Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH2:12][CH:13]=O)[N:8]2[CH3:11])=[C:4]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[N:3]=1.[CH3:21][C:22]1([CH3:28])[CH2:27][O:26][CH2:25][CH2:24][NH:23]1.Cl.C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH2:12][CH2:13][N:23]3[CH2:24][CH2:25][O:26][CH2:27][C:22]3([CH3:28])[CH3:21])[N:8]2[CH3:11])=[C:4]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[N:3]=1
Reactant: Cn1c(CC=O)nc2c(N3CCOCC3)nc(Cl)nc21
Reactant: CC1(C)COCCN1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: Cn1c(CCN2CCOCC2(C)C)nc2c(N3CCOCC3)nc(Cl)nc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 28 %

Procedure:
To a solution of (2-chloro-9-methyl-6-morpholin-4-yl-9H-purin-8-yl)acetaldehyde (119 mg, 0.40 mmol) in DCE (10 mL) was added 3,3-dimethylmorpholine.HCl (61 mg, 0.40 mmol), triethylamine (0.06 mL, 0.40 mmol) and powdered 4 Å molecular sieves. After stirring at room temperature for 4 h, sodium triacetoxyborohydride (171 mg, 0.80 mmol) was added and the resulting mixture stirred for a further 16 h. The reaction mixture was filtered through Celite®, loaded onto an Isolute® SCX-2 cartridge, the cartridge was washed with MeOH then the desired product eluted with 2 M NH3/MeOH in DCM. The resulting residue was purified by column chromatography (Si—PCC, 0-7% MeOH in DCM) to give the title compound as a pale yellow oil (44 mg, 28%). LCMS (Method H): RT=2.45 min, [M+H]+ 395.5
Reaction SMILES: [CH:1]([NH:4][C:5]1[CH:10]=[C:9](Br)[CH:8]=[CH:7][C:6]=1[N+:12]([O-:14])=[O:13])([CH3:3])[CH3:2].[C:15]1([C:21]#[CH:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C(N(CC)CC)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:15]1([C:21]#[C:22][C:9]2[CH:8]=[CH:7][C:6]([N+:12]([O-:14])=[O:13])=[C:5]([NH:4][CH:1]([CH3:3])[CH3:2])[CH:10]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CC(C)Nc1cc(Br)ccc1[N+](=O)[O-]
Reactant: C#Cc1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: CC(C)Nc1cc(C#Cc2ccccc2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 84.4 %

Procedure:
Bubble nitrogen through a mixture of N-[isopropyl]2-nitro-5-bromoaniline (0.34 g, 1.31 mmol), phenylacetylene (0.20 g, 1.96 mmol), palladium(II) acetate (7.3 mg, 0.033 mmol) and triphenylphosphine (17 mg, 0.065 mmol) in triethylamine (5 ml) for 3 minutes, then heat at reflux for 1 hour. Cool to room temperature and concentrate under reduced pressure. Partition the residue between ethyl acetate and saturated aqueous sodium chloride, dry the organic phase over sodium sulfate, and concentrate under reduced pressure. Subject the residue to silica gel chromatography, eluting with 9:1 hexane:ethyl acetate to provide the desired compound as a red solid (0.31 g, 85%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11](=[O:13])[CH3:12])[C:6](=[O:14])[CH2:5]2.[C:15]1([C:20](Cl)=[O:21])[S:19][CH:18]=[CH:17][CH:16]=1>CN(C1C=CN=CC=1)C.CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11](=[O:13])[CH3:12])[C:6](=[O:14])[CH:5]2[C:20](=[O:21])[C:15]1[S:19][CH:18]=[CH:17][CH:16]=1
Reactant: CC(=O)N1C(=O)Cc2cc(Cl)ccc21
Reactant: O=C(Cl)c1cccs1
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Product: CC(=O)N1C(=O)C(C(=O)c2cccs2)c2cc(Cl)ccc21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 21.7 %

