]([C:16]1[CH:17]=[N:18][N:19]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:20]=1[CH2:21][CH2:22][CH3:23])=[O:15])=[CH:8]2
Reactant: CCCc1c(C(=O)N(C)Cc2ccc3cc(O)ccc3c2)cnn1-c1ccccc1
Reactant: BrBr
Solvent: CC(=O)O
Product: CCCc1c(C(=O)N(C)Cc2ccc3c(Br)c(O)ccc3c2)cnn1-c1ccccc1
Reaction time: 48 h
Yield: 98.5 %

Procedure:
1-Phenyl-5-propyl-1H-pyrazole-4-carboxylic acid (6-hydroxy-naphthalen-2ylmethyl)-methyl-amide (3.2 g, 8 mmol), prepared in the previous step, was dissolved in 300 mL glacial acetic acid (with warming). A solution of bromine (0.41 mL, 8 mmol) in 50 mL of glacial acetic acid was added under nitrogen dropwise over 2 h to the reaction at room temperature. After the addition the reaction stirred for 2 days. The solvent was removed under reduced pressure and the residue diluted with methylene chloride. The organic layer was extracted two times with 5% NaHCO3, dried (MgSO4) and the solvent removed under reduced pressure to give 1-phenyl-5-propyl-1H-pyrazole-4-carboxylic acid (5-bromo-6-hydroxy-naphthalen-2-ylmethyl)-methyl-amide (3.77 g, 98.5%) as a pink solid, mp 205-207° C.
Reaction SMILES: C1(C)C=CC(S(O[CH2:11][C@@H:12]2[O:25][C:16]3=[C:17]4[C:21](=[CH:22][CH:23]=[C:15]3[O:14][CH2:13]2)[NH:20][C:19](=[O:24])[CH2:18]4)(=O)=O)=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[F:38][C:39]1[CH:52]=[CH:51][C:42]([C:43]([CH:45]2[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]2)=[O:44])=[CH:41][CH:40]=1.C(N(C(C)C)CC)(C)C.CCCCCC.C(OCC)(=O)C>CS(C)=O>[F:38][C:39]1[CH:40]=[CH:41][C:42]([C:43]([CH:45]2[CH2:50][CH2:49][N:48]([CH2:11][CH:12]3[O:25][C:16]4=[C:17]5[C:21](=[CH:22][CH:23]=[C:15]4[O:14][CH2:13]3)[NH:20][C:19](=[O:24])[CH2:18]5)[CH2:47][CH2:46]2)=[O:44])=[CH:51][CH:52]=1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COc3ccc4c(c3O2)CC(=O)N4)cc1
Reactant: O=C(c1ccc(F)cc1)C1CCNCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CS(C)=O
Solvent: CCCCCC
Solvent: CCN(C(C)C)C(C)C
Product: O=C1Cc2c(ccc3c2OC(CN2CCC(C(=O)c4ccc(F)cc4)CC2)CO3)N1
Temperature: 85 °C
Yield: 35.4 %

Procedure:
(R)-2-(Toluene-4-sulfonyloxymethyl)-2,3,8,9-tetrahydro-7H- 1,4-dioxino[2,3-e]indol-8-one (1.03 g, 2.75 mmole), 4-(4-fluorobenzoyl)piperidine p-toluenesulfonate (4.68 g, 12.4 mmole) and diisopropylethylamine (2.15 ml, 12.3 mmole) were combined in 70 ml of dry DMSO and heated to 85° C. for 5 hours under a nitrogen atmosphere. The reaction was cooled and taken into 400 ml of 1:1 hexane/ethyl acetate. This was washed with 200 ml of water, with 200 ml of saturated brine, dried over MgSO4, filtered and concentrated to yield an oil. This oil was column chromatographed on silica gel using 0.75% methanol/CH2Cl2 as eluant to give the free base of the title compound as a yellow oil (0.40 g, 40%). This oil was crystallized from ethanol with the addition of a solution of fumaric acid in hot ethanol to give 0.37 g of the (S) enantiomer of the title compound as a light yellow solid fumarate, m.p. 237°-238° C.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[OH:11][C@@H:12]1[CH2:17][N:16]([C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:19])[C@@H:15]([CH3:28])[CH2:14][CH2:13]1.C(N(CC)CC)C>C(Cl)Cl>[CH3:28][CH:15]1[CH2:14][CH2:13][C:12](=[O:11])[CH2:17][N:16]1[C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19]
Reactant: C[C@H]1CC[C@H](O)CN1C(=O)OCc1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1CCC(=O)CN1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of oxalyl chloride (13.17 mL, 0.150 mol) in CH2Cl2 (250 mL) at −78° C. was added DMSO (14.23 mL, 0.201 mol) dropwise. The reaction was aged for 20 min at −78° C., then ±Benzyl trans-5-hydroxy-2-methylpiperidine-1-carboxylate (25.0 g, 0.100 mol) was added dropwise over 10 min and aged for an additional 10 min before triethylamine (41.9 mL, 0.301 mol) was added dropwise over 5 min at −78° C. The reaction was warmed to room temperature, then quenched with addition of half-saturated, aqueous NaHCO3 and additional CH2Cl2. The layers were separated, and the organics were dried with MgSO4 and concentrated. The crude material was purified by silica gel gradient chromatography (0-50% ethyl acetate in hexanes), providing ±benzyl 2-methyl-5-oxopiperidine-1-carboxylate.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][NH:22][CH3:23])=[CH:14][CH:15]=3)[CH:10]=[CH:9]2)=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.Cl[C:34]1[CH:39]=[CH:38][N:37]=[C:36]([CH3:40])[N:35]=1.[Na+].[Cl-]>CN(C=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][N:22]([CH3:23])[C:34]4[CH:39]=[CH:38][N:37]=[C:36]([CH3:40])[N:35]=4)=[CH:14][CH:15]=3)[CH:10]=[CH:9]2)=[CH:6][CH:7]=1
Reactant: Cc1nccc(Cl)n1
Reactant: CNCCCCOc1ccc2c(ccn2-c2ccc(F)cc2)c1
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nccc(N(C)CCCCOc2ccc3c(ccn3-c3ccc(F)cc3)c2)n1
Temperature: 100 °C
Reaction time: 2 h
Yield: 73.4 %

