Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH2:4][N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([Cl:15])[CH:13]=2)[C:8](=[O:16])[NH:7][C:6]1=[O:17])([OH:3])=[O:2].S(=O)(=O)(O)O.[CH3:23]O>>[Cl:15][C:12]1[CH:13]=[C:14]2[C:9]([C:8](=[O:16])[NH:7][C:6](=[O:17])[N:5]2[CH2:4][C:1]([O:3][CH3:23])=[O:2])=[CH:10][CH:11]=1
Reactant: O=C(O)Cn1c(=O)[nH]c(=O)c2ccc(Cl)cc21
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)Cn1c(=O)[nH]c(=O)c2ccc(Cl)cc21
Yield: 86.5 %

Procedure:
To a suspension of 1-carboxymethyl-7-chloro-2,4(1H, 3H)-quinazolinedione (1) (5 g) in methanol (70 ml) was added concentrated sulfuric acid (1.92 g) at room temperature, and the reaction solution was refluxed for 20 hours. After the reaction solution was concentrated suitablely to half, water (20 ml) was added to adjust to pH 9 with 20% potassium carbonate solution (27 g). The resulting crystal was collected by filtration, washed with water and dried under vacuum to give 4.56 g of the desired compound (yield, 86.5%).
Reaction SMILES: CSC.B.[Br:5][CH2:6][C:7]1[CH:8]=[C:9]([CH2:13][C:14](O)=[O:15])[CH:10]=[CH:11][CH:12]=1.CO>C1COCC1>[Br:5][CH2:6][C:7]1[CH:8]=[C:9]([CH2:13][CH2:14][OH:15])[CH:10]=[CH:11][CH:12]=1
Reactant: O=C(O)Cc1cccc(CBr)c1
Agent: B
Solvent: CSC
Solvent: CO
Solvent: C1CCOC1
Product: OCCc1cccc(CBr)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Borane dimethylsulphide complex (2M solution in THF, 5.78 mL) was added dropwise to a solution of 2-(3-(bromomethyl)phenyl)acetic acid (1.06 g) in THF (10 mL) at 0° C. and the resulting mixture stirred for 10 min. The reaction was then allowed to warm to room temperature and stirred overnight. Methanol (5 mL) was then added and the mixture concentrated in vacuo. Purification was by silica gel chromatography eluting with isohexane to diethyl ether gradient to give the subtitled compound as a white solid. Yield 1 g.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[C:12]([F:14])[C:11]([N:15]2[C:20](=[O:21])[C:19]([CH2:22]Cl)=[C:18]([CH3:24])[N:17]([CH3:25])[C:16]2=[O:26])=[CH:10][C:3]=1[C:4]([O:6][CH:7]([CH3:9])[CH3:8])=[O:5]>C(O)(C)C>[CH:7]([O:6][C:4](=[O:5])[C:3]1[CH:10]=[C:11]([N:15]2[C:20](=[O:21])[C:19]([CH2:22][O:6][CH:7]([CH3:9])[CH3:8])=[C:18]([CH3:24])[N:17]([CH3:25])[C:16]2=[O:26])[C:12]([F:14])=[CH:13][C:2]=1[Cl:1])([CH3:9])[CH3:8]
Reactant: Cc1c(CCl)c(=O)n(-c2cc(C(=O)OC(C)C)c(Cl)cc2F)c(=O)n1C
Solvent: CC(C)O
Product: Cc1c(COC(C)C)c(=O)n(-c2cc(C(=O)OC(C)C)c(Cl)cc2F)c(=O)n1C

