Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([S:7]([NH:10][C:11]2[CH:12]=[C:13]([CH:17]=[CH:18][CH:19]=2)[C:14]([OH:16])=O)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN([P+](ON1N=NC2C1=CC=CC=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F.Cl.[NH2:48][CH:49]1[CH:54]2[CH2:55][CH2:56][N:51]([CH2:52][CH2:53]2)[CH2:50]1.C(N(CC)C(C)C)(C)C>CN(C=O)C.C([O-])(O)=O.[Na+]>[C:1]1([S:7]([NH:10][C:11]2[CH:12]=[C:13]([CH:17]=[CH:18][CH:19]=2)[C:14]([NH:48][CH:49]2[CH:54]3[CH2:55][CH2:56][N:51]([CH2:52][CH2:53]3)[CH2:50]2)=[O:16])(=[O:8])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)c1cccc(NS(=O)(=O)c2ccccc2)c1
Reactant: NC1CN2CCC1CC2
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(NC1CN2CCC1CC2)c1cccc(NS(=O)(=O)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 34 %

Procedure:
3-(Phenylsulfonyl)aminobenzoic acid as prepared in Example 9 (139 mg, 0.5 mmol), Castro's reagent (benzotriazole-1-yloxytris(dimethylaminophosphonium hexafluorophosphate) (221 mg, 0.5 mmol), 3-aminoquinuclidine hydrochloride (100 mg, 0.5 mmol) and N,N-diisopropylethylamine (0.5 mL) were dissolved in dry DMF (2 mL) and the reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with saturated NaHCO3 and extracted with ethyl acetate (3×). The combined ethyl acetate was washed with brine and dried over Na2SO4. After evaporation, the residue was purified by silica gel chromatography using 86% methylene chloride and 14% methanol containing 0.25 mL of acetic acid to give 65 mg (34% yield). 1H-NMR (300 MHz; DMSO-d6): d 1.69-2.14 (m,5H), 3.07-3.35 (m,6H), 3.63 (t, 1H, J=12 Hz), 4.22 (m, 1H), 7.23-7.77 (m, 9H), 8.53 (d, 1H, J=6 Hz). Mass spectrum (MALDI-TOF) calcd. for C20H23N3 O3S: 386.2 (M+H), Found: 386.2.
Reaction SMILES: Cl[C:2]1[C:11]([CH3:12])=[C:10]([Cl:13])[C:9]2[C:4](=[CH:5][C:6]([F:15])=[CH:7][C:8]=2[F:14])[N:3]=1.[C:16]1([C:22](B2OC(C)(C)C(C)(C)O2)=[CH2:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>CCOC(C)=O.[Pd+2].ClC1C=C[C-](P(C2C=CC=CC=2)C2C=CC=CC=2)C=1Cl.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[Cl:13][C:10]1[C:9]2[C:4](=[CH:5][C:6]([F:15])=[CH:7][C:8]=2[F:14])[N:3]=[C:2]([C:22]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH2:23])[C:11]=1[CH3:12]
Reactant: Cc1c(Cl)nc2cc(F)cc(F)c2c1Cl
Reactant: C=C(B1OC(C)(C)C(C)(C)O1)c1ccccc1
Agent: [Fe+2]
Agent: [Pd+2]
Agent: Clc1cc[c-](P(c2ccccc2)c2ccccc2)c1Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C=C(c1ccccc1)c1nc2cc(F)cc(F)c2c(Cl)c1C
Temperature: 95 °C

