Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[N:5][C:6]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2.[CH3:13][C:14]1[N:19]=[C:18]([SH:20])[N:17]=[C:16]([OH:21])[CH:15]=1.C(N(CC)CC)C>C(O)C>[CH3:13][C:14]1[N:19]=[C:18]([S:20][CH2:2][C:3]2[CH:4]=[N:5][C:6]3[C:11]([CH:12]=2)=[CH:10][CH:9]=[CH:8][CH:7]=3)[N:17]=[C:16]([OH:21])[CH:15]=1
Reactant: Cc1cc(O)nc(S)n1
Reactant: BrCc1cnc2ccccc2c1
Solvent: CCO
Solvent: CCN(CC)CC
Product: Cc1cc(O)nc(SCc2cnc3ccccc3c2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99 %

Procedure:
3-(bromomethyl)quinoline, 6-methyl-2-sulfanylpyrimidin-4-ol (853 mg, 6 mmol) and triethylamine (1 mL, 7 mmol) were mixed in ethanol (50 mL). The mixture was stirred at room temperature for 2 hours. After evaporation, water (100 mL) was added. The suspension was filtered and washed with water and ethyl acetate to provide pure titled product (1.7 g, 99% yield); 1H NMR (400 MHz, DMSO-d6): δ 2.21 (s, 3H), 4.54 (s, 2H), 6.01 (s, 1H), 7.58 (m, 1H), 7.70 (m, 1H), 7.94 (m, 2H), 8.35 (s, 1H), 8.96 (s, 1H); M+284.
Reaction SMILES: N1CCCC1.B.O1CCCC1.C([Li])CCC.[CH2:17]([CH:19]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:20](N(C(C)C(O)C1C=CC=CC=1)C)=[O:21])[CH3:18]>>[CH2:17]([C@@H:19]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH2:20][OH:21])[CH3:18]
Reactant: CCC(C(=O)N(C)C(C)C(O)c1ccccc1)c1ccccc1
Agent: B
Agent: [Li]CCCC
Solvent: C1CCNC1
Solvent: C1CCOC1
Product: CC[C@H](CO)c1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 75.6 %

Procedure:
A dry 200 mL Schlenk flask equipped with a magnetic stirrer was cooled to 0° C. and charged with pyrrolidine (1.61 mL, 19.27 mmol, 3.0 equiv) and borane.tetrahydrofuran (1.0M in tetrahydrofuran, 19.27 mL, 19.27 mmol, 3.0 equiv). The mixture was warmed to 23° C. and stirred for 1 hour, before being recooled to 0° C. n-Butyllithium (1.71M in hexanes, 11.27 mL, 19.27 mmol, 3.0 equiv) was added, and the reaction was stirred at 0° C. for 30 minutes. The ice bath was removed, and [1S-[1R*(R*), 2R*]]-α-ethyl-N-(2-hydroxy-1-methyl-2-phenylethyl)-N-methyl benzeneacetamide (1.99 g, 7.21 mmol, 1.0 equiv) was added neat, and the reaction was stirred at 23° C. overnight. The reaction was quenched with aqueous hydrochloric acid, diluted with 1N HCl (300 mL), and extracted with ether (4×60 mL). The ether extracts were washed with 1:1 brine/1N HCl (2×15 mL), and then concentrated. The residue was stirred in 1N NaOH (100 mL) for 30 minutes at 23° C., and extracted with ether (4×25 mL). These ether extracts were washed with 1:1 brine/1N NaOH (2×20 mL),, dried over sodium sulfate, and concentrated. Flash chromatography (40% ether/petroleum ether) of the residue afforded the desired alcohol (819 mg, 85% yield) as a colorless oil: 1H NMR (300 MHz, C6D6) δ7.0-7.2 (m, 5H), 3.48 (m, 2H), 2.44 (m, 1H), 1.58-1.65 (m, 1H), 1.36-1.45 (m, 1H), 0.91 (t, 1H, J=5.3 Hz), 0.72 (t, 3H, J=7.4 Hz); 13C NMR (75.5 MHz, CDCl3) δ: 142.2, 128.6, 128.1, 126.6, 67.3, 50.4, 24.9, 11.9; FTIR (neat film) cm-1: 3354 (br, s), 3028 (m), 2961 (s), 2930 (s), 2874 (s), 1602 (w), 1494 (s), 1454 (s), 1379 (m), 1038 (S), 760 (S), 700 (S).
Reaction SMILES: [F:1][C:2]1[N:7]=[C:6]2[NH:8][N:9]=[C:10]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[C:5]2=[CH:4][CH:3]=1.CC([O-])(C)C.[K+].[CH3:24][O:25][C:26]1[CH:33]=[CH:32][C:29]([CH2:30]Br)=[CH:28][CH:27]=1>C1COCC1>[F:1][C:2]1[N:7]=[C:6]2[N:8]([CH2:30][C:29]3[CH:32]=[CH:33][C:26]([O:25][CH3:24])=[CH:27][CH:28]=3)[N:9]=[C:10]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[C:5]2=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)c1n[nH]c2nc(F)ccc12
Reactant: COc1ccc(CBr)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COc1ccc(Cn2nc(C(=O)OC(C)(C)C)c3ccc(F)nc32)cc1
Temperature: 7.5 °C
Reaction time: 1 h