Procedure:
using isopropyl 2-chloro-4-fluoro-5-[5-chloromethyl-3,6-dihydro-3,4-dimethyl-2,6-dioxo-1(2H)-pyrimidinyl]-benzoate with isopropanol there is obtained isopropyl-2-chloro-4-fluoro-5-[3,6-dihydro-3,4-dimethyl-5-isopropoxymethyl-2,6-dioxo-1(2H)-pyrimidinyl]-benzoate, 1H-NMR (CDCl3, 400 MHz) 7.82 ppm (d, 1H), 7.32 ppm (d, 1H), 5.22 ppm (m, 1H), 4.45 ppm (d, 1H), 4.34 ppm (d, 1H), 3.69 ppm (m, 1H), 3.48 ppm (s, 3H), 2.44 ppm (s, 3H), 1.35 ppm (d, 6H), 1.21 ppm (d, 6H).
Reaction SMILES: [C:1]1([C:7]2[N:11]3[CH:12]=[C:13]([C:16](=[O:21])N(C)OC)[CH:14]=[CH:15][C:10]3=[N:9][C:8]=2[N:22]2[Si](C)(C)CC[Si]2(C)C)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:31]([Mg]Cl)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.CO.C(O)(=O)C>C1COCC1>[NH2:22][C:8]1[N:9]=[C:10]2[CH:15]=[CH:14][C:13]([C:16](=[O:21])[CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[CH:12][N:11]2[C:7]=1[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CON(C)C(=O)c1ccc2nc(N3[Si](C)(C)CC[Si]3(C)C)c(-c3ccccc3)n2c1
Reactant: Cl[Mg]Cc1ccccc1
Solvent: CC(=O)O
Solvent: CO
Solvent: C1CCOC1
Product: Nc1nc2ccc(C(=O)Cc3ccccc3)cn2c1-c1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 30.4 %

Procedure:
The N-(3-phenyl-6-[N-methyl-N-methoxycarbamoyl]imidazo[1,2-a]pyridin-2-yl)-2,2,5,5-tetramethyl-1-aza-2,5-disilacyclopentane (812 mg, 4 mmol) was dissolved in 30 ml of THF under N2 and benzylmagnesiumchloride (2 M in THF, 6 ml, 12.0 mmol) was added. The mixture was allowed to stir for 18 hours at RT before adding 15 ml of MeOH and 3 ml of acetic acid. The mixture was allowed to stir for 1 hour at RT. The solvents were removed in vacuo and the residue taken up in 400 ml of EtOAc and 60 ml of NaHCO3. The EtOAc was separated and washed with with brine (2×75 ml), dried over NaSO4, and then concentrated in vacuo. The residue was purified by normal phase flash chromatography (EtOAc). The product fractions were recrystalized from EtOAc to yield 398 mg of product. (31.6%). MS(FD), NMR.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:10]2[CH2:11][CH2:12][C:13]3[C:18]([C:9]=2[N:8]([CH3:20])[C:7]=1I)=[N:17][C:16]([NH2:19])=[N:15][CH:14]=3)=[O:5])[CH3:2].C(O[Na])=O>CN(C=O)C.ClCCl.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:1]([O:3][C:4]([C:6]1[C:10]2[CH2:11][CH2:12][C:13]3[C:18]([C:9]=2[N:8]([CH3:20])[CH:7]=1)=[N:17][C:16]([NH2:19])=[N:15][CH:14]=3)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c2c(n(C)c1I)-c1nc(N)ncc1CC2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=CO[Na]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCOC(=O)c1cn(C)c2c1CCc1cnc(N)nc1-2
Temperature: 100 °C
Yield: 83 %

Procedure:
To a solution of 8-amino-2-iodo-1-methyl-4,5-dihydro-1H-1,7,9-triaza-cyclopenta[a]naphthalene-3-carboxylic acid ethyl ester N1 (0.62 mmol) in DMF (5 mL) and under argon, HCOONa (1.4 mmol) and Pd(Ph3P)4 (0.04 mmol) were added and the mixture was heated at 100° C. for 4 h. The mixture was cooled to rt, diluted with dichloromethane and washed with water. The organic phase was dried (Na2SO4) and evaporated to dryness. Chromatography on silica gel (eluant: AcOEt/hexane 1:1) afforded the title compound (83% yield). ESI (+) MS: m/z 273 (MH+). 1H NMR: 1.32 (t, J=7.07, 3H), 2.70 (t, J=7.70, 2H), 2.90 (t, J=7.70, 2H), 4.18 (s, 3H), 4.25 (q, J=7.07, 2H), 6.35 (bs, 2H), 7.73 (s, 1H), 8.01 (s, 1H).
Reaction SMILES: [C:1]1(B(O)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:11]1[CH:16]=[CH:15][N:14]=[C:13]([NH:17][C:18]2[CH:19]=[CH:20][C:21]([F:37])=[C:22]([C@:24]3([CH2:35][F:36])[CH2:29][C@@H:28]([C:30]([F:33])([F:32])[F:31])[O:27][C:26]([NH2:34])=[N:25]3)[CH:23]=2)[CH:12]=1>>[F:37][C:21]1[CH:20]=[CH:19][C:18]([NH:17][C:13]2[CH:12]=[C:11]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH:16]=[CH:15][N:14]=2)=[CH:23][C:22]=1[C@:24]1([CH2:35][F:36])[CH2:29][C@@H:28]([C:30]([F:33])([F:32])[F:31])[O:27][C:26]([NH2:34])=[N:25]1
Reactant: NC1=N[C@](CF)(c2cc(Nc3cc(Cl)ccn3)ccc2F)C[C@@H](C(F)(F)F)O1
Reactant: OB(O)c1ccccc1
Product: NC1=N[C@](CF)(c2cc(Nc3cc(-c4ccccc4)ccn3)ccc2F)C[C@@H](C(F)(F)F)O1

