Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@H:13]([C:14](O)=O)[C@H:12]2[CH2:17][C@@H:9]1[CH2:10][C@@H:11]2[OH:18])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.C(Cl)(=O)OCC(C)C.[NH2:34][C:35]1[CH:39]=[C:38]([Br:40])[S:37][C:36]=1[C:41]([NH2:43])=[O:42]>O1CCCC1.O>[Br:40][C:38]1[S:37][C:36]2[C:41](=[O:42])[NH:43][C:14]([C@@H:13]3[C@H:12]4[CH2:17][C@H:9]([CH2:10][C@@H:11]4[OH:18])[N:8]3[C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])=[N:34][C:35]=2[CH:39]=1
Reactant: CC(C)(C)OC(=O)N1[C@@H]2C[C@H]([C@H]1C(=O)O)[C@@H](O)C2
Reactant: NC(=O)c1sc(Br)cc1N
Agent: CC(C)COC(=O)Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1[C@@H]2C[C@H]([C@H]1c1nc3cc(Br)sc3c(=O)[nH]1)[C@@H](O)C2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 52.7 %

Procedure:
To a solution of (1R*,3S,4R*,5S)-2-(tert-butoxycarbonyl)-5-hydroxy-2-azabicyclo[2.2.1]heptane-3-carboxylic acid (349 mg) and triethylamine (0.190 mL) in tetrahydrofuran (4 mL) was added 2-methylpropyl chlorocarbonate (0.178 mL) at 0° C., and the mixture was stirred at room temperature for 30 min. To the reaction system was added a solution of 3-amino-5-bromothiophene-2-carboxamide (200 mg) produced in Example 1, step D, in tetrahydrofuran (2 mL), and the mixture was stirred at 60° C. for 18 hr. Water was added to the reaction mixture, and the separated aqueous layer was extracted with ethyl acetate. The organic layer was washed with brine, and dried over anhydrous sodium sulfate. Insoluble material was filtered off, the filtrate was concentrated under reduced pressure, and the residue was purified by basic silica gel column chromatography (ethyl acetate/hexane). To the obtained pale-yellow amorphous solid (307 mg) were added 2M aqueous sodium hydroxide solution (1.81 mL) and ethanol (4.0 mL), and the mixture was stirred at 70° C. for 5 hr. The reaction system was neutralized with 1M hydrochloric acid at 0° C. To the reaction system was added water (2 mL), and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, and dried over anhydrous sodium sulfate. Insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was washed with ethyl acetate (2 mL) to give the title compound (211 mg) as a colorless solid.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:17]2[N:25]=[C:24]([CH3:26])[N:23]=[C:22]3[C:18]=2[N:19]=[CH:20][N:21]3C2CCCCO2)[C:5]([NH:8][C:9]2[CH:10]=[N:11][C:12]([O:15][CH3:16])=[CH:13][CH:14]=2)=[N:6][CH:7]=1.[CH3:33][O:34][CH2:35][CH2:36][NH2:37].CC(C)([O-])C.[Na+].C(P(C(C)(C)C)C1C=CC=CC=1C1C(C(C)C)=CC(C(C)C)=CC=1C(C)C)(C)(C)C.Cl>C1COCC1.O.CO.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:33][O:34][CH2:35][CH2:36][NH:37][C:2]1[CH:3]=[C:4]([C:17]2[N:25]=[C:24]([CH3:26])[N:23]=[C:22]3[C:18]=2[N:19]=[CH:20][NH:21]3)[C:5]([NH:8][C:9]2[CH:10]=[N:11][C:12]([O:15][CH3:16])=[CH:13][CH:14]=2)=[N:6][CH:7]=1
Reactant: COc1ccc(Nc2ncc(Cl)cc2-c2nc(C)nc3c2ncn3C2CCCCO2)cn1
Reactant: COCCN
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C(C)(C)C)C(C)(C)C)c(C(C)C)c1
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: COCCNc1cnc(Nc2ccc(OC)nc2)c(-c2nc(C)nc3[nH]cnc23)c1
Temperature: 100 °C
Reaction time: 8 h
Yield: 25.9 %

