Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OCC)(=O)C.C([O:14][C:15]1[CH:16]=[C:17]([CH:37]=[CH:38][C:39]=1[O:40]CC1C=CC=CC=1)[C:18]1[O:19][C:20]2[C:25]([C:26](=[O:28])[CH:27]=1)=[C:24]([O:29][CH3:30])[C:23]([O:31][CH3:32])=[C:22]([O:33][CH3:34])[C:21]=2[O:35][CH3:36])C1C=CC=CC=1>[Pd].CO>[OH:14][C:15]1[CH:16]=[C:17]([CH:37]=[CH:38][C:39]=1[OH:40])[C:18]1[O:19][C:20]2[C:25]([C:26](=[O:28])[CH:27]=1)=[C:24]([O:29][CH3:30])[C:23]([O:31][CH3:32])=[C:22]([O:33][CH3:34])[C:21]=2[O:35][CH3:36]
Reactant: COc1c(OC)c(OC)c2c(=O)cc(-c3ccc(OCc4ccccc4)c(OCc4ccccc4)c3)oc2c1OC
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: COc1c(OC)c(OC)c2c(=O)cc(-c3ccc(O)c(O)c3)oc2c1OC

Procedure:
Into 200 ml. of a mixed solvent of ethyl acetate and methanol at a ratio of 1:1 was dissolved 1.11 g. of 3',4'-bis(benzyloxy)-5,6,7,8-tetramethoxyflavone and added 0.2 to 0.3 g. of 10% palladium-charcoal. The resulting mixture was mixed with shaking in a stream of H2 gas until H2 absorption was completed. After filtering out the catalyst, the obtained filtrate was concentrated. The residue was recrystallized from methanol to give 0.74 g. (97% of the theoretical amount) of the desired compound being a colorless prismatic crystal.
Reaction SMILES: [CH3:1][C:2](=O)[CH2:3][CH2:4][C:5](=O)[CH3:6].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[Cl:21][C:22]1[CH:23]=[C:24]([CH:26]=[C:27]([F:29])[CH:28]=1)[NH2:25].O1CCCC1>C1(C)C=CC=CC=1>[Cl:21][C:22]1[CH:23]=[C:24]([N:25]2[C:5]([CH3:6])=[CH:4][CH:3]=[C:2]2[CH3:1])[CH:26]=[C:27]([F:29])[CH:28]=1
Reactant: Nc1cc(F)cc(Cl)c1
Reactant: CC(=O)CCC(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: Cc1ccc(C)n1-c1cc(F)cc(Cl)c1

Procedure:
2,5-Hexanedione (4.51 mL) and p-toluenesulfonic acid monohydrate (73 mg) were added to a solution of 3-chloro-5-fluoroaniline (5.12 g) in toluene (40 mL)-tetrahydrofuran (40 mL), and the mixture was heated under reflux for 3.5 hours. After being cooled down, the reaction solution was concentrated in vacuo, and the resultant residue was dissolved in chloroform. The solution was washed successively with water and brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The resulted residue was purified by column chromatography on silica gel (Solvent: n-hexane/ethyl acetate=97/3) to give the titled compound (7.63 g) as a yellow oil.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([OH:16])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:17]([O:19][C:20](=[O:47])[CH:21]=[CH:22][CH:23]([NH:39]C(OC(C)(C)C)=O)[CH2:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[CH:27][CH:26]=1)[CH3:18]>>[CH2:17]([O:19][C:20](=[O:47])[CH2:21][CH2:22][CH:23]([NH:39][C:14](=[O:16])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[CH2:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[CH:27][CH:26]=1)[CH3:18]
Reactant: O=C(O)CCCCCCCc1ccccc1
Reactant: CCOC(=O)C=CC(Cc1ccc(OCc2ccccc2)cc1)NC(=O)OC(C)(C)C
Product: CCOC(=O)CCC(Cc1ccc(OCc2ccccc2)cc1)NC(=O)CCCCCCCc1ccccc1

