Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8](=[O:13])[C:7]2([N:20]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[NH:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH3:2].[CH3:32][O:33][C:34]1[CH:39]=[C:38]([O:40][CH3:41])[CH:37]=[CH:36][C:35]=1[S:42](Cl)(=[O:44])=[O:43]>>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([S:42]([C:35]1[CH:36]=[CH:37][C:38]([O:40][CH3:41])=[CH:39][C:34]=1[O:33][CH3:32])(=[O:44])=[O:43])[C:8](=[O:13])[C:7]2([N:20]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[NH:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[CH3:2]
Reactant: CCOC(=O)NN(C(=O)OCC)C1(c2ccccc2)C(=O)Nc2ccc(OCC)cc21
Reactant: COc1ccc(S(=O)(=O)Cl)c(OC)c1
Product: CCOC(=O)NN(C(=O)OCC)C1(c2ccccc2)C(=O)N(S(=O)(=O)c2ccc(OC)cc2OC)c2ccc(OCC)cc21

Procedure:
This compound is prepared according to the procedure described in EXAMPLE 1 from 0.500 g of 5-ethoxy-3-(2-ethoxycarbonyl-1-ethoxycarbonylhydrazino)-1,3-dihydro-3-phenylindol-2-one and 0.280 g of 2,4-dimethoxybenzenesulfonyl chloride. The expected product is obtained after crystallization from a DCM/iso ether mixture. m=0.383 g. M.p.=228°-229° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:16])[CH2:10][N:11]1[CH:15]=[N:14][CH:13]=[N:12]1.[BH4-].[Na+]>CO>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]([OH:16])[CH2:10][N:11]1[CH:15]=[N:14][CH:13]=[N:12]1
Reactant: O=C(Cn1cncn1)c1ccc(Cl)cc1Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OC(Cn1cncn1)c1ccc(Cl)cc1Cl
Reaction time: 0.25 h
Yield: 46.5 %

Procedure:
25.6 g (0.1 mole) of 1-(2,4-dichlorophenyl)-2-(1,2,4-triazol-1-yl)-1-ethanone are dissolved in 610 ml of methanol, and 6.3 g (0.15 mole) of sodium borohydride are added in portions at 5° to 10° C., while stirring. The mixture is then stirred at room temperature for one hour and heated at the boil for one hour. After the solvent has been distilled off, 250 ml of water and 50 ml of concentrated hydrochloric acid are added to the residue and the mixture is boiled up for 15 minutes. After the reaction mixture has been rendered alkaline with sodium hydroxide solution, the solid reaction product can be filtered off. It is recrystallized from aqueous acetonitrile. 12 g (42% of theory) of 1-(2,4-dichlorophenyl)-2-(1,2,4-triazol-1-yl)-1-ethanol of melting point 87° C. are obtained.
Reaction SMILES: [C:1](Cl)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.[SH:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][C:41]([OH:43])=[O:42]>C1(C)C=CC=CC=1>[C:1]([S:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][C:41]([OH:43])=[O:42])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)CCCCCCCCCCS
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: O=C(O)CCCCCCCCCCSC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 97 %

Procedure:
To a solution of trityl chloride (4.6 g, 17 mmol) and diisopropylethylamine (DIEA, 4.2 g, 33 mmol) in toluene (50 mL) was added 11-mercaptoundecanoic acid, 1 (6.0 g, 14 mmol), and the solution was stirred at room temperature for 3 h. The solution was evaporated, and the product separated between dichloromethane and water. The organic phase was washed with water (2×100 mL), dried (MgSO4), filtered, and concentrated to yield crude 2 (6.3 g, 13.6 mmol, 97%). 1H NMR (CDCl3, 500 MHz): δ1.14-1.42 (br m, 14H), 1.59-1.68 (br t, 2H), 2.06-2.09 (br m, 2H), 2.36-2.40 (t, 2H), 7.19-7.23 (m, 6H), 7.26-7.29 (m, 9H).
Reaction SMILES: [C:1]1([CH:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[O:8][CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:21]1[O:23][CH2:22]1.O>CO>[OH:23][CH2:22][CH2:21][N:12]1[CH2:13][CH2:14][CH:9]([O:8][CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:10][CH2:11]1
Reactant: c1ccc(C(OC2CCNCC2)c2ccccc2)cc1
Reactant: C1CO1
Solvent: O
Solvent: CO
Product: OCCN1CCC(OC(c2ccccc2)c2ccccc2)CC1
Reaction time: 3 h