Procedure:
20 mg (0.064 mmol) {4-[1-(4-Fluoro-phenyl)-1H-indol-5-yloxy]-butyl}-methylamine and 0.16 ml (0.96 mmol) N,N-diisopropyl ethyl amine in 1 ml of DMF were treated with 41 mg (0.32 mmol) 4-chloro-2-methylpyrimidine and stirred at 100° C. during 2 hours. After cooling to room temperature the mixture was treated with saturated aqueous NaCl and extracted three times with Et2O. Drying of the combined organic layers over Na2SO4, evaporation of the solvent and column chromatography on silica gel with EtOAc gave 19 mg (73%) {4-[1-(4-Fluoro-phenyl)-1H-indol-5-yloxy]-butyl}-methyl-(2-methyl-pyrimidin-4-yl)-amine as a light yellow oil, MS: 405 (MH+).
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18](=O)[CH:19](Br)[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[CH3:29][C:30]1[C:31]([NH2:37])=[N:32][CH:33]=[C:34]([CH3:36])[CH:35]=1>C(O)C>[C:1]([O:5][C:6](=[O:28])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[N:37]=[C:31]4[C:30]([CH3:29])=[CH:35][C:34]([CH3:36])=[CH:33][N:32]4[C:19]=3[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cnc(N)c(C)c1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(C(=O)C(Br)c3ccccc3)cc2)CCC1
Solvent: CCO
Product: Cc1cc(C)c2nc(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(-c3ccccc3)n2c1
Yield: 14.7 %

Procedure:
500 mg (1.13 mmol) {1-[4-(2-Bromo-2-phenyl-acetyl)phenyl]-cyclobutyl}-carbamic acid tert.-butyl ester, 137.5 mg (1.13 mmol) 3,5-dimethyl-pyridin-2-yl-amine and molecular sieves (4 Å, dried over night at 120° C. in a drying oven) were heated in 10 mL ethanol in a Dean-Stark apparatus for 23 hours. The reaction mixture had been sucked off via a glass fibre filter and evaporated to dryness. The residue was redissolved in dichloromethane, washed with an 1 M hydrochloric acid, saturated sodium bicarbonate and brine and dried (sodium sulfate). After filtration and removal of the solvent the residue was purified by chromatography on silicagel (eluents: hexane/ethyl acetate) yielding 142.6 mg (25.8%) of the pure title compound and 77.5 mg (14.7%) of the title compound which was slightly contaminated.
Reaction SMILES: [Si:1]([O:8][CH2:9][C@@H:10]([NH2:12])[CH3:11])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Cl:13][C:14]1[C:19]([CH2:20][CH:21]=O)=[C:18](Cl)[N:17]=[CH:16][N:15]=1>C(O)C>[Si:1]([O:8][CH2:9][C@@H:10]([N:12]1[C:18]2[N:17]=[CH:16][N:15]=[C:14]([Cl:13])[C:19]=2[CH:20]=[CH:21]1)[CH3:11])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: C[C@H](N)CO[Si](C)(C)C(C)(C)C
Reactant: O=CCc1c(Cl)ncnc1Cl
Solvent: CCO
Product: C[C@@H](CO[Si](C)(C)C(C)(C)C)n1ccc2c(Cl)ncnc21
Yield: 67 %

Procedure:
(S)-2-tert-Butyldimethylsilyloxy-1-methylethylamine (120 g, 636 mmol) was added to (4,6-dichloropyrimidin-5-yl)acetaldehyde (52.8 g, 276 mmol) in ethanol (500 mL). The mixture was heated to reflux for 45 minutes. The reaction mixture was evaporated in vacuo then the residue was diluted with water (400 mL) and extracted with ethyl acetate (600 mL). The organic extract was evaporated in vacuo and the crude material was purified by column chromatography on silica gel (gradient of pentane:EtOAc 90:10 to 80:20) to afford the title compound as a yellow liquid in 67% yield, 60.4 g.