Procedure:
From 8-phenyloctanoic acid 71c and (RS)-5-(4-Benzyloxy-phenyl)-4-tertbutoxycarbonylamino-pent-2-enoic acid ethyl ester 77 (96% yield): 1H nmr (CDCl3) δ 1.20 (t, J=7.1 Hz, 3H), 1.27-1.55 (m, 10H), 2.06 (t, J=7.4 Hz, 2H), 2.52 (t, J=7.4 Hz, 2H), 2.74-2.79 (m, 2H), 4.10 (q, J=7.0 Hz, 2H), 4.84-4.88 (m, 1H), (4.94, s, 2H), 5.80 (br d, J=15.8 Hz, 1H), 6.00 (d J=8.2 Hz, 1H), 6.82-7.36 (m, 15H). 13C nmr (CDCl3) δ 172.5, 165.9, 157.5, 147.2, 142.5, 136.7, 130.1, 128.6, 128.3, 128.1, 128.0, 127.7, 127.2, 121.0, 114.7, 69.7, 60.2, 50.6, 39.3, 36.3, 35.7, 31.2, 29.0, 28.9, 28.1, 25.4, 14.0.
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@H:2]([C:11]([OH:13])=O)[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[CH:5]=1.[NH2:21][C@H:22]([C:33]([O:35][CH3:36])=[O:34])[CH2:23][CH2:24][CH2:25][NH:26][C:27](=[NH:32])[NH:28][N+:29]([O-:31])=[O:30].Cl.OC1C2N=NNC=2C=CC=1.Cl.CNC(N=C=NCC)CCNC>CN(C)C1C=CN=CC=1.C(Cl)Cl>[NH2:1][C@H:2]([C:11]([NH:21][C@H:22]([C:33]([O:35][CH3:36])=[O:34])[CH2:23][CH2:24][CH2:25][NH:26][C:27](=[NH:32])[NH:28][N+:29]([O-:31])=[O:30])=[O:13])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[CH:5]=1
Reactant: COC(=O)[C@@H](N)CCCNC(=N)N[N+](=O)[O-]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1cccc(F)c1)C(=O)O
Agent: CCN=C=NC(CCNC)NC
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: COC(=O)[C@H](CCCNC(=N)N[N+](=O)[O-])NC(=O)[C@@H](N)Cc1cccc(F)c1
Yield: 105.2 %

Procedure:
To a solution of 2.00 gm of BOC-3-F-Phe-OH (7.06 mmol), 2.09 gm of Arg(NO2)-OMe HCl (7.77 mmol), 1.05 gm of hydroxybenzotriazole and 2.58 gm of 4-dimethylaminopyridine in 50 mL of methylene chloride was added 1.5 gm of 1,3-dimethylaminopropyl-3-ethylcarbodiimide hydrochloride. After stirring for 15 hours 100 mL more methylene chloride was added to the reaction, and it was washed three times with 100 mL portions of 10% aqueous hydrochloric acid solution, twice with 100 mL of 50% saturated sodium bicarbonate solution, once with 100 mL of saturated brine, dried over anhydrous magnesium sulfate, filtered, and the solvent removed under reduced pressure to yield 2.96 gm of product. This was dissolved in 100 mL of 10% trifluoroacetic acid in methylene chloride, stirred for 2 hours, and the solvent removed rapidly under reduced pressure. The material was triturated with diethyl ether and dried under high vacuum to yield product.
Reaction SMILES: [NH2:1][C:2]1[CH:8]=[C:7]([S:9][C:10]#[N:11])[CH:6]=[CH:5][C:3]=1[NH2:4].CC(C)=O.[C:16](Br)#[N:17].[OH-].[Na+]>C(O)C>[NH2:17][C:16]1[NH:4][C:3]2[CH:5]=[CH:6][C:7]([S:9][C:10]#[N:11])=[CH:8][C:2]=2[N:1]=1
Reactant: N#CSc1ccc(N)c(N)c1
Reactant: N#CBr
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CC(C)=O
Product: N#CSc1ccc2[nH]c(N)nc2c1
Reaction time: 8 h