Procedure:
To a stirred solution of 0.75 g (3.6 mmole) of 5-chloro-1-acetyl-2-oxindole and 0.96 ml (7.9 mmole) of 4-(N,N-dimethylamino)pyridine in 20 ml of N,N-dimethylformamide, cooled to ca. 0° C., was added a solution of 0.4 ml (3.7 mmole) of 2-thenoyl chloride in 5 ml of N,N-dimethylformamide, dropwise, during a few minutes. The reaction mixture was stirred for 30 minutes at ca. 0° C. and then for 3.5 hours at room temperature, and then it was poured into 500 ml of ice-cold 2N hydrochloric acid. The resulting solution was extracted with ethyl acetate, and the extracts were washed with water, followed by saturated sodium chloride solution, and then they were dried using magnesium sulfate. Evaporation of the dried ethyl acetate solution gave 1.1 g of crude product. The latter was purified by column chromatography using silica gel and eluting with dichloromethane-ethyl acetate mixtures, followed by recrystallization from a small volume of toluene, to give 250 mg of the title compound, m.p. 168°-170° C.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([Cl:11])=[CH:8][CH:9]=2)[NH:4][C:3]=1[C:12]([C:14]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][N:15]=1)=[O:13].[C:21]([O:24][C@@H:25]([CH3:29])[C:26](Cl)=[O:27])(=[O:23])[CH3:22]>>[C:21]([O:24][C@@H:25]([CH3:29])[C:26]([NH:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([Cl:11])=[CH:8][CH:9]=2)[NH:4][C:3]=1[C:12]([C:14]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][N:15]=1)=[O:13])=[O:27])(=[O:23])[CH3:22]
Reactant: Nc1c(C(=O)c2cc(Cl)ccn2)[nH]c2cc(Cl)ccc12
Reactant: CC(=O)O[C@@H](C)C(=O)Cl
Product: CC(=O)O[C@@H](C)C(=O)Nc1c(C(=O)c2cc(Cl)ccn2)[nH]c2cc(Cl)ccc12

Procedure:
The title compound was prepared according to the procedure described in Example 19 employing 3-amino-6-chloro-2-(4-chloropyridine-2-carbonyl)indole (Exampe 68) and (S)-(−)-2-acetoxypropionyl chloride. m.p.: 236-238° C. (recrystallized from ethyl acetate) IR(KBr)ν: 3287, 1738, 1693, 1624, 1585, 1570, 1545, 1489, 1236, 1188, 739 cm−1. 1H-NMR (DMSO-d6) δ: 12.09 (1 H, br s), 10.67 (1 H, br s), 8.77 (1 H, dd, J=5.5 and 1.8 Hz), 8.10 (1 H, t, J=1.9 Hz), 7.93 (1 H, dd, J=9.1, 1.8 Hz), 7.88 (1 H, dt, J=5.4, 2.3 Hz), 7.64 (1 H, t, J=1.9 Hz), 7.12 (1 H, dt, J=9.1, 2.1 Hz), 5.13 (1 H, q, J=6.8 Hz), 2.18 (3 H, s), 1.35 (3 H, d, J=6.9 Hz).
Reaction SMILES: [CH3:1][C:2]1([CH3:41])[CH2:6][CH2:5][N:4]([C:7]2[C:11]([NH:12][C:13]([C:15]3[N:16]=[C:17]([C:20]4[CH:25]=[CH:24][N:23]=[C:22]([N:26]([CH2:34][C:35]([F:38])([F:37])[F:36])C(=O)OC(C)(C)C)[CH:21]=4)[O:18][CH:19]=3)=[O:14])=[CH:10][N:9]([CH3:39])[N:8]=2)[C:3]1=[O:40].C(OC(=O)C)C.[ClH:48]>CO.C(OCC)(=O)C>[ClH:48].[CH3:1][C:2]1([CH3:41])[CH2:6][CH2:5][N:4]([C:7]2[C:11]([NH:12][C:13]([C:15]3[N:16]=[C:17]([C:20]4[CH:25]=[CH:24][N:23]=[C:22]([NH:26][CH2:34][C:35]([F:36])([F:38])[F:37])[CH:21]=4)[O:18][CH:19]=3)=[O:14])=[CH:10][N:9]([CH3:39])[N:8]=2)[C:3]1=[O:40]
Reactant: Cn1cc(NC(=O)c2coc(-c3ccnc(N(CC(F)(F)F)C(=O)OC(C)(C)C)c3)n2)c(N2CCC(C)(C)C2=O)n1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CO
Product: Cn1cc(NC(=O)c2coc(-c3ccnc(NCC(F)(F)F)c3)n2)c(N2CCC(C)(C)C2=O)n1

