Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1([C:6]2[CH:7]=[C:8]([CH2:21][CH2:22][CH2:23][NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[CH:9]=[C:10](B3OC(C)(C)C(C)(C)O3)[CH:11]=2)[CH2:5][CH2:4]1)#[N:2].I[C:33]1[CH:38]=[CH:37][N:36]=[C:35]2[N:39]([C:46]([C:59]3[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=3)([C:53]3[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=3)[C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=3)[N:40]=[C:41]([C:42]([F:45])([F:44])[F:43])[C:34]=12.C(=O)([O-])[O-].[Na+].[Na+].O>O1CCOCC1.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C.C(OCC)(=O)C>[C:1]([C:3]1([C:6]2[CH:7]=[C:8]([CH2:21][CH2:22][CH2:23][NH:24][C:25](=[O:31])[O:26][C:27]([CH3:29])([CH3:28])[CH3:30])[CH:9]=[C:10]([C:33]3[CH:38]=[CH:37][N:36]=[C:35]4[N:39]([C:46]([C:47]5[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=5)([C:53]5[CH:54]=[CH:55][CH:56]=[CH:57][CH:58]=5)[C:59]5[CH:60]=[CH:61][CH:62]=[CH:63][CH:64]=5)[N:40]=[C:41]([C:42]([F:44])([F:45])[F:43])[C:34]=34)[CH:11]=2)[CH2:4][CH2:5]1)#[N:2]
Reactant: FC(F)(F)c1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2nccc(I)c12
Reactant: CC(C)(C)OC(=O)NCCCc1cc(B2OC(C)(C)C(C)(C)O2)cc(C2(C#N)CC2)c1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)NCCCc1cc(-c2ccnc3c2c(C(F)(F)F)nn3C(c2ccccc2)(c2ccccc2)c2ccccc2)cc(C2(C#N)CC2)c1
Temperature: 60 °C
Yield: 84.3 %

Procedure:
tert-Butyl N-[3-[3-(1-cyanocyclopropyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]propyl]carbamate (50 mg, 0.1173 mmol) was dissolved in dioxane (2 mL) and 4-iodo-3-(trifluoromethyl)-1-trityl-pyrazolo[5,4-b]pyridine (65.14 mg, 0.1173 mmol) was added followed by sodium carbonate (176.0 μL of 2 M, 0.3519 mmol). The reaction mixture was degassed and filled with nitrogen 5 times then Pd[P(tBu)3]2 (8.994 mg, 0.01760 mmol) was added and the reaction heated at 60° C. overnight. After cooling, water was added and ethyl acetate. The aqueous layer was extracted three times with ethyl acetate, the combined organics were washed with brine, dried over MgSO4, filtered and the solvent removed under reduced pressure. The crude product was purified on silica (Companion, 12 g) eluting with 2.5-50% EtOAc:Petrol ether to give tert-butyl 3-(3-(1-cyanocyclopropyl)-5-(3-(trifluoromethyl)-1-trityl-1H-pyrazolo[3,4-b]pyridin-4-yl)phenyl)propylcarbamate as a viscous oil (72 mg, 84%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=3[S:7](=[O:15])(=[O:14])[C:6]=2[CH:16]=1.[N+:17]([O-])([OH:19])=[O:18]>S(=O)(=O)(O)O>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[C:9]3[CH:10]=[CH:11][C:12]([N+:17]([O-:19])=[O:18])=[CH:13][C:8]=3[S:7](=[O:15])(=[O:14])[C:6]=2[CH:16]=1
Reactant: O=[N+]([O-])O
Reactant: O=S1(=O)c2ccccc2-c2ccc(F)cc21
Agent: O=S(=O)(O)O
Product: O=[N+]([O-])c1ccc2c(c1)S(=O)(=O)c1cc(F)ccc1-2
Temperature: 18 °C
Reaction time: 1 h
Yield: 70.9 %