Procedure:
8.25 g. of 2-amino-4-thiocyanato-aniline are dissolved in 60 ml. of acetone, whereupon a solution of 6.1 g. of bromo cyane and 20 ml. of ethanol is added dropwise. The reaction mixture is allowed to stand overnight, whereupon it is evaporated to dryness. The residue is taken up in water and the pH of the solution formed is adjusted to 8 by adding a 2N sodium hydroxide solution. The precipitated crystals are filtered off, washed with water and dried. Thus 8.3 g. of 2-amino-5-thiocyanato-1H-benzimidazole are obtained. M.p.: 204°-205° C. (decomposition).
Reaction SMILES: C([O:3][C:4](=[O:13])[C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[N:7][C:6]=1[NH2:12])C.[OH-].[Na+]>C(O)C>[NH2:12][C:6]1[N:7]=[C:8]([NH2:11])[CH:9]=[CH:10][C:5]=1[C:4]([OH:13])=[O:3]
Reactant: CCOC(=O)c1ccc(N)nc1N
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Nc1ccc(C(=O)O)c(N)n1
Reaction time: 2 h
Yield: 100 %

Procedure:
2,6-diamino-nicotinic acid ethyl ester (2 g, 11 mmol) described in Production Example 1-1-3 was dissolved in ethanol (15 mL) followed by the addition of 1 N aqueous sodium hydroxide solution (15 mL) and stirring for 2 hours while heating under reflux. After allowing the reaction mixture to return to room temperature, the ethanol was distilled off under a reduced pressure and the residue was cooled with ice and neutralized with 1 N hydrochloric acid. After filtering the precipitated solid and washing with water, the solid was dried to obtain the title compound (1.72 g, 11 mmol, quantitative).
Reaction SMILES: [NH2:1][C:2]([CH3:23])([CH3:22])[CH2:3][C:4]1[N:5]([CH2:18][CH2:19][O:20][CH3:21])[N:6]=[C:7]2[C:16]=1[C:15]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N:9]=[C:8]2[NH2:17].[C:24](Cl)(=[O:27])[CH2:25][CH3:26]>>[NH2:17][C:8]1[C:7]2=[N:6][N:5]([CH2:18][CH2:19][O:20][CH3:21])[C:4]([CH2:3][C:2]([NH:1][C:24](=[O:27])[CH2:25][CH3:26])([CH3:23])[CH3:22])=[C:16]2[C:15]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N:9]=1
Reactant: CCC(=O)Cl
Reactant: COCCn1nc2c(N)nc3ccccc3c2c1CC(C)(C)N
Product: CCC(=O)NC(C)(C)Cc1c2c(nn1CCOC)c(N)nc1ccccc12
Yield: 73.4 %

Procedure:
Using the general method of Example 599, 1-(2-amino-2-methylpropyl)-2-(2-methoxyethyl)-2H-pyrazolo[3,4-c]quinolin-4-amine (500 mg, 1.60 mmol, prepared as described in Example 590) was reacted with propionyl chloride (370 mg, 4.00 mmol). The crude product was purified by IFC (silica gel eluting with a gradient of 15 to 50% CMA in chloroform) followed by recrystallization from ethyl acetate/hexanes to provide 434 mg of N-{2-[4-amino-2-(methoxyethyl)-2H-pyrazolo[3,4-c]quinolin-1-yl]-1,1-dimethylethyl}propionamide as a white solid, mp 157-158° C. MS (APCI) m/z 370 (M+H)+; Anal. Calcd for C20H27N5O2: C, 65.02; H, 7.37; N, 18.96. Found: C, 64.79; H, 7.58; N, 18.94.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:8]=[CH:9][C:10]3[O:16][CH2:15][CH2:14][CH:13]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:12](=O)[C:11]=3[CH:23]=2)[CH2:3][CH2:2]1.[BH4-].[Na+].C(N(CC)CC)C.CS(Cl)(=O)=O>C1COCC1.CO.O>[O:1]1[CH2:2][CH2:3][N:4]([C:7]2[CH:8]=[CH:9][C:10]3[O:16][CH2:15][CH2:14][C:13]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:12][C:11]=3[CH:23]=2)[CH2:5][CH2:6]1
Reactant: CCOC(=O)C1CCOc2ccc(N3CCOCC3)cc2C1=O
Agent: CS(=O)(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: CCN(CC)CC
Product: CCOC(=O)C1=Cc2cc(N3CCOCC3)ccc2OCC1
Temperature: -50 °C
Reaction time: 0.5 h
Yield: 78.9 %