Procedure:
To a solution of tert-butyl 6-fluoro-1H-pyrazolo[3,4-b]pyridine-3-carboxylate (29.55 g, 125 mmol) in THF (300 mL) cooled in an ice bath was added KOtBu (13.98 g, 125 mmol) at such a rate as to maintain the temperature between 5-10° C., and then 4-methoxybenzyl bromide (18.2 mL, 125 mmol) was added. The resulting mixture was stirred in an ice bath for 1 hour and then stirred at room temperature for 18 hours. The resulting suspension was quenched with saturated aqueous NH4Cl (200 mL) and then extracted with EtOAc (2×300 mL). The combined organic extracts were washed with brine, dried with MgSO4 and the solvent removed in vacuo. The resulting residue was purified on a silica gel (1000 g) column (0-11% EtOAc/hexanes) to give the title compound. LRMS (M+1)=380.1
Reaction SMILES: C1(N([C@H]2CC[C@H](OC)CC2)[C:7](=[O:19])[NH:8][C:9]2[S:10][C:11]([S:14][CH2:15][C:16]([OH:18])=[O:17])=[CH:12][N:13]=2)CCCC1.[CH:28]1([NH:34][C@H:35]2[CH2:40][CH2:39][C@@H:38]([O:41][CH2:42][CH2:43][CH3:44])[CH2:37][CH2:36]2)[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1>C(OC(=O)C)C>[CH:28]1([N:34]([C@H:35]2[CH2:40][CH2:39][C@@H:38]([O:41][CH2:42][CH2:43][CH3:44])[CH2:37][CH2:36]2)[C:7](=[O:19])[NH:8][C:9]2[S:10][C:11]([S:14][CH2:15][C:16]([OH:18])=[O:17])=[CH:12][N:13]=2)[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]1
Reactant: CCCO[C@H]1CC[C@@H](NC2CCCCC2)CC1
Reactant: CO[C@H]1CC[C@H](N(C(=O)Nc2ncc(SCC(=O)O)s2)C2CCCC2)CC1
Solvent: CCOC(C)=O
Product: CCCO[C@H]1CC[C@@H](N(C(=O)Nc2ncc(SCC(=O)O)s2)C2CCCCC2)CC1