Procedure:
The starting material is obtained as follows. The solution of 13.35 g of 4-diphenylmethoxypiperidine in 40 ml of methanol, containing 3.52 g of ethylene oxide and 0.9 ml of water, is stirred and heated in an oil bath at 42°-44° for 4 hours. The bath temperature is raised to 50° and heating and stirring are continued for an additional 3 hours. The solution is then evaporated and the residue taken up in 1 N hydrochloric acid and washed with diethyl ether. The aqueous solution is made basic with 50% aqueous sodium hydroxide and repeatedly extracted with diethyl ether. The extract is washed with brine, dried and evaporated to give the 1-(2-hydroxyethyl)-4-diphenylmethoxypiperidine, melting at 83°-85° after recrystallization from cyclohexane.
Reaction SMILES: [NH2:1][C:2]1[C:14]([Cl:15])=[C:13]2[C:5]([C:6]3[C:11]([CH2:16][CH2:17][CH2:18][CH3:19])([CH2:12]2)[CH2:10][CH2:9][C:8](=[O:20])[CH:7]=3)=[CH:4][C:3]=1[F:21].[Br:22]N1C(=O)CCC1=O>C(Cl)Cl>[NH2:1][C:2]1[C:14]([Cl:15])=[C:13]2[C:5]([C:6]3[C:11]([CH2:16][CH2:17][CH2:18][CH3:19])([CH2:12]2)[CH2:10][CH2:9][C:8](=[O:20])[C:7]=3[Br:22])=[CH:4][C:3]=1[F:21]
Reactant: CCCCC12CCC(=O)C=C1c1cc(F)c(N)c(Cl)c1C2
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Product: CCCCC12CCC(=O)C(Br)=C1c1cc(F)c(N)c(Cl)c1C2
Reaction time: 1 h
Yield: 63.2 %

Procedure:
A solution of 7-amino-9a-butyl-8-chloro-6-fluoro-1,2,9,9a-tetrahydro-3H-fluoren-3-one (1.36 g, 4.42 mmol) in anhydrous CH2Cl2 (13 mL) was cooled in an ice bath, placed under a nitrogen atmosphere, treated with N-bromosuccinimide (0.787 g, 4.42 mmol) and stirred at 0–5° C. for one hour. The reaction mixture was filtered through a pad of silica gel and the pad was washed with EtOAc. The filtrate and washings were evaporated under vacuum. The residue was purified by flash chromatography on a Biotage 40M column using 10:1 hexanes-EtOAc as eluting solvent. The product containing fractions were evaporated under vacuum to afford 7-amino-4-bromo-9a-butyl-8-chloro-6-fluoro-1,2,9,9a-tetrahydro-3H-fluoren-3-one (1.08 g, 63%) as a yellow solid.
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[C@@:30]2([CH3:31])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:29]2[CH2:28][CH2:27][C@@:26]2([CH3:32])[C@H:17]3[CH2:18][CH2:19][C@@H:20]2[CH:21]([C:23]([OH:25])=[O:24])[CH3:22])[CH2:12][C@@H:11]([O:33][Si:34]([C:37]([CH3:40])([CH3:39])[CH3:38])([CH3:36])[CH3:35])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:41]OC(O[C@@H]1[C@@]2(C)C(=CC=C3[C@@H]2CC[C@@]2(C)[C@H]3CC[C@@H]2C(C(O)=O)C)C[C@@H](OC(OC)=O)C1)=O>>[Si:1]([O:8][C@@H:9]1[C@@:30]2([CH3:31])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:29]2[CH2:28][CH2:27][C@@:26]2([CH3:32])[C@H:17]3[CH2:18][CH2:19][C@@H:20]2[CH:21]([C:23]([O:25][CH3:41])=[O:24])[CH3:22])[CH2:12][C@@H:11]([O:33][Si:34]([C:37]([CH3:39])([CH3:38])[CH3:40])([CH3:35])[CH3:36])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C(=O)O)[C@H]1CC[C@H]2C3=CC=C4C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C
Reactant: COC(=O)O[C@@H]1CC2=CC=C3[C@@H]4CC[C@H](C(C)C(=O)O)[C@@]4(C)CC[C@@H]3[C@@]2(C)[C@@H](OC(=O)OC)C1
Product: COC(=O)C(C)[C@H]1CC[C@H]2C3=CC=C4C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C
Yield: 84.6 %