Procedure:
In THF (10 ml) was dissolved ethyl 7-morpholino-5-oxo-2,3,4,5-tetrahydro-1-benzoxepine-4-carboxylate (924 mg, 2.89 mmol), and to the mixture was added at −30° C. a solution of sodium boro hydride (164 mg, 4.34 mmol) in methanol (3 ml). The mixture was stirred at −20° C. to −15° C. for 30 minutes, and the mixture was cooled to −50° C., to which was added water (15 ml). The mixture was extracted with ethyl acetate (15 ml×3), and the organic layer was dried with anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was dissolved in THF (10 ml), and to the mixture were added at 0° C. triethylamine (2.02 ml, 14.5 mmol) and methanesulfonylchloride (0.336 ml, 4.34 mmol). The mixture was stirred at room temperature for 17 hours and concentrated under reduced pressure. To the residue was added water (15 ml), and the mixture was extracted with ethyl acetate (20 ml×3). The organic layer was dried with anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified with column chromatography (silica gel 30 g, ethyl acetate/ hexane=1/5), and the desired fraction was concentrated under reduced pressure to give ethyl 7-morpholino-2,3-dihydro-1-benzoxepine-4-carboxylate (691 mg, 2.28 mmol, 79%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([OH:13])=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:14][NH:15][C@@H:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:19][CH2:18][C@H:17]1[N:26]1[CH2:30][CH2:29][CH2:28][CH2:27]1>>[CH3:14][N:15]([C@@H:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:19][CH2:18][C@H:17]1[N:26]1[CH2:30][CH2:29][CH2:28][CH2:27]1)[C:11](=[O:13])[CH2:10][C:7]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=1
Reactant: CN[C@@H]1c2ccccc2CC[C@H]1N1CCCC1
Reactant: O=C(O)Cc1ccc([N+](=O)[O-])cc1
Product: CN(C(=O)Cc1ccc([N+](=O)[O-])cc1)[C@@H]1c2ccccc2CC[C@H]1N1CCCC1
Yield: 92 %

Procedure:
Using the procedure of Step C of Example 1, 770 mg of (p-nitrophenyl) acetic acid and 700 mg of the product of Step B of Example 1 were reacted to obtain 1.4 g of crude product which was purified by chromatography on silica (eluant: methylene chloride 90, methanol 10) to obtain 1.1 g of product which was crystallized from ethyl ether to obtain 480 mg of product. Two crystallizations from isopropanol were effected to obtain 300 mg of the expected product melting at 135° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([O:12][C:13]2[CH:18]=[CH:17][C:16]([CH:19]3[CH2:24][CH2:23][N:22]([C:25]([O:27][CH2:28][C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[O:26])[CH2:21][CH:20]3[OH:35])=[CH:15][CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[CH2:37][C:38]1[CH:39]=[CH:40][C:41]2[O:46][CH2:45][C:44](=[O:47])[N:43]([CH2:48][CH2:49][CH2:50][O:51][CH3:52])[C:42]=2[CH:53]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([O:12][C:13]2[CH:14]=[CH:15][C:16]([CH:19]3[CH2:24][CH2:23][N:22]([C:25]([O:27][CH2:28][C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=4)=[O:26])[CH2:21][CH:20]3[O:35][CH2:37][C:38]3[CH:39]=[CH:40][C:41]4[O:46][CH2:45][C:44](=[O:47])[N:43]([CH2:48][CH2:49][CH2:50][O:51][CH3:52])[C:42]=4[CH:53]=3)=[CH:17][CH:18]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC(Oc2ccc(C3CCN(C(=O)OCc4ccccc4)CC3O)cc2)C1
Reactant: COCCCN1C(=O)COc2ccc(CCl)cc21
Product: COCCCN1C(=O)COc2ccc(COC3CN(C(=O)OCc4ccccc4)CCC3c3ccc(OC4CN(C(=O)OC(C)(C)C)C4)cc3)cc21

