Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19](Cl)=[N:18][CH:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N:21]1[CH:26]=[CH:25][C:24]([CH2:27][OH:28])=[CH:23][CH:22]=1.C(C(CCC)[O-])(C)(C)C.[K+].C(O)(C)(C)C>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19]([O:28][CH2:27][C:24]3[CH:25]=[CH:26][N:21]=[CH:22][CH:23]=3)=[N:18][CH:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: OCc1ccncc1
Reactant: CC(C)(C)OC(=O)N1CCN(c2nccnc2Cl)CC1
Agent: CCCC([O-])C(C)(C)C
Agent: [K+]
Solvent: CC(C)(C)O
Product: CC(C)(C)OC(=O)N1CCN(c2nccnc2OCc2ccncc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.2 %

Procedure:
To a round bottom flask equipped with a magnetic stir bar was added 3′-chloro-2,3,5,6-tetrahydro-[1,2′]bipyrazinyl-4-carboxylic acid tert-butyl ester (7.89 g, 26.4 mmol, 1.0 eq.), pyridin-4-yl-methanol (3.74 g, 34.3 mmol, 1.3 eq) and 1M potassium tert-butyl butoxide in t-butanol (72 ml, 72 mmol, 2.7 eq). The reaction was then stirred overnight at room temperature after which the solvent was removed. The solid was then diluted with EtOAc, washed 3× with water, 2×NaHCO3, 2× with brine, and dried over NaSO4. Purification was then accomplished on column chromatography with the eluent being 1:2 ethyl acetate/hexane and 2% TEA. Removal of the solvent resulted in the title compound as a cream solid (6.98 g, 33% yield).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].[C:10]([Si:12]([CH3:15])([CH3:14])[CH3:13])#[CH:11]>C(N(CC)CC)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:13][Si:12]([C:10]#[C:11][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6])([CH3:15])[CH3:14]
Reactant: O=Cc1cccc(Br)c1
Reactant: C#C[Si](C)(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: C[Si](C)(C)C#Cc1cccc(C=O)c1
Temperature: 25 °C
Yield: 77.9 %

Procedure:
To a solution of 3-bromobenzaldehyde (10.00 g, 54.08 mmol) and triphenylphosphine (0.500 g, 1.91 mmol) in anhydrous triethylamine (100 mL) under argon were added ethynyltrimethylsilane (6.00 g, 61.09 mmol) and palladium (II) acetate (0.100 g, 0.445 mmol). The final mixture was heated to reflux for 2 hours, and was then cooled to room temperature and filtered. The filtrate was concentrated under vacuum to a thick oil, which was purified by column chromatography (dichloromethane/petroleum ether 1:4) to give 8.52 g (78.0% yield) of 3-(trimethylsilylethynyl)benzaldehyde [1H-NMR (CDCl3) δ ppm: 0.26 (s, 9H, SiMe3), 7.47 (t, 1H, ArH, J=7.5 Hz), 7.70 (d, 1H, ArH, J=7.5 Hz), 7.82 (d, 1H, ArH, J=7.5 Hz), 7.96 (s, 1H ArH), 9.98 (s, 1H, CHO)]. This compound (5.00 g, 24.74 mmol) was treated with K2CO3 (0.500 g) in methanol (50 mL) at 25° C. for 2 hours under argon. The solvent was removed under vacuum, and the residue was dissolved in dichloromethane (100 mL). This solution was washed once with a saturated aqueous NaHCO3 solution, and once with water, before being dried over anhydrous Na2SO4 and the solvent evaporated under vacuum. The yellow residue was purified by column chromatography using dichloromethane/petroleum ether 1:4 for elution, and recrystallized from cyclohexane to give 2.80 g (87.1% yield) of the title compound; MS (EI) m/e 130.0; (M+). 1H-NMR (CDCl3) δ ppm: 3.20 (s, 1H, CH), 7.51 (t, 1H, ArH, J=7.8 Hz), 7.74 (d, 1H, ArH, J=7.8 Hz), 7.87 (d, 1H, ArH, J=7.8 Hz), 7.99 (s, 1H, ArH), 10.02 (s, 1H, CHO).
Reaction SMILES: Br[C:2]1[CH:14]=[CH:13][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][O:10][CH2:9][CH2:8]2)=[CH:4][CH:3]=1.[CH3:15][C:16]1([CH3:25])[C:20]([CH3:22])([CH3:21])[O:19][B:18]([CH:23]=[CH2:24])[O:17]1.CCN(CC)CC>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.C1(C)C=CC=CC=1>[CH3:21][C:20]1([CH3:22])[C:16]([CH3:25])([CH3:15])[O:17][B:18](/[CH:23]=[CH:24]/[C:2]2[CH:14]=[CH:13][C:5]([CH2:6][N:7]3[CH2:12][CH2:11][O:10][CH2:9][CH2:8]3)=[CH:4][CH:3]=2)[O:19]1
Reactant: C=CB1OC(C)(C)C(C)(C)O1
Reactant: Brc1ccc(CN2CCOCC2)cc1
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
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC1(C)OB(/C=C/c2ccc(CN3CCOCC3)cc2)OC1(C)C
Temperature: 80 °C