Procedure:
The title compound was prepared in a similar manner as {2-[3-cyclopentyl-3-(trans-4-methoxy-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-acetic acid using cyclohexyl-cis-(4-propoxycyclohexyl)-amine and amino-thiazol-5-ylsulfanyl)-acetic acid ethyl ester.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C@H:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C@H:11]([OH:18])[CH2:10]2)=[CH:4][CH:3]=1.[Cl:19][C:20]([C:30]([F:33])([F:32])[F:31])=[CH:21][C@@H:22]1[C@H:24]([C:25](Cl)=[O:26])[C:23]1([CH3:29])[CH3:28].N1C=CC=CC=1>C1(C)C=CC=CC=1>[Cl:19][C:20]([C:30]([F:31])([F:32])[F:33])=[CH:21][C@@H:22]1[C@H:24]([C:25]([O:18][C@H:11]2[C:12]3[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=3)[C@H:9]([CH2:8][C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[CH2:10]2)=[O:26])[C:23]1([CH3:29])[CH3:28]
Reactant: CC1(C)[C@H](C=C(Cl)C(F)(F)F)[C@@H]1C(=O)Cl
Reactant: O[C@@H]1C[C@@H](Cc2ccc(F)cc2)c2ccccc21
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: CC1(C)[C@H](C=C(Cl)C(F)(F)F)[C@@H]1C(=O)O[C@@H]1C[C@@H](Cc2ccc(F)cc2)c2ccccc21
Yield: 86.7 %

Procedure:
In the manner of Example 4, the reaction of 1.00 g (0.004 mole) of trans-3-[(4-fluorophenyl)methyl]-1-indanol (96% trans, 4% cis) and 1.07 g (0.004 mole) of cis-3-(2-chloro-3,3,3-trifluoro-1-propenyl)-2,2-dimethylcyclopropanecarbonyl chloride in the presence of 0.32 g (0.004 mole) of pyridine and 50 mL of toluene gave 1.62 g of trans-3-[(4-fluorophenyl)methyl]-1-indanyl cis-3-(2-chloro-3,3,3-trifluoro-1-propenyl)-2,2-dimethylcyclopropanecarboxylate. The ir and nmr spectra were consistent with the proposed structure.
Reaction SMILES: [CH:1]([C@:3]12[CH2:41][CH2:40][C@@H:39]([C:42]([CH3:44])=[CH2:43])[C@@H:4]1[C@@H:5]1[C@@:18]([CH3:21])([CH2:19][CH2:20]2)[C@@:17]2([CH3:22])[C@@H:8]([C@:9]3([CH3:38])[C@@H:14]([CH2:15][CH2:16]2)[C:13]([CH3:24])([CH3:23])[C:12]([C:25]2[CH:37]=[CH:36][C:28]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])=[CH:27][CH:26]=2)=[CH:11][CH2:10]3)[CH2:7][CH2:6]1)=O.C(O)(=O)C.[NH2:49][CH2:50][CH2:51][CH2:52][N:53]1[CH2:58][CH2:57][O:56][CH2:55][CH2:54]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH3:21][C@:18]12[C@@:17]3([CH3:22])[C@@H:8]([C@:9]4([CH3:38])[C@@H:14]([CH2:15][CH2:16]3)[C:13]([CH3:23])([CH3:24])[C:12]([C:25]3[CH:37]=[CH:36][C:28]([C:29]([O:31][C:32]([CH3:33])([CH3:34])[CH3:35])=[O:30])=[CH:27][CH:26]=3)=[CH:11][CH2:10]4)[CH2:7][CH2:6][C@@H:5]1[C@H:4]1[C@H:39]([C:42]([CH3:44])=[CH2:43])[CH2:40][CH2:41][C@:3]1([CH2:1][NH:49][CH2:50][CH2:51][CH2:52][N:53]1[CH2:58][CH2:57][O:56][CH2:55][CH2:54]1)[CH2:20][CH2:19]2
Reactant: C=C(C)[C@@H]1CC[C@]2(C=O)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC(C)(C)C)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Reactant: NCCCN1CCOCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: C=C(C)[C@@H]1CC[C@]2(CNCCCN3CCOCC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC(C)(C)C)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 56.9 %