Procedure:
A solution of tert-butyl (4-(4-((3-(3,3-dimethyl-2-oxopyrrolidin-1-yl)-1-methyl-1H-pyrazol-4-yl)carbamoyl)-1,3-oxazol-2-yl)pyridin-2-yl)(2,2,2-trifluoroethyl)carbamate (280 mg) and 4M hydrogen chloride ethyl acetate solution (4.0 mL) in methanol (1.0 mL) was stirred at room temperature for 3 hr. The reaction mixture was diluted with ethyl acetate (3.0 mL), and the precipitated solid was collected by filtration, washed with ethyl acetate, and dried under reduced pressure to give the title compound (195 mg).
Reaction SMILES: [CH:1]1([CH2:7][C@@H:8]([NH2:25])[CH2:9][N:10]2[CH2:15][CH2:14][N:13]([C:16]3[S:17][C:18]4[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=4[N:20]=3)[CH2:12][CH2:11]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[CH:33]1([C:39](Cl)=[O:40])[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1>ClCCl>[CH:1]1([CH2:7][C@@H:8]([NH:25][C:39]([CH:33]2[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]2)=[O:40])[CH2:9][N:10]2[CH2:11][CH2:12][N:13]([C:16]3[S:17][C:18]4[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=4[N:20]=3)[CH2:14][CH2:15]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: N[C@H](CC1CCCCC1)CN1CCN(c2nc3ccccc3s2)CC1
Reactant: O=C(Cl)C1CCCCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(N[C@H](CC1CCCCC1)CN1CCN(c2nc3ccccc3s2)CC1)C1CCCCC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 0.2 g (0.56 mmol) of {(1R)-1-cyclohexylmethyl-2-[4-(benzothiazol-2-yl)-piperazin-1-yl]-ethyl}-amine and 0.16 mL (1.12 mmol) of triethylamine in 10 mL of dichloromethane at 0° C. was added dropwise 0.086 g (0.59 mmol) of cyclohexanecarboxylic acid chloride in dichloromethane (2 mL). The reaction mixture was allowed to stir under nitrogen for one hour at 0° C. and was then concentrated on a rotary evaporator, diluted with ethyl acetate and washed with H2O and brine. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated on a rotary evaporator to yield the crude product, which was purified by flash chromatography on silica gel (dichloromethane/methanol) and converted to the hydrochloride salt of the title compound with ethereal HCl to yield 0.20 g (70%) as a white solid; mp=229-232° C.; MS (+) ESI m/z=469 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[C:3](=[O:18])[N:4](C)[C:5]2[C:10]([C:11]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:9][CH:8]=[CH:7][CH:6]=2.[CH3:19]C1C=C2C(=CC=1)NC(=O)C2=O>>[OH:1][C:2]1[C:3](=[O:18])[NH:4][C:5]2[C:10]([C:11]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:9][C:8]([CH3:19])=[CH:7][CH:6]=2
Reactant: CCOC(=O)c1c(O)c(=O)n(C)c2ccccc12
Reactant: Cc1ccc2c(c1)C(=O)C(=O)N2
Product: CCOC(=O)c1c(O)c(=O)[nH]c2ccc(C)cc12