Procedure:
A solution of 5-chloro-N-(6-methoxypyridin-3-yl)-3-(2-methyl-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-2-amine (0.150 g, 0.332 mmol) and 2-methoxyethylamine (0.114 mL, 1.328 mmol) (Aldrich, St. Louis, Mo.) in THF (10 mL) was treated with sodium tert-butoxide (0.096 g, 0.996 mmol) and 2-di-t-butylphosphino-2′,4′,6′-tri-isopropyl-1,1-biphenyl (0.030 g). The mixture was deoxygenated and treated with Pd2(dba)3 (0.030 g, 0.033 mmol) under N2. The flask was fitted with a reflux condenser, then placed into a pre-heated bath at 80° C. and stirred overnight. The reaction mixture was diluted with water (10 mL) and extracted with 4:1 CHCl3/isopropanol (2×20 mL). The combined organic extracts were washed with NaHCO3 (20 mL) and dried over Na2SO4. The solution was filtered and concentrated in vacuo to give a tan oil. A glass microwave reaction vessel was charged with the crude oil and 1 N aqueous HCl (1.5 mL) in THF (3 mL). The reaction mixture was stirred and heated in a Discover model microwave reactor (CEM, Matthews, N.C.) at 100° C. for 8 min (100 watts, Powermax feature on). The mixture was diluted with methanol and then concentrated. The mixture was triturated with acetonitrile and allowed to stir 5 minutes. The precipitate was collected by filtration and washed with diethyl ether (3×25 mL). The solid was neutralized with 1 N aqueous sodium hydroxide and extracted with chloroform/isopropanol (4:1). The organic layer was dried over sodium sulfate, filtered and concentrated. The residue was diluted with diethyl ether and the precipitate was collected by filtration, washing with diethyl ether (3×20 ml) and finally with hexanes. This gave N5-(2-methoxyethyl)-N2-(6-methoxypyridin-3-yl)-3-(2-methyl-9H-purin-6-yl)pyridine-2,5-diamine (0.035 g, 0.086 mmol, 25.9% yield) as a tan solid. MS (ESI pos. ion) m/z 407 (M+H)+. 1H NMR (400 MHz, d6-DMSO) δ 12.06 (s, 1H); 9.20 (s, 1H); 8.60 (s, 1H); 8.47 (s, 1H); 8.12 (d, 1H); 7.90 (d, J=2.35 Hz, 1H); 6.82 (d, 1H); 5.42 (s, 1H); 3.82 (s, 6H); 3.58 (t, J=5.58 Hz, 2H); 3.26 (s, 3H); 2.85 (s, 3H).
Reaction SMILES: Cl.[Br:2][C:3]1[CH:4]=[C:5]([NH:10][CH2:11][CH2:12][CH2:13][O:14][CH3:15])[C:6]([NH2:9])=[CH:7][CH:8]=1.C(=O)([O-])O.[Na+].[F:21][C:22]([F:27])([F:26])[C:23](O)=O>>[Br:2][C:3]1[CH:8]=[CH:7][C:6]2[N:9]=[C:23]([C:22]([F:27])([F:26])[F:21])[N:10]([CH2:11][CH2:12][CH2:13][O:14][CH3:15])[C:5]=2[CH:4]=1
Reactant: COCCCNc1cc(Br)ccc1N
Reactant: O=C(O)C(F)(F)F
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: COCCCn1c(C(F)(F)F)nc2ccc(Br)cc21