Procedure:
To a solution of tert-butyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-formyl-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate (0.1 g, 0.167 mmol) in DCE (2 ml) was added acetic acid (1M in DCM) (0.167 ml, 0.167 mmol) and N-(3-Aminopropyl)morpholine (0.029 ml, 0.200 mmol). The mixture was stirred for 15 minutes at rt and sodium triacetoxyborohydride (0.071 g, 0.334 mmol) was added. The mixture was stirred at rt for 1.5 h and an additional 0.1 g of sodium triacetoxyborohydride was added. The mixture was stirred overnight at rt then was quenched with 7 ml of sat. NaHCO3. The mixture was extracted with dichloromethane (3×7 ml) and the combined organic layers were dried with Na2SO4. The drying agent was removed by filtration and the filtrate was concentrated under reduced pressure. The mixture was purified by flash chromatography using a 0-10% MeOH in dichloromethane gradient. The fractions containing the expected product were combined and concentrated under reduced pressure to give the title compound as a white foam (69 mg, 0.095 mmol, 56.8% yield). LCMS: m/e 727.5 (M+H)+, 2.81 min (method 6).
Reaction SMILES: CO.Cl.[CH3:4][O:5][NH2:6].[CH3:7][CH:8]1[O:12][CH:11](O)[CH:10]([S:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)[CH2:9]1>C(N(CC)CC)C>[CH3:4][O:5][N:6]=[CH:11][CH:10]([S:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1)[CH2:9][CH:8]([OH:12])[CH3:7]
Reactant: CON
Reactant: CC1CC(Sc2ccccn2)C(O)O1
Agent: Cl
Solvent: CO
Solvent: CCN(CC)CC
Product: CON=CC(CC(C)O)Sc1ccccn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 102 %

Procedure:
8.0 mL of methanol and 712 mg of O-methylhydroxylamine hydrochloride were added to 1.5 g of 5-methyl-3-(pyridin-2-ylsulfanyl)oxolan-2-ol, and thereafter, 1.1 mL of triethylamine was added dropwise to the mixture. The thus obtained mixture was stirred at room temperature for 2 hours. Thereafter, the solvent was distilled away under reduced pressure, 50 mL of ethyl acetate and 50 mL of water were then added to the residue, and the water layer was then removed. The organic layer was washed with a saturated sodium chloride aqueous solution, and was then dried over anhydrous magnesium sulfate. After that, the solvent was distilled away under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/acetone=4/1), so as to obtain 1.74 g of 5-(methoxyimino)-4-(pyridin-2-ylsulfanyl)pentan-2-ol in the form of a colorless oily product.
Reaction SMILES: CC([O:4][C:5]([CH3:7])=[O:6])=O.O[NH:9][C:10](=[NH:24])[CH2:11][C:12]1[C:17]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:16][CH:15]=[CH:14][N:13]=1.C(OCC)(=O)C>O>[C:5]([O:4][NH:24][C:10](=[NH:9])[CH2:11][C:12]1[C:17]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:16][CH:15]=[CH:14][N:13]=1)(=[O:6])[CH3:7]
Reactant: N=C(Cc1ncccc1-c1ccccc1)NO
Reactant: CC(=O)OC(C)=O
Solvent: O
Solvent: CCOC(C)=O
Product: CC(=O)ONC(=N)Cc1ncccc1-c1ccccc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 42.94 %