Procedure:
The title compound was synthesized by procedures and steps analogous to those described in Method O, Example 111, but using phenylboronic acid and (4S,6S)-4-(5-((4-chloropyridin-2-yl)amino)-2-fluorophenyl)-4-(fluoromethyl)-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-amine (Example 16) as coupling partners. MS m/z=463 [M+H]+. Calculated for C23H19F5N4O: 462.4.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[Al+3].[Cl-].[Cl-].[Cl-].Cl.C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl.O>[CH3:4][CH:5]1[CH2:10][C:3]2[C:4](=[C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:10]3=[CH:1][CH:2]=2)[CH2:6]1
Reactant: c1ccc2ccccc2c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Al+3]
Solvent: O
Solvent: ClCCl
Product: CC1Cc2ccc3ccccc3c2C1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A solution of 20 g (166 mmol) of naphthalene in 50 ml of methylene chloride was added dropwise to a mixture of 22.13 g of AlCl3 (166 mmol) and 22.41 g of 3-bromoisobutene (166 mmol) in 250 ml of the same solvent. During the addition, the temperature was kept at -10° C. After the addition had ended, the mixture was stirred at room temperature for 12 h and then hydrolyzed with 100 ml of water and acidified with 50 ml of conc. HCl. After the separation, the aqueous phase was extracted with methylene chloride and the combined organic phases were extracted with water. The methylene chloride was removed from the solution under reduced pressure and the residue was dissolved in toluene. The solids were separated off and the solution obtained was neutralized using K2CO3 and dried with Na2SO4. To remove byproducts, the filtrate obtained was chromatographed over silica gel 60.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([OH:11])=[O:10])[CH:5]=[N:6][CH:7]=1.S(=O)(=O)(O)O.[CH3:17][CH2:18]O>>[CH2:17]([O:10][C:9](=[O:11])[CH2:8][C:4]1[CH:5]=[N:6][CH:7]=[C:2]([Br:1])[CH:3]=1)[CH3:18]
Reactant: O=C(O)Cc1cncc(Br)c1
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)Cc1cncc(Br)c1

Procedure:
5-Bromo-3-pyridylacetic acid was treated with 5% concentrated sulfuric acid in EtOH at reflux overnight to give (5-bromo-pyridin-3-yl)-acetic acid ethyl ester.
Reaction SMILES: C[O:2][C:3](=[O:43])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:42])[C:12]2[CH:17]=[C:16]([Cl:18])[C:15]([O:19][C:20]3[CH:25]=[CH:24][N:23]=[CH:22][C:21]=3[C:26]([N:28]3[C:37]4[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=4)[N:31]([CH:38]4[CH2:40][CH2:39]4)[CH2:30][CH2:29]3)=[O:27])=[CH:14][C:13]=2[Cl:41])=[CH:6][CH:5]=1.O.O.[OH-].[Li+]>O1CCOCC1>[Cl:41][C:13]1[CH:14]=[C:15]([O:19][C:20]2[CH:25]=[CH:24][N:23]=[CH:22][C:21]=2[C:26]([N:28]2[C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[N:31]([CH:38]3[CH2:39][CH2:40]3)[CH2:30][CH2:29]2)=[O:27])[C:16]([Cl:18])=[CH:17][C:12]=1[C:11]([NH:10][C:7]1[CH:8]=[CH:9][C:4]([C:3]([OH:43])=[O:2])=[CH:5][CH:6]=1)=[O:42]
Reactant: COC(=O)c1ccc(NC(=O)c2cc(Cl)c(Oc3ccncc3C(=O)N3CCN(C4CC4)c4ccccc43)cc2Cl)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)c1ccc(NC(=O)c2cc(Cl)c(Oc3ccncc3C(=O)N3CCN(C4CC4)c4ccccc43)cc2Cl)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 51 %