Procedure:
A screw cap vial was charged with 2,4-dichloro-5,7-difluoro-3-methylquinoline (99 mg, 0.398 mmol), 1-phenylvinylboronic acid pinacol ester (110 mg, 0.478 mmol), dichloro 1,1′-bis(diphenylphosphino)ferrocene palladium(II) (32.5 mg, 0.040 mmol), potassium carbonate (165 mg, 1.195 mmol), and DMF (3.98 mL), and the mixture was heated at 95° C. under a N2 atmosphere for 18 h. The reaction was then cooled to rt, diluted with EtOAc, and washed with water and brine. The organic layer was dried (MgSO4) and concentrated under reduced pressure. The crude product was purified by flash chromatography, eluting with a gradient of 0-10% EtOAc in hexane to give 4-chloro-5,7-difluoro-3-methyl-2-(1-phenylvinyl)-quinoline as an orange solid. Mass Spectrum (ESI) m/e=316.0 (M+1).
Reaction SMILES: [Si:1]([O:8][CH2:9][C@H:10]1[N:15]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:14][C@@H:13]([C:23]#[CH:24])[O:12][CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Br[C:26]1[C:27]([NH2:32])=[N:28][CH:29]=[CH:30][CH:31]=1.C(N(CC)CC)C>C(#N)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[NH2:32][C:27]1[C:26]([C:24]#[C:23][C@H:13]2[O:12][CH2:11][C@@H:10]([CH2:9][O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])[N:15]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:14]2)=[CH:31][CH:30]=[CH:29][N:28]=1
Reactant: Nc1ncccc1Br
Reactant: C#C[C@@H]1CN(C(=O)OC(C)(C)C)[C@H](CO[Si](C)(C)C(C)(C)C)CO1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1C[C@@H](C#Cc2cccnc2N)OC[C@H]1CO[Si](C)(C)C(C)(C)C
Temperature: 60 °C
Reaction time: 2 h

Procedure:
A solution of tert-butyl (2R,5S)-5-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2-ethynylmorpholine-4-carboxylate (1 eq) and 3-bromopyridin-2-amine (1.4 eq) in acetonitrile (0.1M) and triethylamine (25 eq) was flushed with nitrogen for 10 minutes. Then bis(triphenylphosphine)palladium(ii) chloride (0.1 eq) and copper(i) iodide (1.2 eq) were added and the mixture was flushed again with nitrogen for 10 minutes. The reaction mixture was stirred at 60° C. for 2 hours in the dark. It was concentrated to dryness and the residue was purified by automated SiO2 flash chromatography system using solvent gradient of 0% to 10% MeOH/CH2Cl2 to afford the desired compound.
Reaction SMILES: C12(COC3C(C4CC4)=CC(C(O)=O)=C(F)C=3)CC3CC(CC(C3)C1)C2.[C:26]12([CH2:36][O:37][C:38]3[C:46]([Cl:47])=[CH:45][C:41]([C:42](O)=[O:43])=[C:40]([F:48])[CH:39]=3)[CH2:35][CH:30]3[CH2:31][CH:32]([CH2:34][CH:28]([CH2:29]3)[CH2:27]1)[CH2:33]2.CS(N)(=O)=O.[CH3:54][O:55][C:56]1[CH:72]=[CH:71][C:59]([CH2:60][O:61][C@H:62]2[CH2:66][CH2:65][N:64]([S:67]([NH2:70])(=[O:69])=[O:68])[CH2:63]2)=[CH:58][CH:57]=1>>[C:26]12([CH2:36][O:37][C:38]3[C:46]([Cl:47])=[CH:45][C:41]([C:42]([NH:70][S:67]([N:64]4[CH2:65][CH2:66][C@H:62]([O:61][CH2:60][C:59]5[CH:71]=[CH:72][C:56]([O:55][CH3:54])=[CH:57][CH:58]=5)[CH2:63]4)(=[O:69])=[O:68])=[O:43])=[C:40]([F:48])[CH:39]=3)[CH2:27][CH:28]3[CH2:34][CH:32]([CH2:31][CH:30]([CH2:29]3)[CH2:35]1)[CH2:33]2
Reactant: O=C(O)c1cc(Cl)c(OCC23CC4CC(CC(C4)C2)C3)cc1F
Reactant: COc1ccc(CO[C@H]2CCN(S(N)(=O)=O)C2)cc1
Agent: CS(N)(=O)=O
Agent: O=C(O)c1cc(C2CC2)c(OCC23CC4CC(CC(C4)C2)C3)cc1F
Product: COc1ccc(CO[C@H]2CCN(S(=O)(=O)NC(=O)c3cc(Cl)c(OCC45CC6CC(CC(C6)C4)C5)cc3F)C2)cc1