Procedure:
To a mixture of 8.94 g of 3-fluorodibenzothiophene S,S-dioxide in 100 ml of concentrated sulfuric acid, cooled at 18° C. in a water bath, was added dropwise 3.12 g of 71% nitric acid over 3 minutes. The mixture was stirred at room temperature for one hour, then poured over 500 ml of crushed ice and the solid collected, washed with water until neutral then dried at 100° C. This solid was dissolved in 200 ml of acetonitrile, treated with charcoal, filtered through diatomaceous earth and the filtrate concentrated to 110 ml producing successive crops of crystals. The first two crops were combined and recrystallized from 100 ml of acetonitrile, giving 7.56 g of the desired product as a solid, mp 275°-279° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH2:8][NH:9][C:10](=[O:15])[C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:6][CH:5]=[C:4]([Cl:16])[C:3]=1[NH:17][C:18]1[N:22]([CH3:23])[C:21]2[CH:24]=[C:25]([N:31]3[CH2:36][CH2:35][CH:34]([C:37]([F:40])([F:39])[F:38])[CH2:33][CH2:32]3)[C:26]([C:28]([OH:30])=O)=[CH:27][C:20]=2[N:19]=1.ClC(N(C)C)=C(C)C.[Cl:49][C:50]1[CH:51]=[C:52]([CH:54]=[CH:55][C:56]=1[F:57])[NH2:53].CCN(C(C)C)C(C)C>CC#N>[Cl:49][C:50]1[CH:51]=[C:52]([NH:53][C:28]([C:26]2[C:25]([N:31]3[CH2:32][CH2:33][CH:34]([C:37]([F:39])([F:38])[F:40])[CH2:35][CH2:36]3)=[CH:24][C:21]3[N:22]([CH3:23])[C:18]([NH:17][C:3]4[C:4]([Cl:16])=[CH:5][CH:6]=[C:7]([CH2:8][NH:9][C:10](=[O:15])[C:11]([CH3:14])([CH3:13])[CH3:12])[C:2]=4[Cl:1])=[N:19][C:20]=3[CH:27]=2)=[O:30])[CH:54]=[CH:55][C:56]=1[F:57]
Reactant: Cn1c(Nc2c(Cl)ccc(CNC(=O)C(C)(C)C)c2Cl)nc2cc(C(=O)O)c(N3CCC(C(F)(F)F)CC3)cc21
Reactant: Nc1ccc(F)c(Cl)c1
Agent: CC(C)=C(Cl)N(C)C
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: Cn1c(Nc2c(Cl)ccc(CNC(=O)C(C)(C)C)c2Cl)nc2cc(C(=O)Nc3ccc(F)c(Cl)c3)c(N3CCC(C(F)(F)F)CC3)cc21
Reaction time: 0.33 h

Procedure:
A mixture of 2-{2,6-dichloro-3-[(2,2-dimethyl-propionylamino)-methyl]-phenylamino}-6-[4-trifluoromethyl-piperidinyl]-1-methyl-1H-benzimidazole-5-carboxylic acid (72 mg, 0.120 mmol), (1-chloro-2-methyl-propenyl)-dimethylamine (33 mg, 0.25 mmol) and MeCN (2 mL) is stirred for 20 min. This mixture is added to 3-chloro-4-fluoro-aniline (36 mg, 0.25 mmol) and DIPEA (129 μL, 0.75 mmol) in MeCN (3 mL) and it is stirred overnight. The mixture is concentrated and the residue is taken up in DMF (2 mL) and purified by reverse phase HPLC.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:7]=[C:6]([C@H:8]([CH2:17][CH2:18][CH2:19][CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)[CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[O:5][N:4]=1.C1C(=O)[N:30](OC(ON2C(=O)CCC2=O)=O)[C:28](=[O:29])C1.N>CC#N>[NH2:30][C:28]([NH:1][CH2:2][C:3]1[N:7]=[C:6]([C@H:8]([CH2:17][CH2:18][CH2:19][CH:20]2[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]2)[CH2:9][C:10]([O:12][C:13]([CH3:15])([CH3:16])[CH3:14])=[O:11])[O:5][N:4]=1)=[O:29]
Reactant: CC(C)(C)OC(=O)C[C@@H](CCCC1CCCCC1)c1nc(CN)no1
Reactant: O=C(ON1C(=O)CCC1=O)ON1C(=O)CCC1=O
Agent: N
Solvent: CC#N
Product: CC(C)(C)OC(=O)C[C@@H](CCCC1CCCCC1)c1nc(CNC(N)=O)no1
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 72.9 %