Procedure:
The procedure of Example 7 was repeated except that 112 mg of 1α,3β-bis(t-butyldimethylsilyloxy)pregna-5,7-diene-20-carboxylic acid obtained in Example 23 was used in lieu of 85 mg of 1α,3β-bis(methoxycarbonyloxy)pregna-5,7-diene-20-carboxylic acid to give 91 mg of methyl 1α,3β-bis(t-butyldimethylsilyloxy)pregna-5,7-diene-20-carboxylate.
Reaction SMILES: Cl[C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH3:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[OH:19].COCCOCCN(CCOCCOC)CCOCCOC>O1CCOCC1.Cl[Cu]>[Cl:11][C:9]1[CH:8]=[CH:7][C:3]([C:4]([OH:6])=[O:5])=[C:2]([O:19][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[CH3:12])[CH:10]=1
Reactant: O=C(O)c1ccc(Cl)cc1Cl
Reactant: Cc1ccccc1O
Agent: Cl[Cu]
Agent: COCCOCCN(CCOCCOC)CCOCCOC
Solvent: C1COCCO1
Product: Cc1ccccc1Oc1cc(Cl)ccc1C(=O)O
Yield: 79.1 %

Procedure:
A mixture of the sodium salts of 2,4-dichlorobenzoic acid (V: X=Cl, R1 =4-Cl) (27.7 g, 130 mmol) and 2-methylphenol (III: R3 =H) (18.9 g, 145 mmol) were dissolved in dry dioxan (300 mL). CuCl (1.3 g, 13 mmol) and tris-[2-(2-methoxyethoxy)ethyl]amine (TDA-1) (4.2 g, 13 mmol) were added, and the mixture was heated at reflux under N2 for 8 hours. Excess solvent was evaporated under reduced pressure, and the residue was diluted with water and filtered. The filtrate was acidified with 2N HCl, and the resulting precipitate was collected, washed well with water and dried to yield 4-chloro-2-(2-methylphenoxy) benzoic acid (IV: R1 =4-Cl, R3 =H) (27 g, 79%), which was suitable for the next step. A sample was crystallized from aqueous MeOH as prisms, mp 158°-159° C. Anal. (C14H11ClO3), C,H,Cl.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[O:20][C:9]2=[C:10]3[C:15](=[C:16]([CH3:18])[CH:17]=[C:8]2[CH2:7]1)[NH:14][C:13](=[O:19])[CH:12]=[CH:11]3)=[O:5])[CH3:2].[H][H]>C(O)(=O)C.[Pd]>[CH2:1]([O:3][C:4]([CH:6]1[O:20][C:9]2=[C:10]3[C:15](=[C:16]([CH3:18])[CH:17]=[C:8]2[CH2:7]1)[NH:14][C:13](=[O:19])[CH2:12][CH2:11]3)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1Cc2cc(C)c3[nH]c(=O)ccc3c2O1
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)O
Product: CCOC(=O)C1Cc2cc(C)c3c(c2O1)CCC(=O)N3
Yield: 99.1 %