Procedure:
To a mixture of 4-(4-bromobenzyl)morpholine (4.18 g, 16.3 mmol) and 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (3 mL, 17.7 mmol, 1.1 eq.) and toluene (30 mL) in a 20 mL microwave vial was added Et3N (4.56 mL, 32.4 mmol, 2 eq.), followed by Pd(PtBu3)2 (83 mg, 0.16 mmol, 1 mol %). The resulting mixture was purged with argon, then capped and heated at 80° C. oil bath for 1 h. After cooling to rt, the reaction was diluted with half saturated NaHCO3 (40 mL) and the product was extracted with EtOAc (2×60 mL). The organic layer was dried (Na2SO4) and the solvent was evaporated in vacuo. Trituration with hexane and sonication provided a solid that was collected by suction filtration (white solid, 2.55 g). After evaporation of the solvent in vacuo, the residue solidified and a second crop of crystals was obtained by suction filtration from a small amount of hexane (pale yellow crystals, 0.22 g). Evaporation of the mother liquor provided a yellow liquid which was purified using Biotage Isolera (20-80% EtOAc in hexane, SNAP-50 g column) to give a third portion of the product (yellow solid, 1.58 g; total yield 4.35 g, 71%). 1H NMR (400 MHz, CDCl3) δ 7.45 (d, J=8.0 Hz, 2H), 7.40 (d, J=18.4 Hz, 1H), 7.31 (d, J=8.0 Hz, 2H), 6.16 (d, J=18.0 Hz, 1H), 3.72 (t, J=4.4 Hz, 4H), 3.50 (s, 2H), 2.47-2.42 (m, 4H), 1.32 (s, 12H); MS ESI 330.1 [M+H]+, calcd for [C19H28BNO3+H]+ 330.2.
Reaction SMILES: [BH4-].[Na+].[F:3][C:4]([F:44])([F:43])[C:5]1[CH:6]=[C:7]([C:15]([CH3:42])([CH3:41])[C:16]([N:18]([C:20]2[CH:21]=[N:22][C:23]([N:34]3[CH2:39][CH2:38][N:37]([CH3:40])[CH2:36][CH2:35]3)=[CH:24][C:25]=2[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[CH:32]=[O:33])[CH3:19])=[O:17])[CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=1>CO.[Cl-].[Na+].O>[F:44][C:4]([F:3])([F:43])[C:5]1[CH:6]=[C:7]([C:15]([CH3:42])([CH3:41])[C:16]([N:18]([C:20]2[CH:21]=[N:22][C:23]([N:34]3[CH2:35][CH2:36][N:37]([CH3:40])[CH2:38][CH2:39]3)=[CH:24][C:25]=2[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[CH2:32][OH:33])[CH3:19])=[O:17])[CH:8]=[C:9]([C:11]([F:12])([F:13])[F:14])[CH:10]=1
Reactant: CN1CCN(c2cc(-c3ccccc3C=O)c(N(C)C(=O)C(C)(C)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)cn2)CC1
Agent: [BH4-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CN1CCN(c2cc(-c3ccccc3CO)c(N(C)C(=O)C(C)(C)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)cn2)CC1
Reaction time: 0.5 h
Yield: 68.2 %