Procedure:
A solution of tert-butyl(3R)-3-[3-(aminomethyl)-1,2,4-oxadiazol-5-yl]-6-cyclohexylhexanoate (preparation 18) (310 mg, 0.88 mmol) in MeCN (10 ml) was treated with N,N-disuccinimidyl carbonate (271 mg, 1.06 mmol) and stirred at room temperature, under a nitrogen atmosphere for 4.5 hours. NH3 (0.5M in dioxan) was added forming a white precipitate. The reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was filtered and the solvent removed under reduced pressure. The residue was purified on a silica column eluting with a solvent gradient of DCM:MeOH (100:0) gradually changing to (95:5) to afford the title compound as a colourless oil (253 mg, 73%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5](Cl)=[N:6][CH:7]=1.[C:9]1([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH:15][C:16](=[O:36])[O:17][CH:18]1[CH2:23][CH2:22][N:21]([CH2:24][CH2:25][N:26]([C:28](=[O:35])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][NH2:34])[CH3:27])[CH2:20][CH2:19]1.C(N(CC)CC)C>C(O)CCC>[C:9]1([C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH:15][C:16](=[O:36])[O:17][CH:18]1[CH2:19][CH2:20][N:21]([CH2:24][CH2:25][N:26]([C:28](=[O:35])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][NH:34][C:5]2[N:4]=[CH:3][C:2]([Br:1])=[CH:7][N:6]=2)[CH3:27])[CH2:22][CH2:23]1
Reactant: CN(CCN1CCC(OC(=O)Nc2ccccc2-c2ccccc2)CC1)C(=O)CCCCCN
Reactant: Clc1ncc(Br)cn1
Solvent: CCN(CC)CC
Solvent: CCCCO
Product: CN(CCN1CCC(OC(=O)Nc2ccccc2-c2ccccc2)CC1)C(=O)CCCCCNc1ncc(Br)cn1
Yield: 74.6 %

Procedure:
5-Bromo-2-chloropyrimidine (124 mg, 0.643 mmol) and the compound (300 mg, 0.643 mmol) obtained in Example 1a were dissolved in n-butanol (5 mL), triethylamine (0.134 mL, 0.965 mmol) was added, and the mixture was stirred with heating to reflux for 19 hours. The solvent was evaporated under reduced pressure, and the resulting residue was purified by NH silica gel column chromatography (hexane:ethyl acetate=1:1→0:100, v/v) to give the title compound (299 mg; yield, 75%) as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][C:12]([F:15])([F:14])[F:13])[C:5]([OH:7])=O.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[Cl:30][C:31]1[C:39]2[C:34](=[CH:35][CH:36]=[C:37]([C:40]([NH:42]O)=[NH:41])[CH:38]=2)[N:33]([CH2:44][CH2:45][C:46]([O:48][CH2:49][CH3:50])=[O:47])[CH:32]=1>CN(C=O)C>[Cl:30][C:31]1[C:39]2[C:34](=[CH:35][CH:36]=[C:37]([C:40]3[N:41]=[C:5]([C:4]4[CH:8]=[CH:9][C:10]([O:11][C:12]([F:15])([F:14])[F:13])=[C:2]([Cl:1])[CH:3]=4)[O:7][N:42]=3)[CH:38]=2)[N:33]([CH2:44][CH2:45][C:46]([O:48][CH2:49][CH3:50])=[O:47])[CH:32]=1
Reactant: O=C(O)c1ccc(OC(F)(F)F)c(Cl)c1
Reactant: CCOC(=O)CCn1cc(Cl)c2cc(C(=N)NO)ccc21
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CCOC(=O)CCn1cc(Cl)c2cc(-c3noc(-c4ccc(OC(F)(F)F)c(Cl)c4)n3)ccc21
Temperature: 80 °C
Reaction time: 8 h
Yield: 55.6 %