Procedure:
Ac2O (30 mL) was added to N-hydroxy-2-(3-phenyl-pyridin-2-yl)-acetamidine (160) (5.3 g, 23.35 mmol) at room temperature. A purple colored solution was formed, after a few hours a dark brown solution was formed which was stirred for 6 h at room temperature. Silica thin layer chromatography was performed (100% ethyl acetate, Rf=0.6). Cold water was added, the mixture was extracted with ethyl acetate (3×50 mL), the organic part was dried and concentrated, the crude product was purified by a CombiFlash column (eluted at 50% ethyl acetate in hexane) to get 2-(3-phenylpyridin-2-yl)ethanimidamido acetate (161) (2.7 g, 42.94% pure and 2 g mixture) as a yellow solid.
Reaction SMILES: Cl.[C:2]([NH2:7])(=[NH:6])[CH:3]([CH3:5])[CH3:4].CC[O-].[Na+].[C:12]([OH:20])(=[O:19])/[C:13](=[C:15](\[CH:17]=O)/[Br:16])/Br>CCO>[Br:16][C:15]1[C:13]([C:12]([OH:20])=[O:19])=[N:6][C:2]([CH:3]([CH3:5])[CH3:4])=[N:7][CH:17]=1
Reactant: O=C/C(Br)=C(/Br)C(=O)O
Reactant: CC(C)C(=N)N
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CC(C)c1ncc(Br)c(C(=O)O)n1
Temperature: 50 °C
Yield: 38.6 %

Procedure:
To a stirred suspension of isobutyramidine hydrochloride (6.47 g, 47.5 mmol) at rt in EtOH (30 ml) under an argon atmosphere was added NaOEt solution (21 ml, 21% in EtOH) over min. The suspension was heated to 50° C. and a solution of mucobromic acid (5.7 g, 22.1 mmol) in EtOH (24 ml) was added dropwise over 5 min at 50° C. An additional portion of NaOEt solution (12 ml, 21% in EtOH) was added dropwise over 5 min. The mixture was then cooled to rt. The solids were filtered off, and the cake was washed with plenty of ethanol. The filtrate was concentrated to leave the crude product as a light brown solid. The crude material was triturated in 2 N HCl (100 ml). The product was collected by filtration, washed with plenty of H2O and plenty of n-heptane and dried to give the product (2.09 g, 73%) as beige solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([P:8](=[O:11])([CH3:10])[CH3:9])=[CH:4][CH:3]=1.[Cl:12][C:13]1[CH:18]=[C:17](Cl)[N:16]=[CH:15][N:14]=1>CN(C)C=O.C(N(C(C)C)CC)(C)C>[Cl:12][C:13]1[N:14]=[CH:15][N:16]=[C:17]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([P:8]([CH3:9])([CH3:10])=[O:11])=[CH:6][CH:7]=2)[CH:18]=1
Reactant: Clc1cc(Cl)ncn1
Reactant: CP(C)(=O)c1ccc(N)cc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CP(C)(=O)c1ccc(Nc2cc(Cl)ncn2)cc1
Temperature: 25 °C

Procedure:
A suspension of 4-amino-dimethylphenylphosphine oxide (2.2 mmol) in 15 mL of N,N-Dimethylformamide and 3.6 mL of Diisopropylethylamine, is stirred at room temperature until a clear solution is obtained. 4,6-Dichloropyrimidine (2.6 mmol) is added in four portions over 5 minutes. The reaction mixture is stirred at high temperature until formation of the desired compound.
Reaction SMILES: [Br-].[CH3:2][O:3][C:4](=[O:25])[CH2:5][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[Br:36][C:37]1[CH:38]=[C:39]([C:45]2([C:48]#[N:49])[CH2:47][CH2:46]2)[CH:40]=[C:41]([CH:43]=O)[CH:42]=1>C1COCC1>[Br:36][C:37]1[CH:42]=[C:41](/[CH:43]=[CH:5]/[C:4]([O:3][CH3:2])=[O:25])[CH:40]=[C:39]([C:45]2([C:48]#[N:49])[CH2:47][CH2:46]2)[CH:38]=1
Reactant: N#CC1(c2cc(Br)cc(C=O)c2)CC1
Reactant: COC(=O)C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Br-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)/C=C/c1cc(Br)cc(C2(C#N)CC2)c1
Temperature: -25 °C
Reaction time: 0.17 h
Yield: 97.1 %