Procedure:
To a mixture of 15 mg (0.41 mmol) sodium borohydride in 2 ml methanol were added at 0° C. 200 mg (0.338 mmol) 2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-formyl-phenyl)-6-(4-methyl-piperazin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide. After stirring at 0° C. for 1 h 1 ml brine was added at 0° C. The mixture was stirred for 30 min. Methanol was distilled off and the residue was diluted with 20 ml ethyl acetate and washed with 20 ml brine. The organic layer was dried over sodium sulfate, concentrated and purified by flash chromatography to give 137 mg (68%) of the title compound as a light brown solid.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[CH2:9][CH2:8][CH:7]=[C:6]([C:11]([O-:13])=[O:12])[C:5]=2[CH:4]=[N:3]1.[BH4-].[Na+].[CH3:16]O>Cl[Ni]Cl>[CH3:1][N:2]1[C:10]2[CH2:9][CH2:8][CH2:7][CH:6]([C:11]([O:13][CH3:16])=[O:12])[C:5]=2[CH:4]=[N:3]1
Reactant: CO
Reactant: Cn1ncc2c1CCC=C2C(=O)[O-]
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Product: COC(=O)C1CCCc2c1cnn2C
Temperature: 25 °C
Reaction time: 1 h
Yield: 94 %

Procedure:
To a solution of 1-methyl-6,7-dihydro-1H-indazole-4-carboxylate (7.5 g, 38.7 mmol) and NiCl2 (4.9 g, 38.7 mmol) in MeOH (250 mL) was added NaBH4 (14 g, 387 mmol) in portions at 0° C. The resulting mixture was stirred at room temperature for further 1 hour. The solvent was removed and the residue was purified by column chromatography on silica gel (PE/THF=5/1 v/v %) to afford methyl 1-methyl-4,5,6,7-tetrahydro-1H-indazole-4-carboxylate (7 g, 94%).
Reaction SMILES: [H-].[Na+].[OH:3][CH2:4][C@@H:5]1[CH2:10][CH2:9][CH2:8][C@H:7]([C:11]([O:13]C)=[O:12])[CH2:6]1.Cl[C:16]1[N:21]=[C:20]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:19]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[CH:18][N:17]=1>CN(C)C=O>[C:22]1([C:20]2[C:19]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[CH:18][N:17]=[C:16]([O:3][CH2:4][C@@H:5]3[CH2:10][CH2:9][CH2:8][C@H:7]([C:11]([OH:13])=[O:12])[CH2:6]3)[N:21]=2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: COC(=O)[C@H]1CCC[C@@H](CO)C1
Reactant: Clc1ncc(-c2ccccc2)c(-c2ccccc2)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(O)[C@H]1CCC[C@@H](COc2ncc(-c3ccccc3)c(-c3ccccc3)n2)C1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 15.1 %

Procedure:
94 mg (2.34 mmol) of sodium hydride (suspension in oil) were added to a solution of 178 mg (1.03 mmol) of methyl (1S,3R)-3-hydroxymethylcyclohexanecarboxylate in 5 ml of dimethylformamide at 0° C. After 30 minutes, a solution of 250 mg (0.94 mmol) of 2-chloro-4,5-diphenylpyrimidine in 2 ml of dimethylformamide was added. The reaction mixture was allowed to reach room temperature and was then heated at 60° C. for 2 hours. The solvent was concentrated under high vacuum and the residue was mixed with water and dichloromethane. After acidification with 1 N HCl, the aqueous phase was extracted with dichloromethane, dried and concentrated. The crude mixture was purified on silica gel with heptane/ethyl acetate (gradient 0% to 25% in 40 minutes, then isocratic for 20 minutes). 55 mg (15%) of the desired product were obtained.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[CH:4]([C:9]1([C:15]#[N:16])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)C(OC)=O.[Cl-].[Li+].O.[CH3:21]S(C)=O>>[CH2:1]([O:2][C:3](=[O:17])[CH2:4][C:9]1([C:15]#[N:16])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)[CH3:21]
Reactant: COC(=O)C(C(=O)OC)C1(C#N)CCCCC1
Reactant: CS(C)=O
Agent: [Cl-]
Agent: [Li+]
Solvent: O
Product: CCOC(=O)CC1(C#N)CCCCC1
Yield: 74 %