Procedure:
The compound obtained in Example 257 (3 g, 11 mmol) was dissolved in acetic acid (50 ml). To the solution, 10% palladium-on-carbon (3 g) was added, followed by stirring at 80° C. for 4 hours in the stream of hydrogen to carry out hydrogenation. After completion of the reaction, palladium-on-carbon was removed by filtration. The filtrate was thoroughly washed with chloroform and methanol, and condensed. As a result, 3 g of the title compound was obtained as a white solid (99%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])([O-:3])=[O:2].[N:16](OCCC(C)C)=[O:17].[O-]CC.[Na+].[Na].Cl>C(O)C.O>[N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10](=[N:16][OH:17])[C:11]([O:13][CH2:14][CH3:15])=[O:12])([O-:3])=[O:2]
Reactant: CC(C)CCON=O
Reactant: CCOC(=O)Cc1ccccc1[N+](=O)[O-]
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCOC(=O)C(=NO)c1ccccc1[N+](=O)[O-]

Procedure:
A mixture of 50 g of ethyl (2-nitrophenyl)acetate, 30 g of isoamyl nitrite and 400 ml of ethanol was added to sodium ethoxide prepared by treating 5.1 g of sodium with 100 ml of ethanol and diluting with ethanol to 100 ml. The mixture was heated at 50°-60° C. for 4 hours, cooled, 400 ml of water was added, the mixture was acidified with 6N hydrochloric acid and extracted with ether. The extract was stripped of solvent, and the residue was recrystallized from benzene to give ethyl (2-nitrophenyl)glyoxylate oxime (3A), as a white solid, m.p.: 167°-168° C.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:12]3[N:13]=[C:14]4[C:20]([C:21](O)=[O:22])=[CH:19][N:18]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:15]4=[N:16][CH:17]=3)=[N:7][N:8]2[CH3:11])=[CH:4][CH:3]=1.[NH2:32][C@@H:33]([CH3:36])[CH2:34][OH:35].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>C(#N)C>[OH:35][CH2:34][C@@H:33]([NH:32][C:21]([C:20]1[C:14]2[C:15](=[N:16][CH:17]=[C:12]([C:6]3[C:5]4[C:9](=[CH:10][C:2]([F:1])=[CH:3][CH:4]=4)[N:8]([CH3:11])[N:7]=3)[N:13]=2)[N:18]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:29])([CH3:31])[CH3:30])[CH:19]=1)=[O:22])[CH3:36]
Reactant: C[C@H](N)CO
Reactant: Cn1nc(-c2cnc3c(n2)c(C(=O)O)cn3COCC[Si](C)(C)C)c2ccc(F)cc21
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: CC#N
Product: C[C@@H](CO)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4cc(F)ccc34)nc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 58.6 %

Procedure:
A 25 mL round-bottomed flask was charged with 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (115 mg, 0.26 mmol), (S)-2-aminopropan-1-ol (0.21 ul, 0.27 mmol), and HATU (104 mg, 0.27 mmol). Then added acetonitrile (2 mL) followed by N,N-diisopropylethylamine (0.2 mL, 1.12 mmol). The yellow reaction mixture was stirred at room temperature overnight then quenched with water and extracted with EtOAc (3×). The organic layers were combined, dried over sodium sulfate, filtered and concentrated to provide 76 mg (57%) of 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((S)-2-hydroxy-1-methyl-ethyl)-amide as a white solid.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1.[C:13](O)(=[O:15])[CH3:14]>C(OC(=O)C)(=O)C>[C:13]([NH:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1)(=[O:15])[CH3:14]
Reactant: CC(=O)O
Reactant: CCOC(=O)Cc1csc(N)n1
Solvent: CC(=O)OC(C)=O
Product: CCOC(=O)Cc1csc(NC(C)=O)n1
Yield: 91 %