Procedure:
3-Chloro-4-[(trifluoromethyl)oxy]benzoic acid (commercial: ABCR) (168 mg, 0.70 mmol) stirring in DMF (6 ml) was treated with EDC (146 mg, 0.76 mmol) followed by HOBt (104 mg, 0.76 mmol). The resultant solution was stirred for 15 minutes. Added ethyl 3-{3-chloro-5-[(hydroxyamino)(imino)methyl]-1H-indol-1-yl}propanoate (D96) (216 mg, 0.70 mmol) and stirred at RT for 45 minutes. The solution was heated at 80° C. for 6 hours then left standing at room temperature overnight. Single product formed by LC/MS. Added EtOAc (50 ml) and washed with water (50 ml), saturated aqueous sodium hydrogen carbonate (50 ml) and water (50 ml). Dried over MgSO4 and evaporated off the solvent. The residue was crystallised from ethanol to yield 200 mg of white solid. δH (400 MHz, d6-DMSO) 1.11 (3H, t), 2.92 (2H, t), 4.00 (2H, q), 4.49 (2H, t), 7.75 (1H, s), 7.80 (1H, d), 7.85 (1H, dd), 7.95 (1H, dd) 8.23 (1H, d) 8.30 (1H, dd), 8.47 (1H, d). MS (ES) C22H1635Cl37ClF3N3O4 requires 515; found 516 (MH+).
Reaction SMILES: C1(S[CH2:8][N:9]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][C:15]([O:25][CH3:26])=[CH:16][C:17]=3[CH:21]([CH2:23][CH3:24])[CH3:22])[S:10]2(=[O:12])=[O:11])C=CC=CC=1.S(Cl)([Cl:30])(=O)=O>C(Cl)Cl>[Cl:30][CH2:8][N:9]1[C:19](=[O:20])[C:18]2[C:13](=[CH:14][C:15]([O:25][CH3:26])=[CH:16][C:17]=2[CH:21]([CH2:23][CH3:24])[CH3:22])[S:10]1(=[O:12])=[O:11]
Reactant: CCC(C)c1cc(OC)cc2c1C(=O)N(CSc1ccccc1)S2(=O)=O
Reactant: O=S(=O)(Cl)Cl
Solvent: ClCCl
Product: CCC(C)c1cc(OC)cc2c1C(=O)N(CCl)S2(=O)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-phenylthiomethyl-4-sec-butyl-6-methoxysaccharin (2.6 g) in CH2Cl2 (20 mL) was added sulfuryl chloride (0.7 mL). The mixture was stirred at ambient temperature overnight, and the solvent was removed in vacuo. The residue was treated with hexane and the mixture was sonicated for 6 hours. A precipitate formed with a collected by filtration to afford 1.33 g of 2-chloromethyl-4-sec-butyl-6-methoxysaccharin.
Reaction SMILES: C([O:3][C:4](=[O:19])[CH:5]([O:16][CH2:17][CH3:18])[CH2:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]=[CH:10]2)C.Cl[CH2:21][C:22]1[N:23]=[C:24]([C:28]2[CH:33]=[C:32]([F:34])[CH:31]=[C:30]([F:35])[CH:29]=2)[O:25][C:26]=1[CH3:27]>>[F:34][C:32]1[CH:33]=[C:28]([C:24]2[O:25][C:26]([CH3:27])=[C:22]([CH2:21][N:12]3[C:13]4[C:9](=[CH:8][C:7]([CH2:6][CH:5]([O:16][CH2:17][CH3:18])[C:4]([OH:3])=[O:19])=[CH:15][CH:14]=4)[CH:10]=[CH:11]3)[N:23]=2)[CH:29]=[C:30]([F:35])[CH:31]=1
Reactant: Cc1oc(-c2cc(F)cc(F)c2)nc1CCl
Reactant: CCOC(=O)C(Cc1ccc2[nH]ccc2c1)OCC
Product: CCOC(Cc1ccc2c(ccn2Cc2nc(-c3cc(F)cc(F)c3)oc2C)c1)C(=O)O
Yield: 20 %