Procedure:
Intermediate 17 was prepared as a white powder following the procedure described for Intermediate 16 by replacing indoline-2,3-dione with 5-methylindoline-2,3-dione. 1H NMR (400 MHz, chloroform-d) δ ppm 11.23 (1 H, br. s.), 9.64 (1 H, br. s.), 7.83 (1 H, s), 7.01-7.56 (2 H, m), 4.58 (2 H, q, J=7.1 Hz), 2.43 (4 H, s), 1.51 (3 H, t, J=7.1 Hz). LC-MS (ESI) m/z 247.9 (M+H), RT=1.76 min (Method B)
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[Si:13]([N:20]1[C@H:23]([CH:24]2[C:29](=[O:30])[CH2:28][CH2:27][CH2:26][O:25]2)[C@@H:22]([C@H:31]([O:33][Si:34]([C:37]([CH3:40])([CH3:39])[CH3:38])([CH3:36])[CH3:35])[CH3:32])[C:21]1=[O:41])([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14].[CH3:42][Si:43]([CH3:46])([CH3:45])Cl.[Cl-].[NH4+]>C1COCC1>[Si:13]([N:20]1[C@H:23]([C@@H:24]2[C:29]([O:30][Si:43]([CH3:46])([CH3:45])[CH3:42])=[CH:28][CH2:27][CH2:26][O:25]2)[C@@H:22]([C@H:31]([O:33][Si:34]([C:37]([CH3:40])([CH3:39])[CH3:38])([CH3:35])[CH3:36])[CH3:32])[C:21]1=[O:41])([C:16]([CH3:17])([CH3:19])[CH3:18])([CH3:15])[CH3:14]
Reactant: C[Si](C)(C)Cl
Reactant: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]1C(=O)N([Si](C)(C)C(C)(C)C)[C@@H]1C1OCCCC1=O
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]1C(=O)N([Si](C)(C)C(C)(C)C)[C@@H]1[C@H]1OCCC=C1O[Si](C)(C)C
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
To a solution of diisopropylamine (0.294 ml) in dry THF (5 ml) was added butyllithium (1.25 ml, 1.6M in hexane) dropwise at 0° C. and the mixture was stirred for 10 minutes. This solution was cooled to -78° C. and a solution of (3S,4S)-1-(tert-butyldimethylsilyl)-3-[(R)-1-(tert-butyldimethylsilyloxy)ethyl]-4-[(2RS)-3-oxotetrahydropyran-2-yl)azetidin-2-one (441 mg) in dry THF (2 ml) was added dropwise. The mixture was stirred for 30 minutes, after which trimethylchlorosilane (0.267 ml) was added. This mixture was stirred at -20° C. for 10 minutes. The reaction mixture was then poured in a saturated aqueous solution of ammonium chloride (20 ml) and extracted with ether (20 ml). The organic layer was washed successively with water (20 ml), 2% HCl (20 ml), saturated aqueous sodium hydrogen carbonate (20 ml) and saturated aqueous sodium chloride (20 ml). The extract was then dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. Finally, the residue was purified by silica gel column chromatography (230-400 mesh, 26 g; ethyl acetate-hexane=1:15) to give (3S,4S)-1-(tert-butyldimethylsilyl)-3-[(R)-1-(tert-butyldimethylsilyloxy)ethyl]-4-[(2R)-3-trimethylsilyloxy-5,6-dihydropyran-2-yl]azetidin-2-one (228 mg) as a colorless oil.
Reaction SMILES: C([N:5]1[C:9](=[O:10])[C:8]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:7]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[S:6]1(=[O:29])=[O:28])(C)(C)C.Br[CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=1>>[C:22]1([C:7]2[S:6](=[O:28])(=[O:29])[N:5]([CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=3)[C:9](=[O:10])[C:8]=2[NH:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CC(C)(C)N1C(=O)C(NCCCCc2ccccc2)=C(c2ccccc2)S1(=O)=O
Reactant: BrCc1ccccn1
Product: O=C1C(NCCCCc2ccccc2)=C(c2ccccc2)S(=O)(=O)N1Cc1ccccn1