Procedure:
Analogously to Method D, 13.34 g of benzyl 4-[4-(1-tert-butoxycarbonylazetidin-3-yloxy)phenyl]-3-hydroxypiperidine-1-carboxylate and 8.267 g of 6-chloromethyl-4-(3-methoxypropyl)-4H-benzo[1,4]oxazin-3-one are reacted. The title compound is obtained as a yellow oil. Rf=0.33 (2:1 EtOAc-heptane); Rt=5.53.
Reaction SMILES: [CH2:1](O)[CH2:2][CH3:3].N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.[NH2:23][C:24]([NH:26][C:27]1[NH:28][C:29]2[C:34]([C:35]=1[C:36]([NH2:38])=[O:37])=[CH:33][CH:32]=[C:31]([OH:39])[CH:30]=2)=[O:25]>O1CCCC1>[NH2:23][C:24]([NH:26][C:27]1[NH:28][C:29]2[C:34]([C:35]=1[C:36]([NH2:38])=[O:37])=[CH:33][CH:32]=[C:31]([O:39][CH2:1][CH2:2][CH3:3])[CH:30]=2)=[O:25]
Reactant: NC(=O)Nc1[nH]c2cc(O)ccc2c1C(N)=O
Reactant: CCCO
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: CCCOc1ccc2c(C(N)=O)c(NC(N)=O)[nH]c2c1
Reaction time: 2.5 h
Yield: 12.7 %

Procedure:
Under ice-cooling, 1-propanol (60 μL, 0.80 mmol), n-tributylphosphine (100 μL, 0.40 mmol) and 1,1′-(azodicarbonyl)dipiperidine (98 mg, 0.39 mmol) were added to a suspension of 2-aminocarbonylamino-6-hydroxyindole-3-carboxamide (Compound No.2-1, 47 mg, 0.20 mmol) in anhydrous tetrahydrofuran (2 mL) and stirred for 2.5 hours. Moreover the whole was stirred overnight at room temperature, and stirred at 50° C. for 7 hours. The reaction solution was purified by silica gel column chromatography to give the title compound (7 mg) as a green solid (13%).
Reaction SMILES: [NH2:1][C:2]1[C:7]2[C:8](=[O:20])[CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([NH2:18])=[C:14]([F:19])[CH:13]=3)[O:11][C:6]=2[C:5]([F:21])=[CH:4][C:3]=1[F:22].[C:23](OC(=O)C)(=[O:25])[CH3:24]>N1C=CC=CC=1>[C:23]([NH:18][C:15]1[CH:16]=[CH:17][C:12]([C:10]2[O:11][C:6]3[C:5]([F:21])=[CH:4][C:3]([F:22])=[C:2]([NH2:1])[C:7]=3[C:8](=[O:20])[CH:9]=2)=[CH:13][C:14]=1[F:19])(=[O:25])[CH3:24]
Reactant: Nc1ccc(-c2cc(=O)c3c(N)c(F)cc(F)c3o2)cc1F
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)Nc1ccc(-c2cc(=O)c3c(N)c(F)cc(F)c3o2)cc1F
Temperature: 25 °C
Reaction time: 2.2 h
Yield: 96 %