Procedure:
To a solution of 0.040 g (0.065 mmol) 4-{2,5-dichloro-4-[3-(4-cyclopropyl-3,4-dihydro-2H-quinoxaline-1-carbonyl)-pyridin-4-yloxy]-benzoylamino}-benzoic acid methyl ester (Example 43) in 0.5 mL dioxane were added 0.5 mL water and 0.003 g (0.071 mmol) lithiumhydroxide monohydrate. The resulting suspension was stirred at room temperature for 2 h, followed by heating to 80° C. for 1 hour. The organic solvent was removed by evaporation and the pH of the resulting solution was adjusted to 1 to 2 using 1M aqueous hydrochloric acid. The suspension was stirred for 2 hours at room temperature, filtered and washed with water to yield the desired compound as a light brown solid (0.020 g, 51%). MS (ESI): m/z=603.12 [M+H]+.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][C@@H:11]([C:13]([O:15]CC2C=CC=CC=2)=[O:14])[N:10]([C:23](=[O:41])[C@@H:24]([NH:26][C@H:27]([C:36]([O:38][CH2:39][CH3:40])=[O:37])[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[CH3:25])[C:9]1=[O:42])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>[Pd]>[CH2:1]([N:8]1[CH2:12][C@@H:11]([C:13]([OH:15])=[O:14])[N:10]([C:23](=[O:41])[C@@H:24]([NH:26][C@H:27]([C:36]([O:38][CH2:39][CH3:40])=[O:37])[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[CH3:25])[C:9]1=[O:42])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCCCCCC[C@H](N[C@@H](C)C(=O)N1C(=O)N(Cc2ccccc2)C[C@H]1C(=O)OCc1ccccc1)C(=O)OCC
Agent: [Pd]
Product: CCCCCCCC[C@H](N[C@@H](C)C(=O)N1C(=O)N(Cc2ccccc2)C[C@H]1C(=O)O)C(=O)OCC
Yield: 89.9 %

Procedure:
2.7 g of benzyl (4S)-1-benzyl-3-{(2S)-2-[N-((1S)-1-ethoxycarbonyl-n-nonyl)amino]propionyl}-2-oxo-imidazolidine-4-carboxylate and 100 mg of palladium black are treated in the same manner as described in Example 1-(2), whereby 2.05 g of (4S)-1-benzyl-3-{(2S)-2-[N-((1S)-1-ethoxycarbonyl-n-nonyl)amino]propionyl}-2-oxo-imidazolidine-4-carboxylic acid are obtained as colorless crystals. Yield: 89.9%
Reaction SMILES: [CH2:1]([C:11]1[N:15]([CH2:16][C:17]([O:19]CC)=[O:18])[N:14]=[N:13][N:12]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].C(C1N=NN(C(C2C=CC=CC=2)C(OCC)=O)N=1)CCCCCCCCC>>[CH2:1]([C:11]1[N:15]([CH2:16][C:17]([OH:19])=[O:18])[N:14]=[N:13][N:12]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCCCCCc1nnnn1CC(=O)OCC
Agent: CCCCCCCCCCc1nnn(C(C(=O)OCC)c2ccccc2)n1
Product: CCCCCCCCCCc1nnnn1CC(=O)O