Procedure:
Following the procedure as described in Example 50 step 5 and making variations as required to replace 4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzoic acid with 4-(adamantan-1-ylmethoxy)-5-chloro-2-fluorobenzoic acid and methanesulfonamide with (S)-3-((4-methoxybenzyl)oxy)pyrrolidine-1-sulfonamide, the title compound was obtained as colorless solid (0.17 g, 47%): MS (ES+) m/z 607.1, 609.1 (M+1); MS (ES−) m/z 605.3, 607.3 (M−1).
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:4][C:3]=2[O:2]1.Cl[Sn](Cl)(Cl)Cl.[F:20][C:21]1[CH:29]=[CH:28][C:24]([C:25](Cl)=[O:26])=[CH:23][CH:22]=1>C(Cl)Cl>[F:20][C:21]1[CH:29]=[CH:28][C:24]([C:25]([C:6]2[CH:7]=[C:8]3[O:9][CH2:1][O:2][C:3]3=[CH:4][C:5]=2[CH2:10][C:11]([O:13][CH3:14])=[O:12])=[O:26])=[CH:23][CH:22]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: COC(=O)Cc1ccc2c(c1)OCO2
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: ClCCl
Product: COC(=O)Cc1cc2c(cc1C(=O)c1ccc(F)cc1)OCO2

Procedure:
The title compound was prepared from methyl 3,4-methylenedioxyphenylacetate (340 mg, 1.75 mmol) in CH2Cl2 (8 mL), SnCl4 (1.0M solution in CH2Cl2 ; 3.5 mL, 3.5 mmol) and 4-fluorobenzoyl chloride (270 μL, 2.28 mmol) as a solid (350 mg, 63%). 1H NMR (CDCl3) 7.81 (m, 2H), 7.13 (m, 2H), 6.85 (s, 1H), 6.84 (s, 1H), 6.04 (s, 2H), 3.79 (s, 2H), 3.61 (s, 3H).
Reaction SMILES: C[Si](C)(C)N[Si](C)(C)C.[Li].[CH3:11][N:12]([CH3:29])[C:13]1[CH:28]=[CH:27][C:16]([CH2:17][O:18][C:19]2[CH:20]=[C:21]([C:25]#[CH:26])[CH:22]=[CH:23][CH:24]=2)=[CH:15][CH:14]=1.CON(C)[C:33](=[O:40])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>O1CCCC1>[C:34]1([C:33](=[O:40])[C:26]#[C:25][C:21]2[CH:22]=[CH:23][CH:24]=[C:19]([O:18][CH2:17][C:16]3[CH:27]=[CH:28][C:13]([N:12]([CH3:11])[CH3:29])=[CH:14][CH:15]=3)[CH:20]=2)[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: C#Cc1cccc(OCc2ccc(N(C)C)cc2)c1
Reactant: CON(C)C(=O)c1ccccc1
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: [Li]
Solvent: C1CCOC1
Product: CN(C)c1ccc(COc2cccc(C#CC(=O)c3ccccc3)c2)cc1
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
Place lithium hexamethyldisilazane (2 mL of a 1M solution in tetrahydrofuran, 2 mmol) and tetrahydrofuran (8 mL) under an argon atmosphere and cool to 0° C. Add a solution of 3-(4-(dimethylamino)benzyloxy)phenylacetylene (0.51 g, 2 mmol) in tetrahydrofuran and stir the solution for 45 minutes at 0° C. Add N-methoxy-N-methylbenzamide (0.4 g, 2.4 mmol), remove the cooling bath andstir at room temperature for 1 hour. Partition the mixture between ethyl ether and water, separate the organic phase and dry (MgSO4). Filter and evaporate the solvent in vacuo to yield an oil. Filter through silica gel and elute with 10% ethyl acetate/hexane to yield a crude solid. Purifyby silica gel chromatography to give the title compound. Alternatively, compounds of formula (1) can be prepared according to the procedure set forth in Scheme B, wherein all substituents, unless otherwise indicated, are previously described. ##STR3##
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1F)[C:6]#[N:7].[NH:14]([CH2:18][CH2:19][OH:20])[CH2:15][CH2:16][OH:17]>CN(C)C(=O)C>[F:1][C:2]([F:13])([F:12])[C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[N:14]([CH2:18][CH2:19][OH:20])[CH2:15][CH2:16][OH:17])[C:6]#[N:7]
Reactant: N#Cc1ccc(F)c(C(F)(F)F)c1
Reactant: OCCNCCO
Solvent: CC(=O)N(C)C
Product: N#Cc1ccc(N(CCO)CCO)c(C(F)(F)F)c1