Procedure:
0.2 ml of concentrated aqueous hydrochloric acid is added under an argon atmosphere to a solution of 12.83 g of 4-bromo-N2-(3-methoxypropyl)benzene-1,2-diamine in 5.78 ml of trifluoroacetic acid. The reaction mixture is heated to reflux for 4 hours. 2 ml of trifluoroacetic acid are once again added and the reaction mixture is heated to reflux for a further 2 hours. The reaction mixture is cooled to room temperature and neutralized with saturated aqueous sodium hydrogencarbonate solution. The mixture is extracted with ethyl acetate (3×). The combined organic phases are dried over sodium sulphate and concentrated by evaporation. The title compound is obtained as a yellow oil from the residue by means of flash chromatography (SiO2 60F). Rf=0.60 (1:2 EtOAc-heptane). Rt=4.79 (gradient I).
Reaction SMILES: C1(C)C=CC(S([O-])(=O)=O)=CC=1.[CH3:12][N+:13]1[C:17]2[CH2:18][CH2:19][CH2:20][CH2:21][C:16]=2[S:15][C:14]=1SC.[CH2:24]([NH:26][C:27]1[CH:34]=[CH:33][C:30]([C:31]#[N:32])=[CH:29][C:28]=1[N:35]=[C:36]1[N:40]([CH2:41][C:42]2[CH:43]=[N:44][CH:45]=[CH:46][CH:47]=2)[C:39](=[O:48])[CH2:38][S:37]1)[CH3:25]>>[CH2:24]([NH:26][C:27]1[CH:34]=[CH:33][C:30]([C:31]#[N:32])=[CH:29][C:28]=1[N:35]=[C:36]1[N:40]([CH2:41][C:42]2[CH:43]=[N:44][CH:45]=[CH:46][CH:47]=2)[C:39](=[O:48])[C:38](=[C:14]2[N:13]([CH3:12])[C:17]3[CH2:18][CH2:19][CH2:20][CH2:21][C:16]=3[S:15]2)[S:37]1)[CH3:25]
Reactant: CCNc1ccc(C#N)cc1N=C1SCC(=O)N1Cc1cccnc1
Reactant: CSc1sc2c([n+]1C)CCCC2
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Product: CCNc1ccc(C#N)cc1N=C1SC(=C2SC3=C(CCCC3)N2C)C(=O)N1Cc1cccnc1

Procedure:
The title compound was prepared in a manner similar to Example 168 by condensing intermediate 3-methyl-2-methylthio-4,5,6,7-tetrahydrobenzothiazol-3-ium p-toluenesulfonate with 4-ethylamino-3-(4-oxo-3-pyridin-3-ylmethylthiazolidin-2-ylideneamino)benzonitrile. MS(ESI): 503 (MH+).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:12]2[CH:17]=[CH:16][C:15]([C:18]#[N:19])=[C:14]([OH:20])[CH:13]=2)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[CH:21]1([C:24]([CH2:26]Br)=[O:25])[CH2:23][CH2:22]1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[Cl:1][C:2]1[C:3]([C:12]2[CH:17]=[CH:16][C:15]([C:18]#[N:19])=[C:14]([O:20][CH2:26][C:24]([CH:21]3[CH2:23][CH2:22]3)=[O:25])[CH:13]=2)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:9])[F:10])[CH:7]=1
Reactant: O=C(CBr)C1CC1
Reactant: N#Cc1ccc(-c2ncc(C(F)(F)F)cc2Cl)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1ccc(-c2ncc(C(F)(F)F)cc2Cl)cc1OCC(=O)C1CC1
Temperature: 23 °C
Reaction time: 40 h

Procedure:
A mixture of 1.5 g of 3-chloro-2-(4-cyano-3-hydroxyphenyl)-5-trifluoromethylpyridine, 1.2 g of bromomethyl cyclopropyl ketone, 1.5 g of potassium carbonate and 50 ml of anhydrous dimethylformamide was stirred for 40 hours at 23° C. After addition of 200 ml of water, the mixture was extracted three times with 50 ml of methyl tert-butyl ether each time. The combined organic phases were washed with 50 ml of water, then dried over sodium sulfate and concentrated. The residue which remained was crystallized by triturating with n-hexane. Yield: 1.6 g of white crystals having a melting point of 115°-116° C.
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:23])[NH:19][C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:26]([F:29])([F:28])[F:27])[CH:3]=1.[C@@H:30]1([CH2:40]O)[C@@H:39]2[N:34]([CH2:35][CH2:36][CH2:37][CH2:38]2)[CH2:33][CH2:32][CH2:31]1>>[Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:23])[N:19]([CH2:40][C@H:30]5[C@@H:39]6[N:34]([CH2:35][CH2:36][CH2:37][CH2:38]6)[CH2:33][CH2:32][CH2:31]5)[C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:26]([F:27])([F:29])[F:28])[CH:3]=1
Reactant: OC[C@H]1CCCN2CCCC[C@H]12
Reactant: O=C1NC(=O)/C(=C/c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Product: O=C1S/C(=C\c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)C(=O)N1C[C@@H]1CCCN2CCCC[C@H]12