Procedure:
26.9 g (100 mmol) of (1-cyanocyclohexyl)malonic acid dimethyl ester, 4.3 g (100 mmol) or lithium chloride and 3.6 g (200 mmol) of water were heated in 300 ml of dimethyl sulfoxide for 22 hours to 150° C. Then it was cooled, mixed with 700 ml of water and extracted with 1000 ml of pentane. 14.4 g of (1-cyanocyclohexyl)acetic acid ethyl ester was obtained by distillation of the organic phase, corresponding to a yield of 74 percent (relative to the (1-cyanocyclohexyl)malonic acid dimethyl ester used). Data for the product was:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4](/[C:8](/[CH2:38][CH3:39])=[C:9](\[C:25]2[CH:30]=[CH:29][C:28](/[CH:31]=[CH:32]/[C:33]([O:35]CC)=[O:34])=[CH:27][CH:26]=2)/[C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[N:15](C2CCCCO2)[N:14]=[CH:13]3)[CH:5]=[CH:6][CH:7]=1.[CH3:40][C:41]1[N:46]=[CH:45][C:44](B(O)O)=[CH:43][CH:42]=1.BrC1C=CC(OC2C=CC=CC=2)=CC=1Cl>>[NH:15]1[C:16]2[C:12](=[CH:11][C:10](/[C:9](/[C:25]3[CH:26]=[CH:27][C:28](/[CH:31]=[CH:32]/[C:33]([OH:35])=[O:34])=[CH:29][CH:30]=3)=[C:8](/[C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([O:1][C:44]4[CH:45]=[N:46][C:41]([CH3:40])=[CH:42][CH:43]=4)[CH:3]=3)\[CH2:38][CH3:39])=[CH:18][CH:17]=2)[CH:13]=[N:14]1
Reactant: Cc1ccc(B(O)O)cn1
Reactant: CCOC(=O)/C=C/c1ccc(/C(=C(/CC)c2cccc(O)c2)c2ccc3c(cnn3C3CCCCO3)c2)cc1
Agent: Clc1cc(Oc2ccccc2)ccc1Br
Product: CC/C(=C(/c1ccc(/C=C/C(=O)O)cc1)c1ccc2[nH]ncc2c1)c1cccc(Oc2ccc(C)nc2)c1

Procedure:
The title compound was prepared from (E)-ethyl 3-(4-((E)-2-(3-hydroxyphenyl)-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)but-1-en-1-yl)phenyl)acrylate (Compound 346, Step 1) and (6-methylpyridin-3-yl)boronic acid following the procedure outlined for Intermediate 65 and then General Procedures F and G. LCMS: 502 (M+H)+.
Reaction SMILES: C[O-].[Na+].[NH:4]([CH2:11][CH2:12][C:13]#[N:14])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.O[CH:16]([C:22]1[CH:23]=[C:24]([NH:34][CH3:35])[C:25]([CH3:33])=[C:26]([CH:32]=1)[N:27]([CH3:31])[C:28](=[O:30])[CH3:29])CS(C)(=O)=O.CS(C)=O>O>[NH:4]([CH:11]=[C:12]([C:13]#[N:14])[CH2:16][C:22]1[CH:23]=[C:24]([NH:34][CH3:35])[C:25]([CH3:33])=[C:26]([CH:32]=1)[N:27]([CH3:31])[C:28](=[O:30])[CH3:29])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: N#CCCNc1ccccc1
Reactant: CNc1cc(C(O)CS(C)(=O)=O)cc(N(C)C(C)=O)c1C
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CNc1cc(CC(C#N)=CNc2ccccc2)cc(N(C)C(C)=O)c1C

Procedure:
A mixture of 27 g. of sodium methylate, 41 g. of β-anilinopropionitrile and 79.5 g. of 5'-[1-hydroxy-2-(methylsulfonyl)ethyl]-N,2'-dimethyl-3'-methylaminoacetanilide in 350 ml. of absolute dimethylsulfoxide was stirred for 1 hour at 50°C., then diluted with 2 liters of water and extracted with 6 liters of ethyl acetate. The ethyl acetate extract was washed with 1 liter of water, dried over magnesium sulfate and evaporated in vacuo. The residue was chromatographed on 2 kg. of silica gel with ethyl acetate/methylene chloride (1:1), there being obtained 5'-(3-anilino-2-cyanoallyl)-N,2'-dimethyl-3'-methylaminoacetanilide as an oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([NH2:12])=[CH:8][C:7]=1[CH3:13].[CH:15]([C:18]1[N:19]=[C:20]([C:27]2[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=2)[S:21][C:22]=1[CH:23]([CH3:26])[CH:24]=O)([CH3:17])[CH3:16].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:14])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][CH2:26][CH:23]([C:22]2[S:21][C:20]([C:27]3[CH:32]=[CH:31][C:30]([C:33]([F:34])([F:35])[F:36])=[CH:29][CH:28]=3)=[N:19][C:18]=2[CH:15]([CH3:17])[CH3:16])[CH3:24])=[CH:8][C:7]=1[CH3:13]
Reactant: COC(=O)CCc1ccc(N)cc1C
Reactant: CC(C)c1nc(-c2ccc(C(F)(F)F)cc2)sc1C(C)C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: COC(=O)CCc1ccc(NCC(C)c2sc(-c3ccc(C(F)(F)F)cc3)nc2C(C)C)cc1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 68 %