Procedure:
When in the general procedure of Example 79 an appropriate amount of ethyl 5-decyl-1H-tetrazole-1-acetate was substituted for ethyl (±)-5-decyl-α-phenyl-2H-tetrazole-2-acetate, the title compound was obtained, mp 104°-106° C.
Reaction SMILES: [O:1]=[S:2]1(=[O:25])[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[N:20]4[N:21]=[C:22]([NH2:24])[N:23]=[C:19]4[CH:18]=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:4][CH2:3]1.Br[C:27]1[CH:32]=[CH:31][C:30]([N:33]2[CH2:38][CH2:37][N:36]([CH3:39])[CH2:35][CH2:34]2)=[CH:29][CH:28]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)CCCCC1>>[O:25]=[S:2]1(=[O:1])[CH2:3][CH2:4][N:5]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[N:20]4[N:21]=[C:22]([NH2:24])[N:23]=[C:19]4[CH:18]=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:6][CH2:7]1.[O:25]=[S:2]1(=[O:1])[CH2:3][CH2:4][N:5]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[N:20]4[N:21]=[C:22]([NH:24][C:27]5[CH:28]=[CH:29][C:30]([N:33]6[CH2:38][CH2:37][N:36]([CH3:39])[CH2:35][CH2:34]6)=[CH:31][CH:32]=5)[N:23]=[C:19]4[CH:18]=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:6][CH2:7]1
Reactant: CN1CCN(c2ccc(Br)cc2)CC1
Agent: Nc1nc2cccc(-c3ccc(CN4CCS(=O)(=O)CC4)cc3)n2n1
Agent: c1ccc(P(C2CCCCC2)C2CCCCC2)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c1
Product: CN1CCN(c2ccc(Nc3nc4cccc(-c5ccc(CN6CCS(=O)(=O)CC6)cc5)n4n3)cc2)CC1

Procedure:
A suspension of (4-bromomethylphenyl)boronic acid (2.00 g, 9.31 mmol), thiomorpholine 1,1-dioxide (1.50 g, 11.1 mmol) and potassium carbonate (2.60 g, 18.8 mmol) in acetone (25 mL, 340 mmol) was heated at 40° C. for 18 hours then cooled to room temperature. The volatiles were evaporated and the residue was suspended in saturated aqueous ammonium chloride (100 mL). The aqueous was decanted from the waxy solid and the solid was dissolved in methanol (50 mL), filtered to remove insoluble salts and evaporated. 4-[(4-boronophenyl)methyl]-thiomorpholine 1,1-dioxide was isolated as a tan foam. The crude material was used without further purification. 70b) 5-{4-[(1,1-dioxidothiomorpholin-4-yl)methyl]phenyl}[1,2,4]triazolo[1,5-a]pyridin-2-amine was prepared from 5-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine and 4-[(4-boronophenyl)methyl]-thiomorpholine 1,1-dioxide in a manner analogous to Step 2c. The reaction product was taken on to the next step. 70c) 5-{4-[(1,1-dioxidothiomorpholin-4-yl)methyl]phenyl}-N-[4-(4-methylpiperazin-1-yl)phenyl][1,2,4]triazolo[1,5-a]pyridin-2-amine was prepared from 5-{4-[(1,1-dioxidothiomorpholin-4-yl)methyl]phenyl}[1,2,4]triazolo[1,5-a]pyridin-2-amine (75.0 mg, 0.210 mmol) and 1-(4-bromo-phenyl)-4-methyl-piperazine (65.0 mg, 0.255 mmol) with 2,2′-bis-dicyclohexylphosphanyl-biphenyl (22.0 mg, 0.0402 mmol) as the ligand in a manner analogous to Step 2d. The title compound was isolated as a yellow foam (0.045 g, 40%). 1H NMR (400 MHz, CDCl3, δ, ppm): 8.00 (d, J=7.0 Hz, 2H), 7.52-7.43 (m, 6H), 6.98-6.91 (m, 3H), 6.67 (s, 1H), 3.76 (s, 2H), 3.18-3.03 (m, 12H), 2.62-2.56 (m, 4H), 2.36 (s, 3H). MS=532 (MH)+.
Reaction SMILES: [CH3:1][C@H:2]1[C@@H:6]([C:7]2[N:11]3[C:12]4[CH:18]=[CH:17][N:16](S(C5C=CC(C)=CC=5)(=O)=O)[C:13]=4[N:14]=[CH:15][C:10]3=[N:9][N:8]=2)[CH2:5][C@@H:4]([NH:29]C(=O)C)[CH2:3]1.[OH-].[Na+].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.C[C@H]1[C@@H](C2N3C4C=CN(S(C5C=CC(C)=CC=5)(=O)=O)C=4N=CC3=NN=2)C[C@@H](N)C1>[Pd].CO.CCOCC.O1CCOCC1>[CH3:1][C@H:2]1[C@@H:6]([C:7]2[N:11]3[C:12]4[CH:18]=[CH:17][NH:16][C:13]=4[N:14]=[CH:15][C:10]3=[N:9][N:8]=2)[CH2:5][C@@H:4]([NH2:29])[CH2:3]1
Reactant: CC(=O)N[C@H]1C[C@@H](C)[C@@H](c2nnc3cnc4c(ccn4S(=O)(=O)c4ccc(C)cc4)n23)C1
Agent: [Pd]
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cc1ccc(S(=O)(=O)n2ccc3c2ncc2nnc([C@H]4C[C@@H](N)C[C@H]4C)n23)cc1
Solvent: CCOCC
Solvent: CO
Solvent: C1COCCO1
Product: C[C@@H]1C[C@H](N)C[C@@H]1c1nnc2cnc3[nH]ccc3n12
Temperature: 100 °C
Yield: 5 %