Procedure:
(5Z)-5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-3-[(1S,9aR)-octahydro-2H-quinolizin-1-ylmethyl]-1,3-thiazolidine-2,4-dione was prepared from [(5Z)-5-({1-[4-chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2,4-dioxo-1,3-thiazolidine (from Example 1) and [(1S,9aR)-octahydro-2H-quinolizin-1-yl]methanol following General Procedure J.
Reaction SMILES: S(Cl)(Cl)=O.[OH:5][C@H:6]1[CH2:10][NH:9][C@H:8]([C:11]([OH:13])=[O:12])[CH2:7]1.[CH3:14]O>>[CH3:14][O:12][C:11]([C@@H:8]1[CH2:7][C@@H:6]([OH:5])[CH2:10][NH:9]1)=[O:13]
Reactant: CO
Reactant: O=C(O)[C@@H]1C[C@@H](O)CN1
Solvent: O=S(Cl)Cl
Product: COC(=O)[C@@H]1C[C@@H](O)CN1
Reaction time: 8 h

Procedure:
Thionyl chloride (47 g, 393 mmol) was added dropwise at 0° C. to a stirred solution of (2S,4R)-4-hydroxy-pyrrolidine-2-carboxylic acid (40 g, 0.31 mol) in anhydrous methanol (200 mL). The reaction was allowed to proceed overnight, and concentrated to give the title intermediate (50 g). 1H NMR (400 MHz, CD3OD) δ (ppm) 4.56 (m, 2H), 3.85 (s, 3H), 3.41 (m, 1H), 3.28 (m, 1H), 2.40 (m, 1H), 2.22 (m, 1H).
Reaction SMILES: [OH:1][C:2]1[CH2:7][C:6]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)(CCC2C=CC=CC=2)[O:5][C:4](=[O:22])[CH:3]=1.C1C(=O)N(Br)C(=O)C1.[CH:31]([N:34]1[CH2:39][CH2:38][CH2:37][NH:36][C:35]1=[S:40])([CH3:33])[CH3:32].N1CCCCC1>C(Cl)Cl.C(O)(C)(C)C>[OH:1][C:2]1[CH2:7][CH:6]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[O:5][C:4](=[O:22])[C:3]=1[S:40][C:35]1[N:34]([CH:31]([CH3:33])[CH3:32])[CH2:39][CH2:38][CH2:37][N:36]=1
Reactant: CC(C)N1CCCNC1=S
Reactant: O=C1C=C(O)CC(CCc2ccccc2)(c2ccccc2)O1
Agent: O=C1CCC(=O)N1Br
Solvent: C1CCNCC1
Solvent: CC(C)(C)O
Solvent: ClCCl
Product: CC(C)N1CCCN=C1SC1=C(O)CC(c2ccccc2)OC1=O