Procedure:
1.66 g of Compound 26 was dissolved in 20 ml of pyridine, the solution was cooled on ice, 0.46 ml of acetic anhydride was added and the mixture was stirred at room temperature for 2.2 hours. Then, the reaction solution was added to 100 ml of ice water and the precipitated crystals were collected by filtration to give 1.82 g (96%) of Compound 27.
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:26][CH2:25][C@@H:24]([NH:27]C(=O)OC(C)(C)C)[CH2:23]2)=[N:4][CH:5]=[C:6]([C:8](=[O:21])[NH:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=2)[CH:7]=1.[CH3:35][C:36]1[N:41]=[CH:40][C:39](B(O)O)=[CH:38][CH:37]=1>>[NH2:27][C@@H:24]1[CH2:25][CH2:26][N:22]([C:3]2[C:2]([C:39]3[CH:40]=[N:41][C:36]([CH3:35])=[CH:37][CH:38]=3)=[CH:7][C:6]([C:8]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=3)=[O:21])=[CH:5][N:4]=2)[CH2:23]1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCN(c2ncc(C(=O)Nc3ccc(OC(F)(F)F)cc3)cc2Br)C1
Reactant: Cc1ccc(B(O)O)cn1
Product: Cc1ccc(-c2cc(C(=O)Nc3ccc(OC(F)(F)F)cc3)cnc2N2CC[C@@H](N)C2)cn1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 93 using (R)-tert-butyl (1-(3-bromo-5-((4-(trifluoromethoxy)phenyl)carbamoyl)pyridin-2-yl)pyrrolidin-3-yl)carbamate (Stage 93.1) and (6-methylpyridin-3-yl)boronic acid. LC-MS (Condition 6) tR=0.79 min, m/z=458.0 [M+H]+.
Reaction SMILES: CC(C[AlH]CC(C)C)C.C(=O)=O.[F:13][C:14]([F:30])([F:29])[O:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]#[C:23][CH2:24][CH2:25][C:26](=[O:28])[CH3:27])=[CH:18][CH:17]=1.OS([O-])(=O)=O.[K+]>C1COCC1>[F:13][C:14]([F:29])([F:30])[O:15][C:16]1[CH:17]=[CH:18][C:19]([C:22]#[C:23][CH2:24][CH2:25][CH:26]([OH:28])[CH3:27])=[CH:20][CH:21]=1
Reactant: CC(=O)CCC#Cc1ccc(OC(F)(F)F)cc1
Agent: CC(C)C[AlH]CC(C)C
Agent: O=C=O
Agent: O=S(=O)([O-])O
Solvent: C1CCOC1
Product: CC(O)CCC#Cc1ccc(OC(F)(F)F)cc1

Procedure:
DIBAL-H (1.46 ml, 1.75 mmol; 1.2 M solution in toluene) was added dropwise within 15 min to a dry ice cooled (−30° C.) solution of 6-(4-trifluoromethoxy-phenyl)-hex-5-yn-2-one (0.23 g, 0.88 mmol) in THF (4 ml). The reaction was warmed to 0° C. over a time period of 1 h 10 min and neutralized with aqueous 10% KHSO4 solution. The mixture was extracted with ether (three times), the combined organic layers were washed with aqueous 10% NaCl solution, dried (Na2SO4) and evaporated to give 0.24 g (quant.) of the title compound as light brown oil.
Reaction SMILES: [C:1]([N:5]=[C:6]=[S:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.Cl.[NH2:16][C@H:17]([CH2:20][C:21]1[CH:25]=[CH:24][S:23][CH:22]=1)[CH2:18][OH:19]>C(O)C.O>[C:1]([NH:5][C:6]([NH:16][C@H:17]([CH2:20][C:21]1[CH:25]=[CH:24][S:23][CH:22]=1)[CH2:18][OH:19])=[S:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: N[C@@H](CO)Cc1ccsc1
Reactant: CC(C)(C)N=C=S
Agent: Cl
Solvent: CCO
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)(C)NC(=S)N[C@@H](CO)Cc1ccsc1