Procedure:
The title compound was prepared from 2-tert-butyl-5-phenyl-4-[(4-phenylbutyl)amino]isothiazol-3(2H)-one 1,1-dioxide (Example 1) and 2-(bromomethyl)pyridine in a similar manner as described for e.g. Example 2 and 3. 1H NMR (500 MHz CDCl3): δ 8.65-8.60 (m, 1H), 7.74-7.67 (m, 1H), 7.56-7.51 (m, 2H), 7.50-7.41 (m, 4H), 7.31-7.17 (m, 4H), 7.10-7.05 (m, 2H), 5.35-5.28 (m, 1H), 5.01 (s, 2H), 2.94-2.84 (m, 2H), 2.50-2.42 (m, 2H), 1.45-1.35 (m, 4H); 13C NMR (125 MHz, CDCl3): δ 159.4, 154.4, 149.7, 141.6, 137.1, 135.5, 131.7, 129.9, 128.8, 128.5, 128.4, 126.1, 124.9, 123.0, 121.9, 107.2, 44.9, 44.1, 35.3, 29.1, 28.2; Mass Spectrum: M−H+ 448.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:12][C@:11]([CH3:18])([CH:13]([O:16][CH3:17])[O:14][CH3:15])[C@@H:10]3[O:19][C@@H:9]3[C:8]=2[CH:20]=1)([O-:3])=[O:2].[F:21][C:22]([F:39])([F:38])[O:23][C:24]1[CH:29]=[CH:28][C:27]([NH:30][CH2:31][C:32]2[N:33]=[N:34][N:35]([CH3:37])[N:36]=2)=[CH:26][CH:25]=1>>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:12][C@:11]([CH3:18])([CH:13]([O:16][CH3:17])[O:14][CH3:15])[C@H:10]([OH:19])[C@@H:9]([N:30]([C:27]3[CH:26]=[CH:25][C:24]([O:23][C:22]([F:39])([F:38])[F:21])=[CH:29][CH:28]=3)[CH2:31][C:32]3[N:33]=[N:34][N:35]([CH3:37])[N:36]=3)[C:8]=2[CH:20]=1)([O-:3])=[O:2]
Reactant: Cn1nnc(CNc2ccc(OC(F)(F)F)cc2)n1
Reactant: COC(OC)[C@@]1(C)Oc2ccc([N+](=O)[O-])cc2[C@H]2O[C@H]21
Product: COC(OC)[C@@]1(C)Oc2ccc([N+](=O)[O-])cc2[C@H](N(Cc2nnn(C)n2)c2ccc(OC(F)(F)F)cc2)[C@H]1O
Yield: 42 %

Procedure:
The same procedure as step 3 of example 1 was accomplished, except for using the epoxide compound (300 mg, 1.07 mmol) obtained in step 1 of example 2 and N-(4-trifluoromethoxyphenyl)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amine. The crude product was purified by silica gel column chromatography (developing solvent-n-hexane:ethyl acetate=2:1), to give desired compound (248 mg, yield: 42%).
Reaction SMILES: C[O:2][C:3](=[O:26])[C@@H:4]([N:12]1[CH2:16][C:15]([O:17][C:18]2[CH:19]=[C:20]([CH3:24])[CH:21]=[CH:22][CH:23]=2)=[CH:14][C:13]1=[O:25])[CH2:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.[OH-].[Li+]>O1CCCC1.O>[CH:6]1([CH2:5][C@H:4]([N:12]2[CH2:16][C:15]([O:17][C:18]3[CH:19]=[C:20]([CH3:24])[CH:21]=[CH:22][CH:23]=3)=[CH:14][C:13]2=[O:25])[C:3]([OH:26])=[O:2])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: COC(=O)[C@H](CC1CCCCC1)N1CC(Oc2cccc(C)c2)=CC1=O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cccc(OC2=CC(=O)N([C@@H](CC3CCCCC3)C(=O)O)C2)c1
Temperature: 23 °C
Reaction time: 2 h
Yield: 62.6 %