Procedure:
A solution of 3-trifluoromethyl 4-fluoro-benzonitrile (9.45 g, 50 mmol) and diethanolamine (15.8 g, 0.15 mol) in N,N-dimethylacetamide (200 ml) was stirred for 7 days at 50° C. The solvent was evaporated, the residue partitioned between CH2Cl2 (400 ml) and H2O (400 ml), the organic layer dried (MgSO4) and evaporated to dryness. The residue was chromatographed using CH2Cl2-EtOH as eluent.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]([OH:10])=O)[CH:5]=[CH:4][C:3]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[CH3:17][N:18]([CH3:33])[CH2:19][CH2:20][O:21][C:22]1[CH:30]=[C:29]2[C:25]([CH:26]=[CH:27][NH:28]2)=[CH:24][C:23]=1[O:31][CH3:32].C(C1C=CC(C2C=CC(C(O)=O)=CC=2)=CC=1C)(=O)C>>[CH3:17][N:18]([CH3:33])[CH2:19][CH2:20][O:21][C:22]1[CH:30]=[C:29]2[C:25]([CH:26]=[CH:27][N:28]2[C:8]([C:6]2[CH:5]=[CH:4][C:3]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[C:2]([CH3:1])[CH:7]=2)=[O:10])=[CH:24][C:23]=1[O:31][CH3:32]
Reactant: COc1cc2cc[nH]c2cc1OCCN(C)C
Reactant: Cc1cc(C(=O)O)ccc1-c1ccccc1
Agent: CC(=O)c1ccc(-c2ccc(C(=O)O)cc2)cc1C
Product: COc1cc2ccn(C(=O)c3ccc(-c4ccccc4)c(C)c3)c2cc1OCCN(C)C

Procedure:
The title compound was prepared from 2-methylbiphenyl-4-carboxylic acid (D23) and 6-(2-dimethylaminoethoxy)-5-methoxy-1H-indole (D13) using a similar procedure to Example 4 (80%). This was converted to its oxalate salt to afford a white solid. mp 152°-154° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[C:5]([F:11])=[CH:4][C:3]=1[OH:12].[NH4+].[Cl-]>C1COCC1.CO.[Zn]>[NH2:8][C:6]1[C:5]([F:11])=[CH:4][C:3]([OH:12])=[C:2]([Cl:1])[CH:7]=1
Reactant: O=[N+]([O-])c1cc(Cl)c(O)cc1F
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: C1CCOC1
Solvent: CO
Product: Nc1cc(Cl)c(O)cc1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96.7 %

Procedure:
Zinc dust (10 g, 160 mmol) was added portion wise to a solution of 2-chloro-5-fluoro-4-nitro-phenol (3.0 g, 16 mmol) and NH4Cl (8.4 g, 160 mmol) in THF (150 mL) and MeOH (150 mL) and the mixture was stirred at RT for 0.5 h. The reaction mixture was filtered, and the filter cake was washed with EtOAc (3×50 mL). The combined filtrate was washed with brine (3×100 mL), dried over Na2SO4 and concentrated to provide 4-amino-2-chloro-5-fluorophenol (2.5 g, 100% yield). 1H NMR (400 MHz, DMSO-d6): δ 9.39 (s, 1 H), 6.76 (d, J=9.2 Hz, 1 H), 6.65 (d, J=12.4 Hz, 1 H), 4.70 (s, 2 H).
Reaction SMILES: [O:1]=[C:2]1[N:8]2[C@H:9]([C:13]([O:15]C(C)(C)C)=[O:14])[CH2:10][CH2:11][CH2:12][N:7]2[CH2:6][CH2:5][CH2:4][C@@H:3]1[NH:20][C:21](=[O:30])[CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.O=C1CC[C@H](NC(=O)CCC2C=CC=CC=2)C(=O)N2[C@H](C(O)=O)CCCN12>>[O:1]=[C:2]1[N:8]2[C@H:9]([C:13]([OH:15])=[O:14])[CH2:10][CH2:11][CH2:12][N:7]2[CH2:6][CH2:5][CH2:4][C@@H:3]1[NH:20][C:21](=[O:30])[CH2:22][CH2:23][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: CC(C)(C)OC(=O)[C@@H]1CCCN2CCC[C@H](NC(=O)CCc3ccccc3)C(=O)N12
Agent: O=C(CCc1ccccc1)N[C@H]1CCC(=O)N2CCC[C@@H](C(=O)O)N2C1=O
Product: O=C(CCc1ccccc1)N[C@H]1CCCN2CCC[C@@H](C(=O)O)N2C1=O
Yield: 96 %