Procedure:
Starting from rac-2-ethoxy-3-(1H-indol-5-yl)-propionic acid ethyl ester and 4-chloromethyl-2-(3,5-difluoro-phenyl)-5-methyl-oxazole, the title compound was obtained in 20% yield as a brown oil. MS: (M+H)+ 441.3.
Reaction SMILES: [CH3:1][CH:2]1[N:7]([CH2:8][CH2:9][CH2:10][NH2:11])[CH2:6][CH2:5][CH2:4][CH2:3]1.[C:12](Cl)(=[O:28])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]>C(Cl)Cl>[CH3:1][CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[CH2:8][CH2:9][CH2:10][NH:11][C:12](=[O:28])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: CCCCCCCCCCCCCCCC(=O)Cl
Reactant: CC1CCCCN1CCCN
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCC(=O)NCCCN1CCCCC1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.9 %

Procedure:
To a solution of 1-(3-aminopropyl)-2-pipecoline (1.00 g, 6.40 mmole) in methylene chloride (25 mL) was added palmitoyl chloride (1.73 g, 6.40 mmole) in small portions. The reaction mixture was stirred at room temperature overnight. The reaction mixture was washed twice with saturated aqueous sodium bicarbonate and once with brine. The organic layer was dried over magnesium sulfate and the salts removed by filtration. The solvent was removed under reduced pressure and the residue dried in vacuo to give the title compound (2.12 g, 83%), mp. 48°-50° C. 1H NMR (300 MHz, CDCl3): δ0.883 (3H, t, J=6.5 Hz), 1.136 (3H, d, J=5.5 Hz), 1.254 (24H, bs), 1.60 to 1.70 (4H, m), 2.157 (2H, t, J=7.6 Hz), 2.37 to 2.39 (2H, m), 2.89 to 2.94 (3H, m), 3.24 to 3.27 (1H, m), 3.40 to 3.44 (1H, m), and 7.266 (1H, bs). Analysis calculated for C25H50N2O.1/4H2O C, 75.16; H, 12.61; N, 7.01. Found: C, 75.16; H, 12.69; N, 7.16.
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:13]3[CH:14]=[CH:15][C:16](OS(C(F)(F)F)(=O)=O)=[CH:17][C:12]=3[S:11][N:10]=2)=[CH:5][CH:4]=1.[CH3:28][C:29]([N:33]([CH2:37][CH3:38])[CH2:34][CH2:35][OH:36])([CH3:32])[C:30]#[CH:31]>>[CH3:32][C:29]([N:33]([CH2:37][CH3:38])[CH2:34][CH2:35][OH:36])([CH3:28])[C:30]#[C:31][C:16]1[CH:15]=[CH:14][C:13]2[C:9]([C:6]3[CH:5]=[CH:4][C:3]([C:2]([F:26])([F:1])[F:27])=[CH:8][CH:7]=3)=[N:10][S:11][C:12]=2[CH:17]=1
Reactant: C#CC(C)(C)N(CC)CCO
Reactant: O=S(=O)(Oc1ccc2c(-c3ccc(C(F)(F)F)cc3)nsc2c1)C(F)(F)F
Product: CCN(CCO)C(C)(C)C#Cc1ccc2c(-c3ccc(C(F)(F)F)cc3)nsc2c1

Procedure:
In analogy to example 14.1, Trifluoro-methanesulfonic acid 3-(4-trifluoromethyl-phenyl)-benzo[d]isothiazol-6-yl ester and 2-[(1,1-Dimethyl-prop-2-ynyl)-ethyl-amino]-ethanol were converted to yield 2-((1,1-Dimethyl-3-[3-(4-trifluoromethyl-phenyl)-benzo[d]isothiazol-6-yl]-prop-2-ynyl)-ethyl-amino)-ethanol as off-white foam, MS: 433 (MH+).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][C@:8]12[CH2:25][CH2:24][C@H:23]3[C@@H:13]([CH2:14][CH2:15][C:16]4[C@:21]3([CH3:22])[CH2:20][CH2:19][C:18](=[O:26])[CH:17]=4)[C@@H:12]1[CH2:11][CH2:10][C@@H:9]2[C:27](OC)=[O:28]>C1COCC1>[OH:28][CH2:27][C@H:9]1[CH2:10][CH2:11][C@H:12]2[C@H:13]3[C@H:23]([CH2:24][CH2:25][C@:8]12[CH3:7])[C@:21]1([CH3:22])[C:16](=[CH:17][CH:18]([OH:26])[CH2:19][CH2:20]1)[CH2:15][CH2:14]3
Reactant: COC(=O)[C@H]1CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: C[C@]12CC[C@H]3[C@@H](CCC4=CC(O)CC[C@@]43C)[C@@H]1CC[C@@H]2CO
Temperature: 0 °C
Yield: 103.5 %