Procedure:
The title compound was prepared as described in example 41 using the following: 5,6-dihydro-4-hydroxy-6-phenyl-6-(2-phenylethyl)-2H-pyran-2-one (0.250 g, 0.850 mmol), t-butanol (3.5 mL), n-bromosuccinimide (0.151 g, 0.85 mmol), CH2Cl2 (6.0 mL), 1-isopropyltetrahydropyrimidine-2-thione (0.270 g, 1.70 mmol, prepared by the method described by A. F. McKay et al., J. Am. Chem. Soc. 78: 1618 (1956)), piperidine (0.084 mL, 0.85 mmol). Purification was achieved by submitting the final residue to column chromatograpy (SiO2, 1/1 CH2Cl2 /ethyl acetate to 2/14/1 ethyl acetate/CH2Cl2 /methanol) to provide a solid which was redissolved in CH2Cl2, filtered through a fiberglass filter, and the solvent removed in vacuo to provide the title compound (0.356 g, m.p. 103°-105° C.). 1H NMR (400 MHz, DMSO-d6) δ7.440-7.371 (m, 4H), 7.296 (t, 1H, J=7 Hz), 7.233 (t, 2H, J=7 Hz), 7.139 (t, 1H, J=7 Hz), 7.077 (d, 2H, J=7 Hz), 6.515 (bs, 1H), 4.365-4.300 (m, 1H), 3.335-3.308 (m, 2H), 3.024-2.924 (m, 4H), 2.624-2.548 (m, 1H), 2.341-2.265 (m, 1H), 2.156-2.061 (m, 2H), 1.763-1.737 (m, 2H), 1.201-1.180 (m, 6H).
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([O:8][CH:9]2[CH2:12][N:11]([C:13]3[CH:18]=[CH:17][C:16]([C@@H:19]([NH:21][C:22](=[O:24])[CH3:23])[CH3:20])=[CH:15][CH:14]=3)[CH2:10]2)[CH:5]=[CH:4][N:3]=1.[CH:25]1([CH2:28][OH:29])[CH2:27][CH2:26]1.[H-].[Na+]>O1CCOCC1>[CH:25]1([CH2:28][O:29][C:2]2[CH:7]=[C:6]([O:8][CH:9]3[CH2:12][N:11]([C:13]4[CH:18]=[CH:17][C:16]([C@@H:19]([NH:21][C:22](=[O:24])[CH3:23])[CH3:20])=[CH:15][CH:14]=4)[CH2:10]3)[CH:5]=[CH:4][N:3]=2)[CH2:27][CH2:26]1
Reactant: OCC1CC1
Reactant: CC(=O)N[C@@H](C)c1ccc(N2CC(Oc3ccnc(F)c3)C2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CC(=O)N[C@@H](C)c1ccc(N2CC(Oc3ccnc(OCC4CC4)c3)C2)cc1
Temperature: 130 °C
Reaction time: 15 h

Procedure:
To 55 mg (0.17 mmol) (S)—N-(1-{4-[3-(2-Fluoro-pyridin-4-yloxy)-azetidin-1-yl]-phenyl}-ethyl)-acetamide (XI.1) in 5 mL 1,4-dioxane is added 0.14 mL (1.73 mmol) cyclopropanemethanol. 38 mg (0.95 mmol, 60% suspension in mineral oil) NaH is added and the mixture is stirred for 15 h at 130° C. After concentration in vacuo the residue is purified by chormotography (silica, ethylacetate) to yield the desired product.
Reaction SMILES: [Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([CH3:8])[NH:4][C:3]=1[C:9](NC1CCN(C2SC(C#N)=C(O)N=2)CC1)=[O:10].Cl.[NH2:27][CH:28]1[CH2:33][CH2:32][N:31]([C:34]2[S:35][C:36]([C:42]([O:44][CH2:45][CH3:46])=[O:43])=[C:37]([CH2:39][O:40][CH3:41])[N:38]=2)[CH2:30][CH2:29]1>>[Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([CH3:8])[NH:4][C:3]=1[C:9]([NH:27][CH:28]1[CH2:33][CH2:32][N:31]([C:34]2[S:35][C:36]([C:42]([O:44][CH2:45][CH3:46])=[O:43])=[C:37]([CH2:39][O:40][CH3:41])[N:38]=2)[CH2:30][CH2:29]1)=[O:10]
Reactant: CCOC(=O)c1sc(N2CCC(N)CC2)nc1COC
Reactant: Cc1[nH]c(C(=O)NC2CCN(c3nc(O)c(C#N)s3)CC2)c(Cl)c1Cl
Agent: Cl
Product: CCOC(=O)c1sc(N2CCC(NC(=O)c3[nH]c(C)c(Cl)c3Cl)CC2)nc1COC