Procedure:
To a solution of 3-(4-Amino-2-methyl-phenyl)-propionic acid methyl ester (0.7.0 mmol) and 2-[4-Isopropyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-propionaldehyde (0.71 mmol) in anhydrous CH2Cl2 (5 mL) is added 4 Å molecular sieves followed by acetic acid (50 μL, 0.87 mmol). The mixture is stirred at RT for 2 h. Sodium triacetoxyborohydride (0.22 g, 1.04 mmol) is added, and the mixture is stirred at RT for 12 h. The reaction is quenched with saturated NaHCO3. The organics are separated and washed with saturated NaHCO3 and brine, and dried with MgSO4. The crude material is purified by flash chromatography to yield the title compound (0.21 g, 68%).
Reaction SMILES: [NH3:1].CO.[N:4]1[N:5]([C:9]2[N:14]=[C:13]([NH:15][C:16]3[CH:21]=[C:20]([Cl:22])[N:19]=[N:18][C:17]=3[C:23]([O:25]CC)=O)[CH:12]=[CH:11][CH:10]=2)[N:6]=[CH:7][CH:8]=1>>[N:6]1[N:5]([C:9]2[N:14]=[C:13]([NH:15][C:16]3[CH:21]=[C:20]([Cl:22])[N:19]=[N:18][C:17]=3[C:23]([NH2:1])=[O:25])[CH:12]=[CH:11][CH:10]=2)[N:4]=[CH:8][CH:7]=1
Reactant: CCOC(=O)c1nnc(Cl)cc1Nc1cccc(-n2nccn2)n1
Reactant: N
Solvent: CO
Product: NC(=O)c1nnc(Cl)cc1Nc1cccc(-n2nccn2)n1
Temperature: 35 °C
Reaction time: 16 h
Yield: 98 %

Procedure:
Ammonia in methanol (3.94 g, 5 mL, 35.0 mmol) was added to ethyl 4-(6-(2H-1,2,3-triazol-2-yl)pyridin-2-ylamino)-6-chloropyridazine-3-carboxylate (100 mg, 289 μmol) and stirred at 35° C. for 16 h. The mixture was concentrated in vacuo to give 4-(6-(2H-1,2,3-triazol-2-yl)pyridin-2-ylamino)-6-chloropyridazine-3-carboxamide (90 mg, 284 μmol, 98%) as an off-white solid. 1H NMR (400 MHz, DMSO-d) δ ppm 12.30 (s, 1H), 9.13 (s, 1H), 9.54 (s, 1H), 8.94 (s, 1H), 8.29 (s, 1H), 8.27 (s, 2H), 8.05 (t, J=8.1 Hz, 1H), 7.72 (d, J=7.9 Hz, 1H), 7.23 (d, J=8.1 Hz, 1H); MS (EI/CI) m/z: 316.9 [M+H].
Reaction SMILES: [CH3:1][N:2]([CH2:4]Cl)[CH3:3].CN(C)CCCCl.C([N:21]1[C:26](=[O:27])[C:25]2[CH:28]=[N:29][C:30]3[N:34]([C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)[N:33]=[CH:32][C:31]=3[C:24]=2[N:23]2[N:41]=[CH:42][N:43]=[C:22]12)(=O)C1C=CC=CC=1>>[CH3:1][N:2]([CH2:4][N:21]1[C:26](=[O:27])[C:25]2[CH:28]=[N:29][C:30]3[N:34]([C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)[N:33]=[CH:32][C:31]=3[C:24]=2[N:23]2[N:41]=[CH:42][N:43]=[C:22]12)[CH3:3]
Reactant: O=C(c1ccccc1)n1c(=O)c2cnc3c(cnn3-c3ccccc3)c2n2ncnc12
Reactant: CN(C)CCl
Agent: CN(C)CCCCl
Product: CN(C)Cn1c(=O)c2cnc3c(cnn3-c3ccccc3)c2n2ncnc12