Procedure:
To a suspension of (2-methoxy-2-oxo-ethyl)-triphenyl-phosphonium bromide (1.502 g, 3.618 mmol) in THF (15 mL) under nitrogen at room temperature was added LHMDS in THF (3.358 mL of 1 M, 3.358 mmol) dropwise. The mixture was stirred for 10 mins then cooled to −25° C. 1-(3-bromo-5-formyl-phenyl)cyclopropane-1-carbonitrile (500 mg, 1.999 mmol) was dissolved in 1 mL of THF and added to the reaction. The reaction was allowed to warm to room temperature over 1 hour. The reaction was quenched with MeOH (2 mL) and then partitioned between ethyl acetate and brine. The aqueous was extracted with ethyl acetate and dried, filtered and concentrated. The crude product was purified on silica (Companion, 24 g) eluting with 1-20% EtOAc:Petrol ether to give methyl (E)-3-[3-bromo-5-(1-cyanocyclopropyl)phenyl]prop-2-enoate as a yellow solid (594 mg, 97%).
Reaction SMILES: Br[C:2]1[N:11]=[C:5]2[CH:6]=[C:7]([Br:10])[CH:8]=[CH:9][N:4]2[N:3]=1.[CH3:12][NH:13][CH:14]1[CH2:16][CH2:15]1>>[Br:10][C:7]1[CH:8]=[CH:9][N:4]2[N:3]=[C:2]([N:13]([CH:14]3[CH2:16][CH2:15]3)[CH3:12])[N:11]=[C:5]2[CH:6]=1
Reactant: CNC1CC1
Reactant: Brc1ccn2nc(Br)nc2c1
Product: CN(c1nc2cc(Br)ccn2n1)C1CC1
Yield: 41 %

Procedure:
2,7-dibromo-[1,2,4]triazolo[1,5-a]pyridine (1.5 g, 5.42 mmol) was refluxed in N-methylcyclopropanamine (3.85 g, 54.2 mmol) for 4 h. The solvent was evaporated and the residue was diluted with ethyl acetate and washed with water and brine. The organic layer was dried over magnesium sulfate, filtered and applied on SiO2. Column chromatography over 70 g SiO2 using heptane/ethyl acetate affords (7-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-cyclopropyl-methyl-amine (593 mg, 41%) as white powder. MS: m/z=397.1 (M+H+).
Reaction SMILES: CS([O:5][S:6]([CH3:9])(=[O:8])=[O:7])(=O)=O.[Cl:10][C:11]1[S:12][C:13]([CH2:16]O)=[CH:14][N:15]=1.N1C=CC=CC=1>O1CCCC1>[Cl:10][C:11]1[S:12][C:13]([CH2:16][O:5][S:6]([CH3:9])(=[O:7])=[O:8])=[CH:14][N:15]=1
Reactant: CS(=O)(=O)OS(C)(=O)=O
Reactant: OCc1cnc(Cl)s1
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CS(=O)(=O)OCc1cnc(Cl)s1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
1.28 g of methanesulfonic anhydride are added to 1.0 g of 2-chloro-5-hydroxymethyl-thiazole and 0.63 g of pyridine in 10 ml of tetrahydrofuran and the mixture is stirred for three hours at room temperature. Concentration of the solution yields the title compound in the form of a solid (compound 1.3). 1H-NMR (DMSO-d6, 250 MHz): s, 1H, 7.87 ppm; s, 2H, 5.52 ppm; s, 3H, 2.43 ppm.
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[C:15]([F:20])[CH:14]=2)[C:8]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=2)=[C:7]([C:28]2[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:29]=2[Cl:35])[N:6]=1)(=O)=O.[CH:36]([NH:39][CH:40]([CH3:42])[CH3:41])([CH3:38])[CH3:37]>>[CH:36]([N:39]([C:5]1[N:10]=[C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[C:15]([F:20])[CH:14]=2)[C:8]([C:21]2[CH:22]=[CH:23][C:24]([Cl:27])=[CH:25][CH:26]=2)=[C:7]([C:28]2[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:29]=2[Cl:35])[N:6]=1)[CH:40]([CH3:42])[CH3:41])([CH3:38])[CH3:37]
Reactant: CS(=O)(=O)c1nc(OCc2ccc(F)c(F)c2)c(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)n1
Reactant: CC(C)NC(C)C
Product: CC(C)N(c1nc(OCc2ccc(F)c(F)c2)c(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)n1)C(C)C