Procedure:
Approximately 750 ml of dry THF was added to a 3-neck round bottom flask equipped with a condenser, argon bubbler and mechanical stirrer. The flask was cooled to 0° C. and lithium aluminum hydride (LAH) (11.39 g, 0.3 mol) was slowly added. After all of the LAH was added, the flask was warmed to room temperature. A solution of methyl androst-4-ene-3-one-17β-carboxylate (66 g, 0.2 mol) in 600 ml of THF was very slowly added to the LAH slurry. After the addition of the steroid, the reaction mixture was slowly warmed to reflux. After 2 hours the excess LAH was quenched with 11.4 ml water, 11.4 ml 15% sodium hydroxide (NaOH) and 2B ml water. The salts were removed by filtration and washed with approximately 1 liter of warm THF. Concentration of the combined organic solutions afforded 63 g (94%) of 17β-(hydroxymethyl)-androst-4-ene-3-ol as mixture of α and β isomers.
Reaction SMILES: [C:1]([CH2:6][NH:7][CH2:8][CH2:9][N:10]1[C:14]([S:15]CC2C=CC(OC)=CC=2)=[N:13][N:12]=[N:11]1)([O:3]CC)=[O:2].CO.S>O>[C:1]([CH2:6][NH:7][CH2:8][CH2:9][N:10]1[C:14](=[S:15])[NH:13][N:12]=[N:11]1)([OH:3])=[O:2]
Reactant: CCOC(=O)CNCCn1nnnc1SCc1ccc(OC)cc1
Agent: S
Solvent: CO
Solvent: O
Product: O=C(O)CNCCn1nn[nH]c1=S
Temperature: 25 °C
Reaction time: 15 h
Yield: 82.8 %

Procedure:
To a solution of 12.5 g. (35.6 mmol) 1-[2-[[(carbethoxy)methyl]amino]ethyl]-5-[(4-methoxybenzyl)thio]-1H-tetrazole in 250 ml. of methanol and 65 ml. of water was added a solution of 25.5 g. (80 mmol) of mercuric acetate in 80 ml. of water. The mixture was stirred at room temperature for 15 hours and at reflux for 1 hour. After thorough cooling, the mixture was treated with hydrogen sulfide gas for 1.5 hours. The dark mixture was heated over a steam bath for 1.5 hours and filtered. The filtrate was evaporated in vacuo to dryness. The residue was recrystallized from ethyl acetate to give 5.9 g. of 1-[2-[(carboxymethyl)amino]ethyl]-1,4-dihydro-5H-tetrazole-5-thione (82.8% yield) mp 215°-220° dec.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]([O:14]C(C)C)=[O:13])[CH:5]=[N:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].[OH-].[Na+]>C(O)(C)C.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]([OH:14])=[O:13])[CH:5]=[N:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10]
Reactant: CC(C)OC(=O)c1cnc(OC(C)C)c(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Product: CC(C)Oc1ncc(C(=O)O)cc1Cl
Reaction time: 3 h
Yield: 97.1 %