Procedure:
To a stirred solution of (S)-3-cyclohexyl-2-(2-oxo-4-m-tolyloxy-2,5-dihydro-pyrrol-1-yl)-propionic acid methyl ester (0.570 g, 0.002 mol) in tetrahydrofuran-water (3:1, 10 mL) was added lithium hydroxide (0.201 g, 0.008 mol). The reaction mixture was stirred at 23° C. for 2 h. After this time, the mixture was concentrated and the reaction mixture was diluted with water. The reaction mixture was acidified with 2N hydrochloric acid, during which time precipitation occurred. The precipitate was removed by filtration, washed with cold water and dried in vacuo to obtain (S)-3-cyclohexyl-2-(2-oxo-4-m-tolyloxy-2,5-dihydro-pyrrol-1-yl)-propionic acid (430 mg, 79%) as a light brown solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=2)=[C:9]([C:24]2[N:28]([CH3:29])[N:27]=[N:26][N:25]=2)/[CH:10]=[CH:11]\[C@H:12]2[O:17]C(C)(C)[O:15][C@@H:14]([CH2:20][C:21](O)=[O:22])[CH2:13]2)=[CH:4][CH:3]=1.CC1C=CC(S(O)(=O)=O)=CC=1>C1COCC1.Cl>[F:36][C:33]1[CH:34]=[CH:35][C:30]([C:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)=[C:9]([C:24]2[N:28]([CH3:29])[N:27]=[N:26][N:25]=2)/[CH:10]=[CH:11]/[C@H:12]2[O:17][C:21](=[O:22])[CH2:20][C@H:14]([OH:15])[CH2:13]2)=[CH:31][CH:32]=1
Reactant: Cn1nnnc1C(/C=C\[C@@H]1C[C@H](CC(=O)O)OC(C)(C)O1)=C(c1ccc(F)cc1)c1ccc(F)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: C1CCOC1
Product: Cn1nnnc1C(/C=C/[C@@H]1C[C@@H](O)CC(=O)O1)=C(c1ccc(F)cc1)c1ccc(F)cc1
Reaction time: 16 h
Yield: 40.7 %

Procedure:
Cis-(4R,6S)-6-[4,4-bis(4-fluorophenyl)-3-(1-methyl-1H-tetrazol-5-yl)-1,3-butadienyl]-2,2-dimethyl-1,3-dioxane-4-acetic acid (3.7 g, 7.45 mmol) was dissolved in a solution of THF (90 mL) and 0.2N HCl (60 mL) and allowed to stand for 16 hours. The solution was partitioned between ethyl acetate and water. The organic layer was washed with brine (2x), dried (Na2SO4), and concentrated under reduced pressure. The residue was dissolved in dry methylene chloride (60 mL) and stirred for 4 hours in the presence of 1-cyclohexyl-3-(2-morpholinomethyl) carbodiimide metho-p-toluenesulfonate (6.6 g, 15.6 mmol). The solution was concentrated under reduced pressure and the residue was partioned between ethyl acetate and water. The organic layer was dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (1:1/ethyl acetate:diethyl ether). After recrystallization from ethyl acetate-hexane, 1.33 g (40.1%) of the title compound was obtained as a white solid; m.p.=172°-173° C. [α]D25 =237.8° (c=2.17, CHCl3).
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=3)[CH:13]=[N:12]2)[C:8]([OH:10])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:29][C:30]1[CH:34]=[CH:33][N:32]([CH2:35][C:36]([CH3:39])([OH:38])[CH3:37])[N:31]=1>>[CH:1]1([CH2:6][CH:7]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:26])[F:27])[CH:20]=3)[CH:13]=[N:12]2)[C:8]([NH:29][C:30]2[CH:34]=[CH:33][N:32]([CH2:35][C:36]([OH:38])([CH3:37])[CH3:39])[N:31]=2)=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C(O)C(CC1CCCC1)n1ncc(Cc2cccc(C(F)(F)F)c2)cc1=O
Reactant: CC(C)(O)Cn1ccc(N)n1
Product: CC(C)(O)Cn1ccc(NC(=O)C(CC2CCCC2)n2ncc(Cc3cccc(C(F)(F)F)c3)cc2=O)n1
Yield: 63 %