Procedure:
2-(Methylsulfonyl)-4-(3,4-difluorobenzyloxy)-5-[4-chlorophenyl]-6-[2,4-dichlorophenyl]pyrimidine (Reference Example 6, 55 mg, 0.10 mmol) was reacted in neat diisopropyl amine heated at 150° C. overnight in a stainless steel pressure bottle by the general procedure described in Example 31, Step A. Workup (excess isopropyl amine removed under reduced pressure) and flash column chromatography on silica gel (eluted with 97/3 hexanes/ethyl acetate) afforded the title compound. HPLC: Rt=4.22 min. 1H-NMR 500 MHz (CDCl3): δ 1.28 (d, J=6 Hz, 6H), 4.217 (q, J=6 Hz, 1H), 5.39 (s, 2H), 7.04 (d, J=8 Hz, 2H), 7.08-7.14 (m, J=2H), 7.17 (m, 5H), 7.31 (d, J=2 Hz, 1H).
Reaction SMILES: [CH3:1][C:2](/[CH:4]=[N:5]/O)=O.[C:7]1(=[O:14])[CH2:12][CH2:11][CH2:10][C:9](=O)[CH2:8]1.C(O)(=O)C.[OH-].[K+]>[Zn].O>[CH3:1][C:2]1[C:8]2[C:7](=[O:14])[CH2:12][CH2:11][CH2:10][C:9]=2[NH:5][CH:4]=1
Reactant: O=C1CCCC(=O)C1
Reactant: CC(=O)/C=N/O
Agent: [K+]
Agent: [OH-]
Agent: [Zn]
Solvent: CC(=O)O
Solvent: O
Product: Cc1c[nH]c2c1C(=O)CCC2
Temperature: 25 °C
Yield: 44.7 %

Procedure:
The subtitle compound was prepared according to the literature procedure (Hauptmann, S. et al., Z. Chem., 1966, 3, 107. Ravina, E. et al., Bio. Med. Chem. Lett., 1995, 5, 579.). A mixture of anti-pyruvic aldehyde 1-oxime (1.3 g, 15 mmol), 1,3-cyclohexanedione (1.7 g, 15 mmol), glacial acetic acid (12 mL) and water (3.0 mL) was stirred vigorously at room temperature. Zinc dust (3 g) was added slowly keeping the temperature below 60° C. After addition, this resulting brown solution was heated under reflux temperature for 2 hours. After cooling, the reaction mixture was basified by an addition of 1 M aqueous KOH. The whole was extracted with CH2Cl2 (50 mL×3), and the combined organic layers were dried over MgSO4, and concentrated in vaciio. The residue was purified by flash chromatography eluting with hexane-ethyl acetate (3:1→EtOAc only) to afford the subtitle compound (1.0 g, 46% yield) of as a yellow solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]([OH:18])=O)=[C:11]([C:19]#[N:20])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:21]1[CH2:24][CH2:23][CH2:22]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[N:21]1([C:16](=[O:18])[CH2:15][C:12]2[CH:13]=[CH:14][C:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[CH:10][C:11]=2[C:19]#[N:20])[CH2:24][CH2:23][CH2:22]1
Reactant: C1CNC1
Reactant: N#Cc1cc(OCc2ccccc2)ccc1CC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: N#Cc1cc(OCc2ccccc2)ccc1CC(=O)N1CCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
[4-(benzyloxy)-2-cyanophenyl]acetic acid (0.40 g, 1.50 mmol) was dissolved in DMF (5 ml) and azetidine (0.128 g, 2.25 mmol), DIEA (0.78 ml, 4.49 mmol), and HATU (1.14 g, 2.99 mmol) added. The mixture was stirred at RT for 1 hr. The solution was loaded directly onto a Biotage RP C18 cartridge (30 g) and purified using a gradient eluant of 10-100% water:acetonitrile+0.05% formic acid. The volatiles were removed in vacuo to afford the title compound. LC/MS (m/z): 307 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:9][C@@H:10]([CH3:13])[CH2:11][OH:12])=[N:4][CH:5]=[C:6]([Br:8])[CH:7]=1.[C:14]1([CH3:24])[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1>N1C=CC=CC=1>[Br:8][C:6]1[CH:7]=[C:2]([NH:1][S:20]([C:17]2[CH:18]=[CH:19][C:14]([CH3:24])=[CH:15][CH:16]=2)(=[O:22])=[O:21])[C:3]([NH:9][C@@H:10]([CH3:13])[CH2:11][OH:12])=[N:4][CH:5]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: C[C@@H](CO)Nc1ncc(Br)cc1N
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)Nc2cc(Br)cnc2N[C@@H](C)CO)cc1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 90.5 %