Procedure:
1-methylethyl 5-chloro-6-[(1-methylethyl)oxy]-3-pyridinecarboxylate (D60) (1.6 g, 6.21 mmol) in isopropanol (70 ml) and water (35.0 ml) was treated with 2N sodium hydroxide (6.21 ml, 12.42 mmol) and stirred for 3 hours to give a single product. Evaporated off the IPA, acidified with glacial acetic acid and extracted product into EtOAc (100 ml). Dried over MgSO4 and evaporated off the solvent to yield 1.30 g of the title compound as a white solid. MS (ES) C9H1035ClNO3 requires 215; found 214 (M−H+).
Reaction SMILES: [CH3:1][S:2][C:3]1[N:4]=[C:5]([C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)[S:6][C:7]=1[NH2:8].CN(C1C=CC=CN=1)C.[CH3:24][S:25][CH2:26][CH2:27][C:28](Cl)=[O:29]>C(Cl)Cl.O>[CH3:24][S:25][CH2:26][CH2:27][C:28]([NH:8][C:7]1[S:6][C:5]([C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)=[N:4][C:3]=1[S:2][CH3:1])=[O:29]
Reactant: CSc1nc(-c2cccnc2)sc1N
Reactant: CSCCC(=O)Cl
Agent: CN(C)c1ccccn1
Solvent: O
Solvent: ClCCl
Product: CSCCC(=O)Nc1sc(-c2cccnc2)nc1SC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 21.8 %

Procedure:
To a nitrogen-purged solution of 4-(methylthio)-5-nitro-2-(pyridin-3-yl)thiazole (253 mg, 1 mmol) in ethyl acetate (50 mL) in a Parr bottle were added glacial acetic acid (601 mg, 10 mmol), followed by Pd on carbon (35 mg, 10% (w)). Hydrogen was added and the mixture was shaken in a Parr shaker for 2 hours and filtered through a bed of Celite®. The filtrate was concentrated under vacuum to give 4-(methylthio)-2-(pyridin-3-yl)thiazol-5-amine as a pale yellow solid, which was placed under high vacuum to remove residual acetic acid. This crude was found to be 95% pure by GC-MS. The crude 4-(methylthio)-2-(pyridin-3-yl)thiazol-5-amine was used without further purification to prepare 3-(methylthio)-N-(4-(methylthio)-2-(pyridin-3-yl)thiazol-5-yl)propanamide. To a solution of 4-(methylthio)-2-(pyridin-3-yl)thiazol-5-amine (100 mg, 0.45 mmol) in methylene chloride (2 mL) were added dimethylaminopyridine (137 mg, 1.12 mmol) followed by 3-(methylthio)propanoyl chloride (68 mg, 0.49 mmol). The mixture was stirred at room temperature for 30 min. The mixture was diluted with dichloromethane (10 mL) and water (5 mL). The organic phase was separated, rinsed with brine, dried over MgSO4 and concentrated in vacuo to give a yellow solid. This solid was purified by silica gel chromatography (methylene chloride-methanol) to give 3-(methylthio)-N-(4-(methylthio)-2-(pyridin-3-yl)thiazol-5-yl)propanamide as a yellow solid (32 mg, 22%): mp 72-74° C., 1H NMR (300 MHz, DMSO-d6) δ 10.90 (s, 1H), 9.08 (m, 1H), 8.64 (d, J=4.8 Hz, 1H), 8.32 (d, J=9.0 Hz, 1H), 7.57 (dd, J=5.1 Hz, 8.4 Hz, 1H), 3.25 (s, 3H), 2.85 (m, 2H), 2.73 (m, 2H), 2.07 (s, 3H); ESIMS m/z 326.1 (M+1), 324.1 (M−1).
Reaction SMILES: N1C=CN=C1.[Si:6](Cl)([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7].[OH:14][C@H:15]1[CH2:23][N:22]2[C@H:17]([CH2:18][C:19](=[O:24])[CH2:20][CH2:21]2)[CH2:16]1.O>ClCCl>[Si:6]([O:14][C@H:15]1[CH2:23][N:22]2[C@H:17]([CH2:18][C:19](=[O:24])[CH2:20][CH2:21]2)[CH2:16]1)([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7]
Reactant: O=C1CCN2C[C@H](O)C[C@H]2C1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)O[C@@H]1C[C@H]2CC(=O)CCN2C1
Temperature: 25 °C
Reaction time: 20 h
Yield: 90.7 %