Procedure:
was prepared from (1S,9S)t-butyl octahydro-10-oxo-9-(3-phenylpropionylamino)-6H-pyridazino[1,2-a][1,2]diazepine-1-carboxylate (44b) by the method described for compound 45a to afford 657 mg (96%) of 45b as a crystalline solid: mp. 198-202° C.; [α]D23 -86.2° (c 0.5, CH3OH); IR (KBr) 3294, 2939, 1729, 1645, 1620, 1574, 1453, 1214; 1H NMR (CD3OD) δ 7.92 (1H, d, J=7.9), 7.20 (5H, m), 5.29 (1H, m), 4.90 (1H, m), 3.47 (1H, m), 3.08 (2H, m), 2.90 (2H, m), 2.55 (3H, m), 2.36 (1H, m), 1.81 (5H, m), 1.43 (2H, m). MS(FAB, m/z) 360 (M+ +1), 211,143,91.
Reaction SMILES: [CH:1]1([PH2:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:8]([CH:10]=[O:11])=[O:9]>>[CH:1]1([P:7]2[CH:8]([OH:9])[CH:10]([OH:11])[P:7]([CH:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)[CH:8]([OH:9])[CH:10]2[OH:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=CC=O
Reactant: PC1CCCCC1
Product: OC1C(O)P(C2CCCCC2)C(O)C(O)P1C1CCCCC1
Yield: 92 %

Procedure:
Following the procedure of Example 2, 150 parts of monocyclohexyl phosphine are reacted with 190 parts of 40% aqueous glyoxal solution to give 207 parts (92% yield) of 1,4-dicyclohexyl-2,3,5,6-tetrahydroxy-1,4-diphosphorinane, m.p. 182°-215° C.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[O:10][CH2:9][CH2:8][CH2:7][C:6]=2[C:5]([CH3:12])=[CH:4][CH:3]=1.[Br:13]Br>CC(O)=O.C1(C)C=CC=CC=1>[Br:13][C:4]1[CH:3]=[C:2]([Cl:1])[C:11]2[O:10][CH2:9][CH2:8][CH2:7][C:6]=2[C:5]=1[CH3:12]
Reactant: Cc1ccc(Cl)c2c1CCCO2
Reactant: BrBr
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: Cc1c(Br)cc(Cl)c2c1CCCO2
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 54.1 %