Procedure:
A solution of crude (S)-2-(3-amino-5-bromopyridin-2-ylamino)propane-1-ol (5.85 g, 23.77 mmol) dissolved in pyridine (58 mL) was cooled to 0° C. and treated with p-toluenesulfonyl chloride (4.53 g, 23.77 mmol) in one portion. The reaction mixture was stirred at 0° C. After 45 min, the solution was concentrated under reduced pressure. The residue was partitioned between water (60 mL) and ethyl acetate. The ethyl acetate layer was separated and washed with 5% aqueous sodium chloride solution (2×50 mL) and concentrated under reduced pressure. The resulting syrup was dissolved in toluene (100 mL), which was then removed under reduced pressure in an effort to remove residual pyridine. The crude product (10.4 g) was purified by column chromatography on silica gel (eluting with 3:1 dichloromethane-ethyl acetate followed by 2:1 dichloromethane-ethyl acetate and finally 3:2 dichloromethane-ethyl acetate). The product-containing fractions were combined and concentrated. The resulting syrup was dissolved in dichloromethane and the solution diluted with heptane. The mixture was concentrated under reduced pressure to yield (S)-N-(5-bromo-2-(1-hydroxypropan-2-ylamino)pyridin-3-yl)-4-methylbenzenesulfonamide (8.6 g, 21.5 mmol, 90%) as a nearly colorless foam/solid. MS (ESI, pos. ion) m/z 400, 402 [M+1]+.
Reaction SMILES: [CH:1]1([O:6][C:7]2[C:12]([O:13][CH3:14])=[CH:11][N:10]=[C:9]([CH2:15][OH:16])[CH:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1>C(OCC)C.ClCCl.[O-2].[O-2].[Mn+4]>[CH:1]1([O:6][C:7]2[C:12]([O:13][CH3:14])=[CH:11][N:10]=[C:9]([CH:15]=[O:16])[CH:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COc1cnc(CO)cc1OC1CCCC1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Solvent: CCOCC
Product: COc1cnc(C=O)cc1OC1CCCC1
Temperature: 25 °C
Reaction time: 90 h
Yield: 83.3 %

Procedure:
Manganese dioxide (6.0 g) is added to a solution of 4-cyclopentyloxy-2-hydroxymethyl-5-methoxypyridine (2.0 g) in diethyl ether (80 mL) and dichloromethane (10 mL) and the mixture stirred at room temperature for 90 hours. After filtering the filter pad is washed with dichloromethane and the combined filtrate and washings are evaporated to give a white solid. The solid is dried under high vacuum to give 4-cyclopentyloxy-5-methoxypyridine-2-carboxaldehyde (1.65 g). [1Hnmr in D6-DMSO shifts relative to Me4Si: 1.55-1.79, 6H, m; 1.97, 2H, m; 3.96, 3H, s; 5.03, 1H, m; 7.45, 1H, s; 8.41, 1H, s; 9.83, 1H, s.].