Procedure:
The title compound was prepared from 3,4-dichloro-5-methyl-1H-pyrrole-2-carboxylic acid (Intermediate 3) and ethyl 2-(4-aminopiperidin-1-yl)-4-(methoxymethyl)-1,3-thiazole-5-carboxylate hydrochloride (Intermediate 36) in a manner analogous to Example 29.
Reaction SMILES: [CH:1](NC(C)C)(C)C.C([Li])CCC.[O:13]=[C:14]1[O:18][CH2:17][C@H:16]([NH:19][C:20](=[O:29])[O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:15]1.CI.[Cl-].[NH4+]>C1COCC1.CCCCCC.C[C@H]1O[C@H]2[C@H](O)[C@@H](O)[C@H](OC3C4C(=CC5OCOC=5C=4)[C@@H](C4C=C(OC)C(O)=C(OC)C=4)[C@@H]4[C@@H]3COC4=O)O[C@@H]2CO1.C1COP(NCCCl)(=O)N(CCCl)C1.[NH2-].[NH2-].Cl[Pt+2]Cl.O>[CH3:1][C@H:15]1[C:14](=[O:13])[O:18][CH2:17][C@@H:16]1[NH:19][C:20](=[O:29])[O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CC(C)NC(C)C
Reactant: O=C1C[C@@H](NC(=O)OCc2ccccc2)CO1
Agent: Cl[Pt+2]Cl
Agent: COc1cc([C@@H]2c3cc4c(cc3C(O[C@@H]3O[C@@H]5CO[C@@H](C)O[C@H]5[C@H](O)[C@H]3O)[C@H]3COC(=O)[C@H]23)OCO4)cc(OC)c1O
Agent: O=P1(NCCCl)OCCCN1CCCl
Solvent: CI
Solvent: O
Solvent: C1CCOC1
Product: C[C@H]1C(=O)OC[C@@H]1NC(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
272 μl (1.9 mmol) diisopropylamine are placed in 3 ml THF and while cooling with ice 1.2 ml (1.9 mmol) of an n-butyllithium solution in hexane (1.6M) are added. The mixture is stirred for 10 minutes at 0° C., then cooled to −78° C. and a solution of 200 mg (0.85 mmol) benzyl (R)-(5-oxo-tetrahydrofuran-3-yl)-carbamate in 1 ml THF is added dropwise. The mixture is stirred for one hour at −78° C. Then 210 μl (3.3 mmol) methyl iodide are added dropwise, and the mixture is heated to −60° C. within one hour. Then 0.5 ml sat. ammonium chloride solution is added and the mixture is heated to ambient temperature. Water is added and the mixture is extracted three times with ethyl acetate. The combined organic phases are dried over sodium sulphate and evaporated to dryness. The residue is taken up in DMF, acidified with TFA and purified by reversed-phase chromatography.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH3:22])[CH2:9][C:10](N(OC)C)=[O:11])=[CH:4][CH:3]=1.[Cl:23][C:24]1[C:25](I)=[CH:26][C:27]([F:30])=[N:28][CH:29]=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH3:22])[CH2:9][C:10]([C:25]2[C:24]([Cl:23])=[CH:29][N:28]=[C:27]([F:30])[CH:26]=2)=[O:11])=[CH:6][CH:7]=1
Reactant: Fc1cc(I)c(Cl)cn1
Reactant: CON(C)C(=O)CC(c1ccc(Br)cc1)c1ccccc1C
Product: Cc1ccccc1C(CC(=O)c1cc(F)ncc1Cl)c1ccc(Br)cc1