Procedure:
By substituting dimethylaminomethyl chloride for the 3-(dimethylamino)propyl chloride in the procedure of Example 2 and utilizing 8-phenyl-4H-pyrazolo-[4',3':5,6]pyrido[3,4-e][1,2,4]triazolo[1,5-a]pyrimidin-5(8H)-one product of Example 18 instead of 8-ethyl-4H-pyrazolo[4',3':5,6]pyrido[3,4-e][1,2,4]triazolo[1,5-a]pyrimidin-5(8H)-one, 4-dimethylaminomethyl-8-phenyl-4H-pyrazolo[4',3':5,6]pyrido[3,4-e][1,2,4]triazolo[1,5-a]pyrimidin-5(8H) -one is obtained.
Reaction SMILES: [CH3:1][CH:2]([CH3:5])[C:3]#[CH:4].[Cl:6][C:7]1[CH:12]=[C:11]2[NH:13][C:14](=[O:40])[C:15]3([CH:20]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[CH:22]=4)[CH2:19][C:18](=[O:28])[NH:17][CH:16]3[C:29]3[CH:34]=[C:33](I)[CH:32]=[CH:31][C:30]=3[O:36][CH2:37][CH2:38][OH:39])[C:10]2=[CH:9][CH:8]=1.C(N(CC)CC)C>CN(C)C=O.[Cu]I.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>[Cl:6][C:7]1[CH:12]=[C:11]2[NH:13][C:14](=[O:40])[C:15]3([CH:20]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[CH:22]=4)[CH2:19][C:18](=[O:28])[NH:17][CH:16]3[C:29]3[CH:34]=[C:33]([C:4]#[C:3][CH:2]([CH3:5])[CH3:1])[CH:32]=[CH:31][C:30]=3[O:36][CH2:37][CH2:38][OH:39])[C:10]2=[CH:9][CH:8]=1
Reactant: C#CC(C)C
Reactant: O=C1CC(c2cccc(Cl)c2)C2(C(=O)Nc3cc(Cl)ccc32)C(c2cc(I)ccc2OCCO)N1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)C#Cc1ccc(OCCO)c(C2NC(=O)CC(c3cccc(Cl)c3)C23C(=O)Nc2cc(Cl)ccc23)c1

Procedure:
In a manner similar to the method described in example 209a, 3-methyl-1-butyne (0.22 g, 3.2 mmol) was used in place of 3,3-dimethyl-1-butyne to react with racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-[5-iodo-2-(2-hydroxy-ethoxy)-phenyl]spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (0.2 g, 0.32 mmol) prepared in Example 190c, CuI (3 mg), triethylamine (0.97 g, 9.6 mmol), and dichlorobis(triphenylphosphine)palladium (11.2 mg, 0.016 mmol) in anhydrous N,N-dimethylformamide to give racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-[5-(3-methyl-1-butynyl)-2-(2-hydroxy-ethoxy)-phenyl]spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a off white solid (Yield 50 mg, 28%)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[O:12][N:11]=[C:10]([CH2:13][N:14]3[CH2:20][CH2:19][CH2:18][CH2:17][N:16]4[C:21]([C:24]5[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=5)=[N:22][N:23]=[C:15]34)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:30]S(OC(C1N=C(C2C=CC=C(Cl)C=2)ON=1)C)(=O)=O.N1C=CC(C2N3CCCCNC3=NN=2)=CC=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[O:12][N:11]=[C:10]([CH:13]([N:14]3[CH2:20][CH2:19][CH2:18][CH2:17][N:16]4[C:21]([C:24]5[CH:25]=[CH:26][N:27]=[CH:28][CH:29]=5)=[N:22][N:23]=[C:15]34)[CH3:30])[N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Clc1cccc(-c2nc(CN3CCCCn4c(-c5ccncc5)nnc43)no2)c1
Reactant: CC(OS(C)(=O)=O)c1noc(-c2cccc(Cl)c2)n1
Agent: c1cc(-c2nnc3n2CCCCN3)ccn1
Product: CC(c1noc(-c2cccc(Cl)c2)n1)N1CCCCn2c(-c3ccncc3)nnc21
Yield: 4 %