Procedure:
To a mixture of N-((1S,3R,4S)-3-methyl-4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl)acetamide (1.52 g, 3.36 mmol, prepared using Y from Example #7, step H and Pd/C, G, AA [Table 2, Method 3, Rt=6.1 min, or =ND], Z with NaOH, A with Example #1 Step D, HATU, and TEA, and B with TEA) and 1,4-dioxane (25 mL) was added aqueous HCl (6 N, 25 mL, 150 mmol). The reaction was heated at about 100° C. for about 14 h and then was cooled to ambient temperature and concd under reduced pressure. To the resulting brown residue was added MeOH (30 mL) and the solution was concd under reduced pressure. To the resulting residue was added MeOH (5 mL) followed by slow addition of Et2O (20 mL). Initially a cloudy solution formed and then a dark oil/gum formed and the mixture was concd under reduced pressure. To the resulting brown residue was added MeOH (30 mL), (1S,3R,4S)-3-methyl-4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentan-amine (1.35 g, 2.50 mmol, UV purity 75%) from a separate reaction, and silica gel (7 g). The mixture was concd under reduced pressure and purified by silica gel chromatography eluting with a gradient of 0-100% (DCM/[2 M NH3 in MeOH] (9:1)) in DCM, the column was further flushed with MeOH then MeOH/aqueous NH4OH (9:1), to give (1S,3R,4S)-3-methyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentanamine [Preparation #19.1] (0.092 g, 5%) as a dark brown solid: LC/MS (Table 1, Method a) Rt=1.35 min; MS m/z: 257 (M+H)+ and 2.9 g of brown residue that was partitioned between DCM and saturated aqueous NaHCO3 (50 mL each). The layers were separated and the aqueous layer was extracted with additional DCM (2×50 mL). The combined organic layers were washed with brine, dried over anhydrous MgSO4, filtered, and concd under reduced pressure to give (1S,3R,4S)-3-methyl-4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentanamine [Preparation #19.2](1.94 g, 78%) as a taupe foam: LC/MS (Table 1, Method a) Rt=1.80 min; MS m/z: 411 (M+H)+.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:12]3[N:13]([N:17]=[C:18]([NH2:20])[N:19]=3)[CH:14]=[CH:15][CH:16]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].Br[C:22]1[CH:35]=[CH:34][C:25]([O:26][CH2:27][CH2:28][N:29]2[CH2:33][CH2:32][CH2:31][CH2:30]2)=[CH:24][CH:23]=1>>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:12]3[N:13]([N:17]=[C:18]([NH:20][C:22]4[CH:23]=[CH:24][C:25]([O:26][CH2:27][CH2:28][N:29]5[CH2:30][CH2:31][CH2:32][CH2:33]5)=[CH:34][CH:35]=4)[N:19]=3)[CH:14]=[CH:15][CH:16]=2)=[CH:7][CH:6]=1)(=[O:3])=[O:4]
Reactant: Brc1ccc(OCCN2CCCC2)cc1
Reactant: CS(=O)(=O)c1ccc(-c2cccn3nc(N)nc23)cc1
Product: CS(=O)(=O)c1ccc(-c2cccn3nc(Nc4ccc(OCCN5CCCC5)cc4)nc23)cc1