Procedure:
0.9 cm3 of tert-butyl isothiocyanate and then 0.82 cm3 of triethylamine are added to a suspension of 0.9 g of (2R)-2-amino-3-(3-thienyl)-1-propanol hydrochloride in 9 cm3 of absolute ethanol stirred and under an inert atmosphere. After stirring for 66 hours at room temperature, the reaction medium is evaporated under reduced pressure (2 kPa) at a temperature in the region of 40° C. The thick brown oil obtained is taken up in 6 cm3 of water and then extracted with twice 12 cm3 of ethyl acetate. The organic phase is filtered through Celite and washed with twice 4 cm3 of saturated aqueous sodium chloride solution, dried over magnesium sulfate and evaporated under reduced pressure (2 kPa) at a temperature in the region of 40° C. A brown oil is obtained, which crystallizes rapidly under cold conditions and which is dried in an oven under vacuum (10 Pa) at a temperature in the region of 48° C. to give 0.97 g of N-(tert-butyl)-N′-[(1R)-2-hydroxy-1-(3-thienylmethyl)ethyl]thiourea in the form of a beige-colored solid melting at 109° C. 1H NMR spectrum (400 MHz, (CD3)2SO-d6, δ in ppm): 1.43 (s: 9H); 2.84 (mt: 2H); 3.38 (mt: 2H); 4.42 (unres. mult.: 1H); 4.86 (broad t, J=4.5 Hz: 1H); 7.04 (broad d, J=5 Hz: 1H); from 7.10 to 7.20 (mt: 2H); 7.25 (broad s: 1H); 7.46 (dd, J=5 and 3 Hz: 1H).
Reaction SMILES: [H-].[Na+].Cl.[CH3:4][NH:5][CH3:6].Br[CH2:8][CH2:9][CH2:10][N:11]1[C:23]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[C:17]2[C:12]1=[CH:13][CH:14]=[CH:15][CH:16]=2.C(Cl)Cl>CN(C=O)C.CO>[CH:22]1[C:23]2[N:11]([CH2:10][CH2:9][CH2:8][N:5]([CH3:6])[CH3:4])[C:12]3[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:18]=2[CH:19]=[CH:20][CH:21]=1
Reactant: BrCCCn1c2ccccc2c2ccccc21
Reactant: CNC
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Solvent: CN(C)C=O
Product: CN(C)CCCn1c2ccccc2c2ccccc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 84.2 %

Procedure:
A 250-mL round-bottomed flask was charged with NaH (5.6 g, 140.00 mmol, 4.00 equiv, 60%) in DMF (100 mL). To this was added dimethylamine hydrochloride (4.23 g, 52.22 mmol, 1.50 equiv) in DMF (50 mL) at room temperature. To this mixture 9-(3-bromopropyl)-9H-carbazole (10 g, 34.70 mmol, 1.00 equiv) was added and the resulting mixture was stirred at room temperature for 4 hours. The reaction progress was monitored by TLC (DCM:MeOH=10:1). Upon completion, the reaction was then quenched by the addition of ice/salt (100 mL). The resulting mixture was extracted with ethyl acetate (3×50 mL). Combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated on a rotary evaporator affording 3-(9H-carbazol-9-yl)-N,N-dimethylpropan-1-amine as yellow oil (7.37 g, 80%).
Reaction SMILES: [CH3:1][C:2]([Si:5](Cl)([CH3:7])[CH3:6])([CH3:4])[CH3:3].[C:9]([NH:12][NH:13][C:14](=[O:30])[C@H:15]([NH:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]#[N:27])=[C:22]([Cl:28])[C:21]=1[CH3:29])[C@@H:16]([OH:18])[CH3:17])(=O)[CH3:10].N1C=CN=C1.CCN(CC)CC.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>CN(C=O)C.CCOC(C)=O.C(Cl)Cl.O>[Si:5]([O:18][C@@H:16]([CH3:17])[C@@H:15]([NH:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]#[N:27])=[C:22]([Cl:28])[C:21]=1[CH3:29])[C:14]1[O:30][C:9]([CH3:10])=[N:12][N:13]=1)([C:2]([CH3:4])([CH3:3])[CH3:1])([CH3:7])[CH3:6]
Reactant: CC(=O)NNC(=O)[C@H](Nc1ccc(C#N)c(Cl)c1C)[C@H](C)O
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1nnc([C@H](Nc2ccc(C#N)c(Cl)c2C)[C@H](C)O[Si](C)(C)C(C)(C)C)o1
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.3 %