Procedure:
Ethyl 2-amino-4-thiazoleacetate (3.72 g 20 mmole) was taken up in acetic acid (4 mL) and acetic anhydride (4 mL), and the resulting suspension was heated at reflux for 3 hr. Concentration and flash chromatography on silica gel (5% MeOH/CH2H2) gave the title compound (4.1 g, 91%) as a white solid: MS (ES) m/e 229 (M+H)+.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[CH:5][C:6]2[CH:16]([C:17]3[C:18](=[O:24])[NH:19][C:20](=[O:23])[NH:21][CH:22]=3)[C:11]3[N:12]=[C:13]([CH3:15])[O:14][C:10]=3[CH2:9][CH2:8][C:7]=2[CH:25]=1)[CH3:2].Br[CH2:27][C:28]1[CH:29]=[C:30]([CH:35]=[CH:36][CH:37]=1)[C:31]([O:33][CH3:34])=[O:32]>>[CH2:1]([C:3]1[CH:4]=[CH:5][C:6]2[CH:16]([C:17]3[C:18](=[O:24])[NH:19][C:20](=[O:23])[N:21]([CH2:27][C:28]4[CH:29]=[C:30]([CH:35]=[CH:36][CH:37]=4)[C:31]([O:33][CH3:34])=[O:32])[CH:22]=3)[C:11]3[N:12]=[C:13]([CH3:15])[O:14][C:10]=3[CH2:9][CH2:8][C:7]=2[CH:25]=1)[CH3:2]
Reactant: COC(=O)c1cccc(CBr)c1
Reactant: CCc1ccc2c(c1)CCc1oc(C)nc1C2c1c[nH]c(=O)[nH]c1=O
Product: CCc1ccc2c(c1)CCc1oc(C)nc1C2c1cn(Cc2cccc(C(=O)OC)c2)c(=O)[nH]c1=O

Procedure:
The subtitle compound was prepared from the product of step (ii) (0.38 g) and methyl 3-[bromomethyl]benzoate according to the method of example 1 step (viii).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:41])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][C:11]([NH:14][CH2:15][C@@H:16]([C:25]2[CH:30]=[CH:29][C:28]([O:31]CC3C=CC=CC=3)=[C:27]([CH2:39][OH:40])[CH:26]=2)[O:17][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19])([CH3:13])[CH3:12])[CH:5]=1>CO.[Pd]>[CH3:1][O:2][C:3](=[O:41])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][C:11]([NH:14][CH2:15][C@H:16]([O:17][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19])[C:25]2[CH:30]=[CH:29][C:28]([OH:31])=[C:27]([CH2:39][OH:40])[CH:26]=2)([CH3:13])[CH3:12])[CH:5]=1
Reactant: COC(=O)c1cccc(CC(C)(C)NC[C@H](O[Si](C)(C)C(C)(C)C)c2ccc(OCc3ccccc3)c(CO)c2)c1
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1cccc(CC(C)(C)NC[C@H](O[Si](C)(C)C(C)(C)C)c2ccc(O)c(CO)c2)c1
Reaction time: 18 h

Procedure:
3-{2-[(2R)-2-(4-benzyloxy-3-hydroxymethyl-phenyl)-2-(tert-butyldimethyl-silanyloxy)ethylamino]-2-methylpropyl}benzoic acid methyl ester (Preparation 35) (2.12 g, 3.70 mmol) and palladium-on-carbon (10%, 300 mg) in methanol (50 ml) were hydrogenated at room temperature and 60 psi for 18 hours. The reaction mixture was filtered through arbocel and the filtrate concentrated in vacuo, the residue was purified by flash column chromatography on silica gel eluting with dichloromethane:methanol:ammonia (95:5:0.5 by volume) to furnish the title compound, this material was taken up in diethylether and evaporated (×3) to yield a white foam (1.50 g).
Reaction SMILES: [CH3:1][CH2:2][CH:3]([N:6]1[C:10]2=[N:11][C:12]([C:15]#[C:16][Si](C)(C)C)=[CH:13][N:14]=[C:9]2[N:8]=[C:7]1[OH:21])[CH2:4][CH3:5].[F-].[K+]>CO.C1COCC1.O>[C:15]([C:12]1[N:11]=[C:10]2[N:6]([CH:3]([CH2:4][CH3:5])[CH2:2][CH3:1])[C:7]([OH:21])=[N:8][C:9]2=[N:14][CH:13]=1)#[CH:16]
Reactant: CCC(CC)n1c(O)nc2ncc(C#C[Si](C)(C)C)nc21
Agent: [F-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: C#Cc1cnc2nc(O)n(C(CC)CC)c2n1
Temperature: 25 °C
Yield: 36.9 %