Procedure:
A mixture of the 8-chloro-5-methyl-3,4-dihydro-2H-1-benzopyran (7d) (5.74 g, 31.4 mmol) and acetic acid (75 mL) is treated with bromine (1.93 mL, 37.7 mmol) in AcOH (35 mL). The mixture was stirred at room temperature for 15 minutes, then diluted with toluene (100 mL). The mixture was concentrated in vacuo. The residue was dissolved in ethyl acetate (70 mL) and successively washed with a 15% sodium thiosulfate solution (50 mL) and a saturated solution of sodium hydrogenocarbonate (50 mL). The organic layer was dried over sodium sulfate and concentrated in vacuo. The product was recrystallized in ethanol, to provide 6-bromo-8-chloro-5-methyl-3,4-dihydro-2H-1-benzopyran (7e) (4.44 g, 17.0 mmol, 54%) as a white solid.
Reaction SMILES: FC1C=CC=CC=1C(Cl)=O.[CH3:11][O:12][C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][CH:21]=1)[C:16](Cl)=[O:17].[NH2:22][C:23]1[CH:24]=[C:25]([CH:36]=[CH:37][N:38]=1)[C:26]([NH:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:27]>>[CH2:29]([NH:28][C:26](=[O:27])[C:25]1[CH:36]=[CH:37][N:38]=[C:23]([NH:22][C:16](=[O:17])[C:15]2[CH:19]=[CH:20][CH:21]=[C:13]([O:12][CH3:11])[CH:14]=2)[CH:24]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: Nc1cc(C(=O)NCc2ccccc2)ccn1
Reactant: COc1cccc(C(=O)Cl)c1
Agent: O=C(Cl)c1ccccc1F
Product: COc1cccc(C(=O)Nc2cc(C(=O)NCc3ccccc3)ccn2)c1
Yield: 46 %

Procedure:
Following the procedure as describe in Example 6, making variations as required to replace 2-fluorobenzoyl chloride with 3-methoxybenzoyl chloride to react with 2-amino-N-benzylisonicotinamide, N-benzyl-2-(3-methoxybenzamido)isonicotinamide was obtained as a colorless solid in 46% yield: mp 95-96° C. (hexanes/ethyl acetate); 1H NMR (300 MHz, CDCl3) δ 8.88 (s, 1H), 8.64 (s, 1H), 8.36 (d, J=5.1 Hz, 1H), 7.56 (dd, J=5.1, 1.4 Hz, 1H), 7.43-7.25 (m, 8H), 7.11-7.07 (m, 1H), 6.80 (t, J=4.7 Hz, 1H), 4.63 (d, J=5.8 Hz, 2H), 3.84 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 165.8, 165.1, 160.0, 151.9, 148.6, 144.2, 137.4, 135.0, 129.9, 128.8, 128.0, 127.8, 118.9, 118.8, 118.6, 112.4, 110.5, 55.5, 44.2; MS (ES+) m/z 362.5 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[O:5][CH2:6][CH2:7][NH2:8].C(=O)([O-])[O-].[K+].[K+].[Br:18][CH2:19][C:20](Br)=[O:21].O>ClCCl>[Br:18][CH2:19][C:20]([NH:8][CH2:7][CH2:6][O:5][C:4]1[CH:9]=[CH:10][CH:11]=[C:2]([F:1])[CH:3]=1)=[O:21]
Reactant: O=C(Br)CBr
Reactant: NCCOc1cccc(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Product: O=C(CBr)NCCOc1cccc(F)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A mixture of 2-(3-fluorophenoxy)ethylamine (0.93 g) and potassium carbonate (1.24 g in dichloromethane (20 mL) at 0° C. was treated with bromoacetyl bromide (1.04 mL). The reaction mixture was stirred at 0° C. for 30 mins then at room temperature for 6 h. Water was added and the mixture was stirred until effervescence ceased. The organic layer was separated and the organic layer was evaporated to afford the crude product which was purified by silica gel chromatography eluting with 0-50% EtOAc/pentane to give the sub-titled compound (1.17 g) as a brown oil.
Reaction SMILES: S(O[C@H:12]1[CH2:29][CH2:28][C@@:27]2([CH3:30])[C@@:14]([OH:33])([C@H:15]([OH:32])[CH2:16][C@@H:17]3[C@@H:26]2[CH2:25][CH2:24][C@@:22]2([CH3:23])[C@H:18]3[CH2:19][CH2:20][C:21]2=[O:31])[CH2:13]1)(C1C=CC(C)=CC=1)(=O)=O.N1C(C)=CC(C)=CC=1C>>[OH:33][C@:14]12[CH2:13][CH:12]=[CH:29][CH2:28][C@:27]1([CH3:30])[C@@H:26]1[C@H:17]([C@H:18]3[C@@:22]([CH2:24][CH2:25]1)([CH3:23])[C:21](=[O:31])[CH2:20][CH2:19]3)[CH2:16][C@H:15]2[OH:32]
Reactant: Cc1ccc(S(=O)(=O)O[C@H]2CC[C@]3(C)[C@H]4CC[C@]5(C)C(=O)CC[C@H]5[C@@H]4C[C@@H](O)[C@@]3(O)C2)cc1
Solvent: Cc1cc(C)nc(C)c1
Product: C[C@]12CC[C@H]3[C@@H](C[C@@H](O)[C@@]4(O)CC=CC[C@]34C)[C@@H]1CCC2=O
Temperature: 160 °C
Reaction time: 1.5 h
Yield: 100.6 %