Procedure:
Using the method described in Example 17, 3-cyclopentyl-2-[6-oxo-4-(3-trifluoromethyl-benzyl)-6H-pyridazin-1-yl]-propionic acid (Intermediate 64) and 1-(3-amino-pyrazol-1-yl)-2-methyl-propan-2-ol (Intermediate 1) afforded 3-cyclopentyl-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-2-[6-oxo-4-(3-trifluoromethyl-benzyl)-6H-pyridazin-1-yl]-propionamide as a white solid (43.7 mg, 63%); ES+-HRMS m/e calcd for C27H32N5O3F3 [M+H+] 532.2530, found 532.2526. 1H-NMR (300 MHz, DMSO-d6) δ ppm 1.03-1.08 (m, 1H) 1.04 (br s, 3H) 1.06 (br s, 3H) 1.17-1.73 (m, 8H) 1.90 (br s, 1H) 2.15-2.31 (m, 1H) 3.88 (s, 2H) 3.99 (s, 2H) 4.66 (s, 1H) 5.47 (dd, J=10.7, 4.4 Hz, 1H) 6.37 (d, J=2.1 Hz, 1H) 6.72 (s, 1H) 7.51 (d, J=2.1 Hz, 1H) 7.54-7.72 (m, 3H) 7.75 (s, 1H) 7.98 (d, J=2.1 Hz, 1H) 10.77 (s, 1H).
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH2:6][CH2:5]1.[OH:28][CH2:29][C:30](O)=[O:31]>>[O:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:29](=[O:28])[CH2:30][OH:31])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH2:6][CH2:5]1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3CCO4)CC2)CC1
Reactant: O=C(O)CO
Agent: Cl
Product: O=C(CO)N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3CCO4)CC2)CC1

Procedure:
The title compound, white solid (110 mg, 94%), MS (ISP) m/z=389.3 [(M+H)+], mp 237° C., was prepared in accordance with the general method of example 32 from trans-4-{2-[4-(2,3-dihydrofuro[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexanamine trihydrochloride (intermediate C) (132 mg, 0.3 mmol) and hydroxyacetic acid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([C:21](=[O:23])[CH3:22])=[C:17]([F:24])[CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([N-]C(C)C)(C)C.[Li+].Br[CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36]>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([C:21](=[O:23])[CH2:22][CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])=[C:17]([F:24])[CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)CBr
Reactant: CC(=O)c1ccc(OC2CCN(C(=O)OC(C)(C)C)CC2)cc1F
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)CCC(=O)c1ccc(OC2CCN(C(=O)OC(C)(C)C)CC2)cc1F
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 80.7 %