Procedure:
A mixture of 1-(pentan-3-yl)-6-((trimethylsilyl)ethynyl)-1H-imidazo[4,5-b]pyrazin-2-ol (3.2 g, 10.6 mmol), KF (1.6 g, 27.5 mmol) in MeOH/THF/H2O (50 mL, 2/2/1) was stirred at room temperature. Upon complete conversion by LCMS, the solution was concentrated in vacuo, diluted with EtOAc, washed with NH4Cl solution, dried over Na2SO4, and concentrated in vacuo. Purification over silica gel (Biotage MPLC 10-80% EtOAc/Heaxanes) gave a brown solid, which was washed with 15% EtOAc/hexanes to give product the title compound as a white solid (0.9 g, 37%).
Reaction SMILES: [F:1][C:2]1[CH:20]=[C:19]2[C:5]([C:6](=[O:22])[C:7](=[O:21])[C:8]3[S:18][CH2:17][C:11]4([CH2:16][CH2:15][NH:14][CH2:13][CH2:12]4)[O:10][C:9]=32)=[CH:4][CH:3]=1.[C:23]([C:27]1[CH:37]=[CH:36][C:30]([O:31][CH2:32][C@@H:33]2[CH2:35][O:34]2)=[CH:29][CH:28]=1)([CH3:26])([CH3:25])[CH3:24]>>[C:23]([C:27]1[CH:37]=[CH:36][C:30]([O:31][CH2:32][C@@H:33]([OH:34])[CH2:35][N:14]2[CH2:15][CH2:16][C:11]3([O:10][C:9]4[C:19]5[C:5]([C:6](=[O:22])[C:7](=[O:21])[C:8]=4[S:18][CH2:17]3)=[CH:4][CH:3]=[C:2]([F:1])[CH:20]=5)[CH2:12][CH2:13]2)=[CH:29][CH:28]=1)([CH3:24])([CH3:25])[CH3:26]
Reactant: CC(C)(C)c1ccc(OC[C@@H]2CO2)cc1
Reactant: O=C1C(=O)c2ccc(F)cc2C2=C1SCC1(CCNCC1)O2
Product: CC(C)(C)c1ccc(OC[C@@H](O)CN2CCC3(CC2)CSC2=C(O3)c3cc(F)ccc3C(=O)C2=O)cc1

Procedure:
Compound 191 was synthesized using 9-fluorospiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione, (2S)-2-[(4-tert-butylphenoxy)methyl]oxirane and conditions outlined in procedure Y. M.p.=114-116° C., 400 MHz 1H NMR (DMSO-d6) δ: 7.99-7.95 (m, 1H), 7.46-7.37 (m, 2H), 7.29-7.27 (d, J=8.60 Hz, 2H), 6.86-6.84 (d, J=8.99 Hz, 2H), 4.85 (br s, 1H), 3.96-3.4 (m, 2H), 3.86-3.84 (m, 1H), 3.34 (s, 2H), 2.79-2.74 (m, 3H), 2.50-2.44 (m, 3H), 1.99-1.96 (m, 2H), 1.83-1.81 (m, 2H), 1.24 (s, 9H); LCMS: 526 [M+H]
Reaction SMILES: [F:1][C:2]([C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][CH:12]=1)[C:8]#N)([F:4])[CH3:3].[H-].C([Al+]CC(C)C)C(C)C.C(=O)=[O:24].CC(O)=O>C1(C)C=CC=CC=1.O>[F:1][C:2]([C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][CH:12]=1)[CH:8]=[O:24])([F:4])[CH3:3]
Reactant: O=C=O
Reactant: CC(F)(F)c1cccc(C#N)c1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Solvent: O
Product: CC(F)(F)c1cccc(C=O)c1
Temperature: -78 °C