Procedure:
70 g (0.147 mol) of the above-obtained 3β-tosyloxy-5α,6β-dihydroxy-17-oxo-androstane are dissolved in 350 ml. of collidine and the reaction mixture is heated in a nitrogen atmosphere, under stirring for 1.5 hours in an oil bath of 160° C. The collidine is then distilled off under reduced pressure, the evaporation residue is triturated with 400 ml. of water, filtred and washed with 10% aqueous hydrochloric acid solution, then with water to remove the last traces of collidine. The so-obtained product is dried in vacuo over phosphorous pentoxide at 40° C, and may be purified, if desired, by mixing with a fivefold amount of diethyl ether. 45 g of 5α,6β-dihydroxy-17-oxo-androst-2-ene (90%) are obtained; m.p. 183°-186° C; [α]D25 = +81° (c = 1 in chloroform).
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[CH2:3][NH:4][C:5]1[C:10]([NH2:11])=[CH:9][C:8]([C:12]([F:15])([F:14])[F:13])=[CH:7][N:6]=1.[CH2:18]([S:20][C:21]1[C:22]([C:31](O)=[O:32])=[N:23][CH:24]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:26]=1)[CH3:19].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>N1C=CC=CC=1>[F:17][C:2]([F:1])([F:16])[CH2:3][NH:4][C:5]1[C:10]([NH:11][C:31]([C:22]2[C:21]([S:20][CH2:18][CH3:19])=[CH:26][C:25]([C:27]([F:29])([F:30])[F:28])=[CH:24][N:23]=2)=[O:32])=[CH:9][C:8]([C:12]([F:13])([F:14])[F:15])=[CH:7][N:6]=1
Reactant: CCSc1cc(C(F)(F)F)cnc1C(=O)O
Reactant: Nc1cc(C(F)(F)F)cnc1NCC(F)(F)F
Agent: CCN=C=NCCCN(C)C
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: On1nnc2ccccc21
Solvent: c1ccncc1
Product: CCSc1cc(C(F)(F)F)cnc1C(=O)Nc1cc(C(F)(F)F)cnc1NCC(F)(F)F
Temperature: 25 °C
Reaction time: 3 h
Yield: 90.8 %

Procedure:
A mixture of N2-(2,2,2-trifluoroethyl)-5-trifluoromethylpyridin-2,3-diamine (0.52 g), 3-ethylsulfanyl-5-trifluoromethylpyridin-2-carboxylic acid (0.50 g), WSC (0.46 g), HOBt (27 mg) and pyridine (2 ml) was stirred at room temperature for 3 hours. To the reaction mixture was poured aqueous 10% citric acid solution, and then the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over sodium sulfate, and concentrated under reduced pressure to give 3-ethylsulfanyl-5-trifluoromethylpyridin-2-carboxylic acid [2-(2,2,2-trifluoroethyl)amino-5-trifluoromethylpyridin-3-yl]amide (0.89 g), which is hereinafter referred to as “intermediate compound (M3-44)”.
Reaction SMILES: [NH:1]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[C@@H:2]([C:6]([OH:8])=O)[CH:3]([CH3:5])[CH3:4].Br.Br.[CH3:18][N:19]1[CH2:24][CH2:23][CH:22]([CH:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH2:21][CH2:20]1.C(N(CC)CC)C.C1C=CC2N(O)N=NC=2C=1.C1CCC(N=C=NC2CCCCC2)CC1.[Li+].[Cl-]>CN(C=O)C>[C:9]([NH:1][C@@H:2]([C:6]([N:28]1[CH2:29][CH2:30][CH:25]([CH:22]2[CH2:21][CH2:20][N:19]([CH3:18])[CH2:24][CH2:23]2)[CH2:26][CH2:27]1)=[O:8])[CH:3]([CH3:4])[CH3:5])([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10]
Reactant: CN1CCC(C2CCNCC2)CC1
Reactant: CC(C)[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: Br
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)[C@@H](NC(=O)OC(C)(C)C)C(=O)N1CCC(C2CCN(C)CC2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.7 %