Procedure:
[8-(4-Methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-amine was prepared from 8-(4-methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (100.0 mg, 0.3468 mmol) and 1-[2-(4-bromo-phenoxy)-ethyl]-pyrrolidine (0.10 mL, 0.48 mmol) in a manner analogous to Step 2d. The title compound was isolated as a yellow solid (0.025 g, 15%). MP=170-173° C. 1H NMR (400 MHz, CDCl3, δ, ppm): 8.49-8.45 (m, 1H), 8.25-8.20 (m, 2H), 8.10-8.06 (m, 2H), 7.65-7.61 (m, 1H), 7.51-7.46 (m, 2H), 7.00 (t, J=6.9 Hz, 1H), 6.97-6.93 (m, 2H), 6.70 (s, 1H), 4.11 (t, J=6.1 Hz, 2H), 3.10 (s, 3H), 2.91 (t, J=6.0 Hz, 2H), 2.67-2.60 (m, 4H), 1.86-1.87 (m, 4H). MS=478 (MH)+.
Reaction SMILES: Br[CH2:2][CH2:3][Cl:4].[NH:5]1[C:13]2[C:8](=[C:9]([N:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[CH:10]=[CH:11][CH:12]=2)[CH:7]=[CH:6]1.CCN(C(C)C)C(C)C>O>[Cl:4][CH2:3][CH2:2][N:17]1[CH2:18][CH2:19][N:14]([C:9]2[CH:10]=[CH:11][CH:12]=[C:13]3[C:8]=2[CH:7]=[CH:6][NH:5]3)[CH2:15][CH2:16]1
Reactant: ClCCBr
Reactant: c1cc(N2CCNCC2)c2cc[nH]c2c1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: ClCCN1CCN(c2cccc3[nH]ccc23)CC1
Temperature: 25 °C
Yield: 36 %

Procedure:
8.3 mL of 1-bromo-2-chloroethane, 1.2 g of 1-(4-indolyl)piperazine and 1.2 mL of DIPEA was stirred at 60° C. for 3 h under nitrogen atmosphere. To the solution, cooled at r.t., was added 30 mL of H2O. The mixture was then extracted with CH2Cl2-MeOH 7:3 (3×15 mL). The organic layer, dried on an. Na2SO4, was evaporated to dryness. The crude was purified by flash chromatography (CH2Cl2-MeOH 98:2) to give 0.57 g (36%) of the title compound.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][C:12]=1[N:13]([CH2:18][CH3:19])[CH2:14][CH:15]([CH3:17])[CH3:16])[CH:8]=[O:9])([CH3:4])([CH3:3])[CH3:2].[C:20]([Mg]Br)#[CH:21]>>[C:1]([C:5]1[CH:6]=[C:7]([CH:8]([OH:9])[C:20]#[CH:21])[CH:10]=[CH:11][C:12]=1[N:13]([CH2:18][CH3:19])[CH2:14][CH:15]([CH3:16])[CH3:17])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCN(CC(C)C)c1ccc(C=O)cc1C(C)(C)C
Reactant: C#C[Mg]Br
Product: C#CC(O)c1ccc(N(CC)CC(C)C)c(C(C)(C)C)c1