Procedure:
Dissolve 3-(1,1-difluoro-ethyl)-benzonitrile (4.39 g, 26.26 mmol) in toluene (44 mL). Place the reaction under nitrogen, cool to −78° C. in a dry-ice bath, then add diisobutylaluminum hydride (52.5 mmol, 1 M solution in toluene) dropwise over 30 minutes with stirring. Stir the reaction in the dry-ice bath for 30 minutes, then add glacial HOAc (14 mL) dropwise to control foaming, followed by water (100 mL). Stir the reaction mixture overnight at room temperature. Separate the layers; extract the cloudy aqueous with toluene. Wash the toluene extracts with brine, dry the organics over magnesium sulfate, filter, and evaporate to afford 3-(1,1-difluoro-ethyl)-benzaldehyde as a pale yellow oil. (4.0 g, 90%). 1H NMR (400 MHz, CDCl3): δ 10.03 (s, 1H), 8.00 (s, 1H), 7.92 (d, J=7.5 Hz, 1H), 7.75 (d, J=7.5 Hz, 1H), 7.58 (t, J=7.7 Hz, 1H), 1.98-1.89 (m, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[CH2:14][CH2:13][CH:12]([C:15]([C:28]3[CH:33]=[CH:32][C:31]([O:34][C:35]([F:38])([F:37])[F:36])=[CH:30][CH:29]=3)([C:17]3[CH:22]=[CH:21][C:20]([O:23][C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=3)[OH:16])[CH2:11][CH2:10]2)=[CH:4][CH:3]=1.Cl[C:40]([O:42][CH3:43])=[O:41].N1C=CC=CC=1.[Cl-].[Na+]>O1CCCC1.C(OCC)(=O)C>[CH3:43][O:42][C:40]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[CH2:14][CH2:13][CH:12]([C:15]([C:28]3[CH:29]=[CH:30][C:31]([O:34][C:35]([F:38])([F:36])[F:37])=[CH:32][CH:33]=3)([C:17]3[CH:18]=[CH:19][C:20]([O:23][C:24]([F:25])([F:26])[F:27])=[CH:21][CH:22]=3)[OH:16])[CH2:11][CH2:10]2)=[CH:4][CH:3]=1)=[O:41]
Reactant: COC(=O)Cl
Reactant: Nc1ccc(CN2CCC(C(O)(c3ccc(OC(F)(F)F)cc3)c3ccc(OC(F)(F)F)cc3)CC2)cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: COC(=O)Nc1ccc(CN2CCC(C(O)(c3ccc(OC(F)(F)F)cc3)c3ccc(OC(F)(F)F)cc3)CC2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A stirred solution of 0.8 gram (0.0014 mole) of N-(4-aminophenylmethyl)-4-[bis(4-trifluoromethoxyphenyl)hydroxymethyl]piperidine in 15 mL of tetrahydrofuran was cooled to 0° C., and 0.11 mL of methyl chloroformate was added dropwise from a syringe. Upon completion of the addition, 0.12 mL of pyridine was added in one portion. The reaction mixture was allowed to warm to ambient temperature where it stirred for about 18 hours. After this time the reaction mixture was poured into a mixture of ethyl acetate and an aqueous solution saturated with sodium chloride. After a period of stirring, the organic layer was separated and dried with sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure to a residual solid. The solid was subjected to column chromatography on silica gel, with pure methylene chloride, and 1:9, 1:4, 1:3, and 3:7 mixtures of acetone:methylene chloride as eluants. The product-containing fractions were combined and concentrated under reduced pressure, yielding 0.45 gram of N-[4-(methoxycarbonylamino)phenylmethyl]-4-[bis(4-trifluoromethoxyphenyl)hydroxymethyl]piperidine. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [NH:1]([C:5]1[S:6][CH:7]=[C:8]([CH:10]2[CH2:14][CH2:13][CH:12]([NH2:15])[CH2:11]2)[N:9]=1)[C:2]([NH2:4])=[NH:3].[CH3:16][N:17]=[C:18]=[S:19]>C(O)C>[NH:1]([C:5]1[S:6][CH:7]=[C:8]([CH:10]2[CH2:14][CH2:13][CH:12]([NH:15][C:18]([NH:17][CH3:16])=[S:19])[CH2:11]2)[N:9]=1)[C:2]([NH2:4])=[NH:3]
Reactant: CN=C=S
Reactant: N=C(N)Nc1nc(C2CCC(N)C2)cs1
Solvent: CCO
Product: CNC(=S)NC1CCC(c2csc(NC(=N)N)n2)C1