Procedure:
To a solution of Boc-D-Val-OH (33.0 g, 152 mmol) in anhydrous DMF (1.5 L) is added 4-(1-methylpiperidin-4-yl)-piperidine dihydrobromide (52.2 g, 152 mmol) [4-(1-methyl-piperidin-4-yl)piperidine dihydrobromide is also named 1-methyl-4,4′-bispiperidine dihydrobromide; and its preparation is described in WO 00/76971 at pages 163-164.] followed by triethylamine (63.5 mL, 456 mmol), HOBt (20.5 g, 152 mmol) and DCC (31.3 g, 152 mmol) at room temperature. The reaction is allowed to stir at room temperature overnight. The mixture is then poured into aqueous LiCl (1.5 L) and extracted with CH2Cl2 (3×2 L). The organic layers are combined, dried over Na2SO4, filtered and concentrated in vacuo. The residue is dissolved in CHCl3 (1 L), filtered and concentrated in vacuo. The crude material is purified using chromatography over silica gel, eluting with 4% (2 M NH3 in MeOH)/CHCl3 to give 43.3 g (75%) of the title compound as a tan foam.
Reaction SMILES: [O:1]([CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(C)C=CC=CC=1.CCOC(C)=O>C(O)(=O)C.C(Cl)Cl.[Pt]>[O:1]([CH2:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][NH:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc(OCc2ccccn2)cc1
Agent: [Pt]
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: c1ccc(OCC2CCCCN2)cc1
Reaction time: 5 h

Procedure:
To a solution of 2-phenoxymethylpyridine (1.0 g, 5.4 mmol) in 23 mL of acetic acid was added 0.13 g of 5% Pt/C. The mixture was hydrogenated on a Parr shaker at 50 psi for 5 h. Toluene and EtOAc were added to the mixture and it was filtered and concentrated under reduced pressure to give an oil. The oil was dissolved in CH2Cl2 and washed with 10% NaOH. The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure to give a 50/50 mixture of the title compound and starting material as a yellow oil (1.0 g, 98%). ES (+) MS m/e=192 (M+H).
Reaction SMILES: C(=O)(O)[O-].[Na+].C([O:8][CH2:9][C:10]([CH3:17])=[CH:11][CH2:12][O:13][C:14](=[O:16])[CH3:15])=O.O.Cl>CO.C(OCC)(=O)C>[C:14]([O:13][CH2:12][CH:11]=[C:10]([CH3:17])[CH2:9][OH:8])(=[O:16])[CH3:15]
Reactant: CC(=O)OCC=C(C)COC=O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(=O)OCC=C(C)CO
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.7 %

Procedure:
Sodium bicarbonate (0.40 g, 4.75 mmol, 10 mol %) was added to a solution of 4-acetoxy-2-methyl-2-buten-1-ol formate (8.18 g, 47.5 mmol) in methanol (40 ml). The mixture was stirred at room temperature for 2 hours. After completion of the reaction, most of the methanol was evaporated under reduced pressure. The resulting reaction mixture was poured into a mixture of ice-cooled water (20 ml) and ethyl acetate (100 ml). The pH of the aqueous layer was adjusted to 5 to 6 with 1N hydrochloric acid, and the ethyl acetate layer was separated. The aqueous layer was extracted with ethyl acetate (50 ml) twice. The ethyl acetate layers were combined and dried over anhydrous sodium sulfate. Evaporation of the ethyl acetate gave 4-acetoxy-2-methyl-2-buten-1-ol (6.69 g, 46.4 mmol; Yield: 97.7%) as an oil.