Procedure:
1.70 g (24.9 mmol) of imidazole and 1.88 g (12.5 mmol) of t-butyldimethylsilyl chloride were added to a solution of 1.30 g (8.1 mmol) of (2R,8aS)-2-hydroxy-1,2,3,5,6,7,8,8a-octahydroindolizin-7-one [obtained as described in Preparative Example 2(i)′ above] in 30 ml of dichloromethane and the resulting mixture was stirred for 20 hours at room temperature. At the end of this time, water was added and the reaction mixture was extracted with dichloromethane. The organic extract was washed with water and concentrated by evaporation under reduced pressure, and the resulting residue was then purified by chromatography on an alumina column using a 9:1 by volume mixture of hexane and ethyl acetate as the elaunt to afford 1.98 g (yield: 88%) of the title compound as a colorless oil.
Reaction SMILES: Cl.[CH3:2][C:3]1([OH:8])[CH2:7][CH2:6][NH:5][CH2:4]1.C(=O)([O-])[O-].[K+].[K+].CS(O[CH2:20][CH:21]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)(=O)=O>C(#N)C>[C:22]1([CH:21]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH2:20][N:5]2[CH2:6][CH2:7][C:3]([CH3:2])([OH:8])[CH2:4]2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CC1(O)CCNC1
Reactant: CS(=O)(=O)OCC(c1ccccc1)c1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC1(O)CCN(CC(c2ccccc2)c2ccccc2)C1
Reaction time: 12 h
Yield: 58.23 %

Procedure:
According to Example 15, 3-methylpyrrolidin-3-ol hydrochloride was synthesized. To a 500 mL reaction flask were added 3-methylpyrrolidin-3-ol hydrochloride (11.46 g, 83 mmol), anhydrous potassium carbonate (28.75 g, 208 mmol) and acetonitrile (220 mL). To the resulting mixture was slowly added a solution of 2,2-diphenylethyl methanesulfonate (23 g, 83 mmol) in acetonitrile dropwisely at 85° C. The reaction was conducted for 12 hours. After the completion of reaction monitored by TLC, the resulting mixture was evaporated under reduced pressure to remove acetonitrile. A mixed solution of dichloromethane and water was added for extraction. The organic phase was dried over anhydrous sodium sulfate, and evaporated to remove the solvent to produce a crude product. The crude product was purified by column chromatography (silica gel column, eluted with petroleum ether:ethyl acetate=30:1 (volumetric ratio)) to produce 1-(2,2-diphenylethyl)-3-methylpyrrolidin-3-ol (13.6 g) in a yield of 58.23%.
Reaction SMILES: CCCC[N+](CCCC)(CCCC)CCCC.[F-].[F:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][C:27]([O:29][CH3:30])=[O:28])=[C:22]([C:31]#[C:32][Si](C)(C)C)[CH:21]=1>C(Cl)Cl.O>[C:31]([C:22]1[CH:21]=[C:20]([F:19])[CH:25]=[CH:24][C:23]=1[CH2:26][C:27]([O:29][CH3:30])=[O:28])#[CH:32]
Reactant: COC(=O)Cc1ccc(F)cc1C#C[Si](C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: ClCCl
Solvent: O
Product: C#Cc1cc(F)ccc1CC(=O)OC

Procedure:
A solution of TBAF (1.0 M in THF; 2.0 mL, 2.0 mmol) was added to a stirred solution of methyl 2-(4-fluoro-2-((trimethylsilyl)ethynyl)phenyl)acetate (A49) (0.212 g, 0.802 mmol) in DCM (5 mL). After 2 minutes the resulting mixture was diluted with water (100 mL) and DCM (50 mL). The organic fraction was separated and adsorbed onto silica gel then purified using column chromatography (Biotage Isolera, 12 g SiO2 Cartridge, 0-20% EtOAc in petroleum benzine 40-60° C.) to give the title compound A50 as a brown oil (0.106 g, 69%); 1H NMR (400 MHz, CDCl3) δ 7.37-7.26 (m, 1H), 7.23 (dd, J=9.0, 2.8 Hz, 1H), 7.06 (m, 1H), 3.84 (s, 2H), 3.73 (s, 3H), 3.33 (s, 1H). LCMS-A: rt 5.838 min; m/z 193 [M+H]+.