Procedure:
In analogy to example 74, step 5, from 3-(4-bromo-phenyl)-N-methoxy-N-methyl-3-o-tolyl-propionamide (example 74, step 4) and 5-chloro-2-fluoro-4-iodopyridine (CAS RN: [659731-48-3]) was prepared the title compound as a light yellow oil, MS (ESI−): m/z=430.0014 ([M−H]−, 1Br).
Reaction SMILES: [C:1]([N:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[C:18]([C:20]3[C:31](=[O:32])[N:30]([CH3:33])[C:23]4[N:24]=[C:25](NC)[N:26]=[CH:27][C:22]=4[CH:21]=3)[C:17]([CH3:34])=[CH:16][C:15]=2[F:35])=[O:12])[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[C:36]1([C@@H:42]([NH2:44])[CH3:43])[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>C1COCC1>[C:1]([N:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[C:18]([C:20]3[C:31](=[O:32])[N:30]([CH3:33])[C:23]4[N:24]=[C:25]([NH:44][C@H:42]([C:36]5[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=5)[CH3:43])[N:26]=[CH:27][C:22]=4[CH:21]=3)[C:17]([CH3:34])=[CH:16][C:15]=2[F:35])=[O:12])[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CNc1ncc2cc(-c3cc(NC(=O)Nc4cnn(C(C)(C)C)c4)c(F)cc3C)c(=O)n(C)c2n1
Reactant: C[C@H](N)c1ccccc1
Solvent: C1CCOC1
Product: Cc1cc(F)c(NC(=O)Nc2cnn(C(C)(C)C)c2)cc1-c1cc2cnc(N[C@@H](C)c3ccccc3)nc2n(C)c1=O
Yield: 56.3 %

Procedure:
Using a procedure analogous to Example A1, 1-(1-tert-butyl-1H-pyrazol-4-yl)-3-(2-fluoro-4-methyl-5-(8-methyl-2-(methylsulfinyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)urea from Example 109 (0.075 g, 0.15 mmol) and (S)-1-phenylethanamine (0.053 g, 0.44 mmol) were combined in THF (1 mL) to afford (S)-1-(1-tert-butyl-1H-pyrazol-4-yl)-3-(2-fluoro-4-methyl-5-(8-methyl-7-oxo-2-(1-phenylethylamino)-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)urea as a white solid (0.048 g, 58% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.62 (s, 1H), 8.60 (s, 1H), 8.48 (d, J=8.0 Hz, 1H), 8.39 (brs, 1H), 7.90 (d, J=8.4 Hz, 1H), 7.76 (s, 1H), 7.62 (s, 1H), 7.44-7.35 (m, 3H), 7.31-7.27 (m, 2H), 7.18 (t, J=7.2 Hz, 1H), 7.09 (d, J=12.4 Hz, 1H), 5.12 (t, J=6.8 Hz, 1H), 3.55-3.46 (m, 3H), 2.01 (s, 3H), 1.44 (s, 9H); (ESI) m/z: 569.3 (M+H+).
Reaction SMILES: [CH3:1][C:2]1([CH3:25])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([C:14]3[O:18][C:17]([CH:19]4[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]4)=[N:16][N:15]=3)[CH:5]=[CH:4][C:3]1=2.[OH:26][CH2:27][CH2:28][CH2:29][CH2:30][CH:31]=O>>[CH3:1][C:2]1([CH3:25])[CH2:11][CH2:10][C:9]([CH3:12])([CH3:13])[C:8]2[CH:7]=[C:6]([C:14]3[O:18][C:17]([CH:19]4[CH2:24][CH2:23][N:22]([CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][OH:26])[CH2:21][CH2:20]4)=[N:16][N:15]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: CC1(C)CCC(C)(C)c2cc(-c3nnc(C4CCNCC4)o3)ccc21
Reactant: O=CCCCCO
Product: CC1(C)CCC(C)(C)c2cc(-c3nnc(C4CCN(CCCCCO)CC4)o3)ccc21

Procedure:
The preparation was carried out as already described via a reductive amination starting from 50 mg (0.10 mmol) of 4-[5-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-1,3,4-oxadiazol-2-yl]piperidine and 21 mg (0.20 mmol) of 5-hydroxypentanal.
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[C:3]1[N:4]=[CH:5][NH:6][CH:7]=1.[H-].[Na+].[CH3:12][Si:13]([CH2:16][CH2:17][O:18][CH2:19]Cl)([CH3:15])[CH3:14]>O1CCCC1>[F:1][C:2]([F:9])([F:8])[C:3]1[N:4]=[CH:5][N:6]([CH2:19][O:18][CH2:17][CH2:16][Si:13]([CH3:15])([CH3:14])[CH3:12])[CH:7]=1
Reactant: C[Si](C)(C)CCOCCl
Reactant: FC(F)(F)c1c[nH]cn1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCn1cnc(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 61.3 %