Procedure:
In a 250 mL round bottom flask, 4-(4-acetyl-3-fluoro-phenoxy)-piperidine-1-carboxylic acid tert-butyl ester (4.0 g, 12 mmol) in tetrahydrofuran (00 mL) were cooled to −78° C. Lithium diisopropylamide (1.4 g, 13 mmol) was added and stirred 30 min. then warmed to 0° C. Re-cooled to −78° C. and ethyl bromoacetate (1.4 mL, 13 mmol) in tetrahydrofuran (25 mL) was added. The reaction warmed to ambient temperature over 14 h. The reaction was quenched with NH4Cl sol. and the solvents were concentrated under vacuum. The reaction was chromatographed through silica gel with hexanes/ethyl acetate (7:3) as eluent to produce 4.10 g (82%) of oil.
Reaction SMILES: Br[CH2:2][C:3]1[C:7]2[CH:8]=[C:9]([Cl:12])[CH:10]=[CH:11][C:6]=2[O:5][C:4]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14].[CH3:18][O:19][CH:20]([O:24][CH3:25])[CH2:21][NH:22][CH3:23].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:12][C:9]1[CH:10]=[CH:11][C:6]2[O:5][C:4]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:3]([CH2:2][N:22]([CH2:21][CH:20]([O:24][CH3:25])[O:19][CH3:18])[CH3:23])[C:7]=2[CH:8]=1
Reactant: CCOC(=O)c1oc2ccc(Cl)cc2c1CBr
Reactant: CNCC(OC)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)c1oc2ccc(Cl)cc2c1CN(C)CC(OC)OC
Reaction time: 30 h

Procedure:
A mixture of ethyl 3-bromomethyl-5-chloro-2-benzofurancarboxylate (52.75 g, 0.166 mol), methylaminoacetaldehyde dimethyl acetal (19.0 g, 0.167 mol) and potassium carbonate (45 g) in dry acetone (600 ml) was stirred under argon for 30 hours, filtered and the filtrate evaporated. The residue was partitioned between ethyl ether and water and the organic phase was dried with magnesium sulfate, filtered, and concentrated to give ethyl 5-chloro-3-[N-(2,2-dimethoxyethyl)-N-methyl(aminomethyl)]-2-benzofurancarboxylate: mp 58°-60° C.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([S:9]([Cl:12])(=[O:11])=[O:10])=[CH:5][C:4]=1[O:13][CH2:14][CH3:15])#[N:2].Br[CH2:17][CH2:18]CC>>[CH2:14]([O:13][C:4]1[CH:5]=[C:6]([S:9]([Cl:12])(=[O:11])=[O:10])[CH:7]=[CH:8][C:3]=1[C:1]#[N:2])[CH2:15][CH2:17][CH3:18]
Reactant: CCCCBr
Reactant: CCOc1cc(S(=O)(=O)Cl)ccc1C#N
Product: CCCCOc1cc(S(=O)(=O)Cl)ccc1C#N

Procedure:
The titled compound was prepared analogously to 4-cyano-3-ethoxy-benzenesulfonyl chloride (Intermediate 127c) by replacing bromoethane with 1-bromobutane.
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:9][C:10]1[C:19](Br)=[C:18]2[C:13]([CH:14]=[CH:15][C:16]([O:21][CH3:22])=[N:17]2)=[N:12][CH:11]=1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C)C=O>[CH2:1]([NH:8][C:19]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([O:21][CH3:22])[N:17]=2)[N:12]=[CH:11][C:10]=1[Br:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc2ncc(Br)c(Br)c2n1
Reactant: NCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccc2ncc(Br)c(NCc3ccccc3)c2n1
Temperature: 120 °C
Reaction time: 2 h
Yield: 46.9 %

Procedure:
Benzylamine (67 mg, 0.63 mmol, 2.0 eq) is added at room temperature to a stirred solution of 7,8-dibromo-2-methoxy-[1,5]naphthyridine (100 mg, 0.31 mmol, 1.0 eq) in N,N-dimethylformamide (10 mL), followed by potassium carbonate (87 mg, 0.63 mmol, 2.0 eq). After 2 hours stirring at 120° C., solvent is removed and the residue is extracted with ethyl acetate (3×10 mL) and water (10 mL). The combined organic layers are dried over sodium sulfate, filtered and concentrated to give the crude product that is purified by column chromatography (silica gel, eluent: petroleum ether:ethyl acetate, 5:1, v/v) to afford benzyl-(3-bromo-6-methoxy-[1,5]naphthyridin-4-yl)-amine as a light yellow solid (50 mg, 46% yield).