Procedure:
In a manner analogous to example 1 e, the process is carried out by a reaction of 800 mg (3 mmol) of 3-tert-butyl-4-(ethylisobutylamino)benzaldehyde with 8 ml (4 mmol) of a 0.5M solution of ethynylmagnesium bromide. 700 mg of 1-[3-tert-butyl-4-(ethylisobutyl-amino)phenyl]prop-2-yn-1-ol are obtained in the form of a colourless oil (yield=81%).
Reaction SMILES: [CH3:1][C@@:2]12[C@H:12]3[CH2:13][CH2:14][C@:15]4([CH3:21])[C@@H:19]([OH:20])[CH2:18][CH2:17][C@H:16]4[C@@H:11]3[CH2:10][CH2:9][C@H:8]1[CH2:7][C:5](=[O:6])[CH2:4][CH2:3]2.C(N(CC)CC)C.[Cl:29][CH2:30][C:31](Cl)=[O:32]>C(Cl)Cl.ClCl>[Cl:29][CH2:30][C:31]([O:20][C@H:19]1[CH2:18][CH2:17][C@H:16]2[C@H:11]3[C@H:12]([CH2:13][CH2:14][C@:15]12[CH3:21])[C@:2]1([CH3:1])[C@H:8]([CH2:7][C:5](=[O:6])[CH2:4][CH2:3]1)[CH2:9][CH2:10]3)=[O:32]
Reactant: O=C(Cl)CCl
Reactant: C[C@]12CCC(=O)C[C@@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](O)CC[C@@H]12
Agent: ClCl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@]12CCC(=O)C[C@@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](OC(=O)CCl)CC[C@@H]12
Temperature: 0 °C
Reaction time: 4 h

Procedure:
Dihydrotestosterone (2.6 mmol) was dissolved in anhydrous methylene chloride (3 mL) and triethylamine (2.6 mmol) under argon. The solution was stirred at 0° C. for 30 minutes at which time chloroacetyl chloride (3.75 mmol) dissolved in anhydrous methylene chloride (2 mL) was added. The resulting mixture was stirred for an additional 30 min at 0° C. and at room temperature for 4 hr. The solution was diluted with CH2 Cl2 (30 mL) and was washed with aqueous 0.05N hydrochloric acid (2×30 mL) and water (2×30 mL). The organic layer was dried over sodium sulfate and evaporated under vacuum to give crude product as a white solid. The product was purified by silica gel column chromatography (Davisil grade 633, 200-425 mesh, 60 Å) using CHCl3 as eluent. Yield, 0.38 g (41%); mp 135°-136° C. (lit. Ferguson et al., J. Chem. Soc., Perkin II, 3, 267-272 (1978)), 138° C.); 1H NMR δ0.78 (s, 3 H, CH3 -19), 0.98 (s, 3 H, CH3 -18), 0.78-2.49 (m, 22 H), 4.37 (d, 2 H, CH2Cl), 4.62 (t, 1 H, H-17); MS (EI) calcd m/z for C21H31O335Cl 366.1961, found, 366.1932; calcd. m/z for C21H31O337Cl 368.1932, found, 368.1911.
Reaction SMILES: [O:1]1[CH2:3][C@H:2]1[C:4]([OH:6])=O.CCN(CC)CC.Cl.[CH3:15][O:16][NH:17][CH3:18].CCN=C=NCCCN(C)C>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:15][O:16][N:17]([CH3:18])[C:4]([C@@H:2]1[CH2:3][O:1]1)=[O:6]
Reactant: O=C(O)[C@@H]1CO1
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CON(C)C(=O)[C@@H]1CO1
Temperature: 0 °C
Reaction time: 4 h
Yield: 0.1 %

Procedure:
To a solution of the crude acid 2 (˜72.0 g, ˜0.810 mol, 1.0 equiv.) in CH2Cl2 (1600 mL) was added NEt3 (120 mL, 0.859 mol, 1.06 equiv.), DMAP (92 mg, 0.00082 mol, 0.001 equiv.) and O,N-Dimethyl-hydroxylamine hydrochloride (95.74 g, 0.982 mol, 1.21 equiv.) at 0° C. The resultant mixture was stirred for 10 minutes at −5° C. and EDCI (198.5 g, 1.035 mol, 1.27 equiv.) was added. The reaction mixture was stirred for 4 hours at 0° C. and diluted with hexanes (800 mL). The mixture was filtered through a pad of silica gel (2 cm thick of silica gel in a 3 L filtration funnel) and washed with Et2O (10×300 mL). The solvent was removed under reduced pressure to afford the crude amide 3 (92.2 g, 0.709 mmol, 87.5% for two steps) as slight-yellow oil. This crude product was dissolved in 1,2-dichloroethane (200 mL) and dried over molecular sieves at −20° C. for 2 hours before used in the next step).