Procedure:
Into a 250-mL three neck round-bottom flask, which was purged and maintained with an inert atmosphere of nitrogen, was placed a solution of 4-(trifluoromethyl)-1H-imidazole (compound 216.1, 5 g, 36.74 mmol) in tetrahydrofuran (100 mL). This was followed by the addition of sodium hydride (1.6 g, 40.00 mmol, 60%) in portions at 0° C. and stirred for 1 h at 0° C. To this was added SEMCl (7.1 mL, 40.36 mmol) dropwise at 0° C. The resulting solution was stirred for 4 h at 0° C., then carefully quenched with 100 mL of brine. The pH of the solution was adjusted to 7-8 with hydrogen chloride (1 M). The aqueous phase was extracted with 2×100 mL of ethyl acetate and the combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography with ethyl acetate/petroleum ether (1:5) as eluent to furnish 6 g (61%) of the title compound as a light yellow oil.
Reaction SMILES: P(Cl)(Cl)Cl.[Cl:5][C:6]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[CH:9]=[CH:8][N+:7]=1[O-].C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl>[Cl:5][C:6]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[CH:9]=[CH:8][N:7]=1
Reactant: O=[N+]([O-])c1cc[n+]([O-])c(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClP(Cl)Cl
Solvent: ClC(Cl)Cl
Product: O=[N+]([O-])c1ccnc(Cl)c1
Temperature: 25 °C
Yield: 77.7 %

Procedure:
Phosphorus trichloride (4.2 mL, 48.7 mmol) was added to a solution of 2-chloro-4-nitro-pyridine-1-oxide (1.70 g, 9.74 mmol) in dry chloroform (25 mL) at r.t. The reaction mixture was then heated to reflux and maintained at this temperature overnight. The reaction was cooled to r.t. then poured onto ice, basified to between pH 7-8 with saturated aq. sodium bicarbonate solution and extracted with chloroform (×2). The combined organic phase was washed with water and brine, dried over sodium sulfate and concentrated. Drying under high vacuum afforded 2-chloro-4-nitro-pyridine (1.2 g, 78%) as a solid.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([CH2:9][CH2:10][O:11][C:12]2[CH:25]=[CH:24][C:15]([CH:16]=[C:17]3[S:21][C:20](=[O:22])[NH:19][C:18]3=[O:23])=[CH:14][CH:13]=2)=[N:7][CH:8]=1)[CH3:2]>[Pd].CN(C)C=O>[CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([CH2:9][CH2:10][O:11][C:12]2[CH:25]=[CH:24][C:15]([CH2:16][CH:17]3[S:21][C:20](=[O:22])[NH:19][C:18]3=[O:23])=[CH:14][CH:13]=2)=[N:7][CH:8]=1)[CH3:2]
Reactant: CCc1ccc(CCOc2ccc(C=C3SC(=O)NC3=O)cc2)nc1
Agent: [Pd]
Solvent: CN(C)C=O
Product: CCc1ccc(CCOc2ccc(CC3SC(=O)NC3=O)cc2)nc1
Reaction time: 5 h

Procedure:
To a dimethylformamide solution of 5-{4-[2-(5-ethyl-2-pyridyl)ethoxy]benzylidene}-2,4-thiazolidinedione (1.0 g) was added palladium black (0.2 g) and catalytic reduction was carried out at 50° C. and 50 kg/cm2 for 5 hours. The catalyst was filtered off and the filtrate was concentrated to dryness. The residue was dissolved in 6N-hydrochloric acid and the solution was neutralized with sodium hydrogen carbonate to give 5-{4-[2-(5-ethyl-2-pyridyl)ethoxy]benzyl}-2,4-thiazolidinedione as crystals. Yield: 650 mg (64.8%); m.p.: 173°-174° C.