Procedure:
TBDMS-Cl (3.20 g, 21.25 mmol) was added to a pre-cooled (0° C.) solution of (2R,3S)—N′-acetyl-2-(3-chloro-4-cyano-2-methylphenylamino)-3-hydroxybutane hydrazide (2.30 g, 7.08 mmol) and imidazole (2.41 g, 35.41 mmol) in DMF (47 mL). The reaction mixture was allowed to warm to room temperature and stirred overnight, whereupon it was poured into H2O (300 mL) and diluted with EtOAc (50 mL). The organic layer was separated and the aqueous layer extracted with EtOAc (3×50 mL). The combined organic layers were dried (Na2SO4), filtered and concentrated under reduced pressure to provide crude title compound. Step 2: In a separate flask, 12 (2.70 g, 10.63 mmol) and Et3N (3.98 mL, 28.34 mmol) were added sequentially to a solution of PS-Ph3P (3.54 g, 3.0 mmol/g loading) in CH2Cl2 (25 mL) at 0° C. To this solution was added crude hydrazide in CH2Cl2 (51 mL). After 30 min, the reaction mixture was filtered and the mother liquid washed with 10% Na2S2O3 (200 mL), separated and the aqueous layer extracted with CH2Cl2 (3×50 mL). The combined organic extracts were dried (Na2SO4), filtered and concentrated to provide a yellow oil, which was purified by flash chromatography over SiO2 (30% EtOAc in hexanes) yielding the title compound (2.9 g, 97%): 1H NMR (400 MHz, DMSO-d6, δ in ppm) 7.49 (d, J=8.8 Hz, 1H), 6.86 (d, J=8.8 Hz, 1H), 5.66-5.63 (m, 1H), 4.98 (dd, J=6.8, 8.8 Hz, 1H), 4.58-4.52 (m, 1H), 2.46 (s, 3H), 2.32 (s, 3H), 1.38 (d, J=6.0 Hz, 3H), 0.83 (s, 9H), 0.09 (s, 3H), 0.01 (s, 3H).
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:7])[C:4]#[C:5][CH3:6].Cl[C:9]1[CH:14]=[C:13]([O:15][CH2:16][C:17]([C:23]([F:26])([F:25])[F:24])([C:19]([F:22])([F:21])[F:20])[CH3:18])[N:12]=[CH:11][N:10]=1.[Cl-].[NH4+]>O1CCCC1>[CH2:3]([O:7][C:9]1[CH:14]=[C:13]([O:15][CH2:16][C:17]([C:23]([F:24])([F:25])[F:26])([C:19]([F:22])([F:21])[F:20])[CH3:18])[N:12]=[CH:11][N:10]=1)[C:4]#[C:5][CH3:6]
Reactant: CC(COc1cc(Cl)ncn1)(C(F)(F)F)C(F)(F)F
Reactant: CC#CCO
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC#CCOc1cc(OCC(C)(C(F)(F)F)C(F)(F)F)ncn1
Reaction time: 0.17 h

Procedure:
In 4 ml of tetrahydrofuran was suspended 0.11 g of sodium hydride (60% in oil), to which 0.5 ml of a solution containing 0.16 g of 2-butyn-1-ol in tetrahydrofuran was added dropwise at room temperature, followed by stirring for 10 minutes. To this was added dropwise 0.5 ml of a solution containing the above 4-chloro-6-[2,2-bis(trifluoromethyl)propoxy]pyrimidine in tetrahydrofuran, followed by stirring at room temperature for 6 hour. The reaction mixture was then poured into a saturated aqueous ammonium chloride solution, which was extracted three times with t-butyl methyl ether. The combined organic layers were washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated. The residue was subjected to silica gel column chromatography to give 0.30 g of 4-(2-butynyloxy)-6-[2,2-bis(trifluoromethyl)propyloxy]pyrimidine (the present compound (9)).