Procedure:
To a solution of 2-guanidino-4-(3-aminocyclopentyl)thiazole (0.3 g.) in ethanol (5 ml.) was added methyl isothiocyanate (0.15 g.) and the mixture heated under reflux for 1 hour. The reaction mixture was evaporated to dryness and the residue subjected to preparative thin layer chromatography on silica gel GF plates (Uniplate, Analtech Inc., Delaware, U.S.A.) using chloroform/methanol/aqueous ammonia (s.g. 0.88) 135:15:1 v/v/v for development. The appropriate region of the chromatogram was eluted with warm ethanol/chloroform (3:1 v/v) and the extract evaporated to give 2-guanidino-4-[3-(3-methylthioureido)cyclopentyl]thiazole as a light brown glass. The n.m.r. spectrum in d6 dimethyl sulphoxide included signals at 1.2-2.2 (m) 2.8 (d, 3H) 4.2 (br m, 1H), 6.27 (s, 1H) and 6.78 (br s, 4H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)[CH:31]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21](S(C)(=O)=O)[N:20]=2)=[CH:10][CH:9]=1)=[O:6].[NH:38]1[CH2:43][CH2:42][CH:41]([OH:44])[CH2:40][CH2:39]1>>[F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)[CH:31]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21]([N:38]3[CH2:43][CH2:42][CH:41]([OH:44])[CH2:40][CH2:39]3)[N:20]=2)=[CH:10][CH:9]=1)=[O:6]
Reactant: OC1CCNCC1
Reactant: CS(=O)(=O)c1nccc(Oc2ccc(NC(=O)c3cc(F)cc(N4CCOCC4)c3)c3ccccc23)n1
Product: O=C(Nc1ccc(Oc2ccnc(N3CCC(O)CC3)n2)c2ccccc12)c1cc(F)cc(N2CCOCC2)c1

Procedure:
Compound is prepared from 3-fluoro-N-(4-{[2-(methylsulfonyl)pyrimidin-4-yl]oxy}-1-naphthyl)-5-morpholin-4-ylbenzamide and piperidin-4-ol according to conditions described in general procedure C. Mp: 106-108° C.; 1H NMR (400 MHz, CDCl3) δ 1.37-1.46 (m, 2 H), 1.81-1.85 (m, 2 H), 3.13-3.20 (m, 2H), 3.24 (t, J=4.4 Hz, 4 H), 3.83-3.92 (m, 5 H), 4.20 (d, J=12.4 Hz, 1 H), 5.98 (d, J=5.6 Hz, 1 H), 6.76 (d, J=11.6 Hz, 1 H), 7.07 (d, J=8.0 Hz, 1 H), 7.30 (d, J=8.0 Hz, 1 H), 7.49-7.58 (m, 3 H), 7.88-7.93 (m, 2 H), 7.99 (d, J=8.4 Hz, 1 H), 8.16 (d, J=5.2 Hz, 1 H), 8.21 (s, 1 H).