Procedure:
The title compound was prepared analogous to 9-{[5-(3-chlorophenyl)-1,2,4-oxadiazol-3-yl]methyl}-3-pyridin-4-yl-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[4,3-a][1,3]diazepine from 1-[5-(3-chlorophenyl)-1,2,4-oxadiazol-3-yl]ethyl methanesulfonate (186 mg, 0.61 mmol), 3-pyridin-4-yl-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[4,3-a][1,3]diazepine (200 mg, 0.56 mmol) to give 8.1 mg (4%) of the title compound. 1H NMR: 1.83 (d, 3H), 1.86-1.95 (m, 4H), 3.16-3.27 (m, 1H), 3.43-3.53 (m, 1H), 3.75-3.87 (m, 1H), 3.95-4.07 (m, 1H), 5.54 (q, 1H), 7.41-7.52 (m, 3H), 7.52-7.58 (m, 1H), 8.01 (m, 1H), 8.12 (m, 1H), 8.73 (m, 2H).
Reaction SMILES: [C:1]([O:4][C@H:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C:7](=[CH:8][C@H:9]([OH:29])[C@@H:10]3[C@@H:19]2[CH2:18][CH2:17][C@@:15]2([CH3:16])[C@H:11]3[C@@H:12]3[CH2:28][C@@H:13]3[C:14]32[O:27][CH2:26][CH2:25][O:24]3)[CH2:6]1)(=[O:3])[CH3:2].C([O:34]O)(C)(C)C>C1(C)C=CC=CC=1.C(OCC)C>[C:1]([O:4][C@H:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C@@:7]3([O:34][C@@H:8]3[C@H:9]([OH:29])[C@@H:10]3[C@@H:19]2[CH2:18][CH2:17][C@@:15]2([CH3:16])[C@H:11]3[C@@H:12]3[CH2:28][C@@H:13]3[C:14]32[O:27][CH2:26][CH2:25][O:24]3)[CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@H]1CC[C@@]2(C)C(=C[C@H](O)[C@H]3[C@@H]4[C@@H]5C[C@@H]5C5(OCCO5)[C@@]4(C)CC[C@@H]32)C1
Reactant: CC(C)(C)OO
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: CC(=O)O[C@H]1CC[C@]2(C)[C@H]3CC[C@@]4(C)[C@@H]([C@@H]5C[C@@H]5C45OCCO5)[C@@H]3[C@@H](O)[C@H]3O[C@]32C1
Temperature: 80 °C

Procedure:
A solution of 23.3 g of 3β-acetoxy-17,17-ethylenedioxy-15β,16β-methylene-5-androsten-7β-ol in 350 ml of toluene was combined dropwise, after adding vanadium(IV) oxide acetylacetonate, within 35 minutes with 23.3 ml of 80% tert.-butyl hydroperoxide, dissolved in 115 ml of toluene. The reaction solution was maintained at 80° C. for another 30 minutes, then cooled, diluted with diethyl ether, washed with sodium bisulfite solution, sodium bicarbonate solution, and water, and dried and evaporated, thus obtaining 24.5 g of 3β-acetoxy-5,6β-epoxy-17,17-ethylenedioxy-15β,16β-methylene-5β-androstan-7β-ol, mp 162°-163° C. (diisopropyl ether).
Reaction SMILES: [CH2:1]([C:3]1[C:4]([O:15]C)=[N:5][C:6]([CH3:14])=[C:7]([C:9]2[S:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=1)[CH3:2].[I-].[K+].C(#N)C.Cl[Si](C)(C)C>O>[CH2:1]([C:3]1[C:4](=[O:15])[NH:5][C:6]([CH3:14])=[C:7]([C:9]2[S:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=1)[CH3:2]
Reactant: CCc1cc(-c2cccs2)c(C)nc1OC
Agent: C[Si](C)(C)Cl
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CCc1cc(-c2cccs2)c(C)[nH]c1=O
Temperature: 80 °C
Yield: 90 %

Procedure:
To a solution of 3-ethyl-2-methoxy-6-methyl-5-(thiophen-2-yl)pyridine (6.15 g, 26.36 mmol) of the above reaction, potassium iodide (8.75 g, 52.71 mmol) and acetonitrile (80 mL) is added chlorotrimethylsilane (6.69 mL, 52.71 mmol) and the resulting cloudy mixture is heated to 80° C. for 2 hr. The reaction is cooled, poured into water and the solids collected by filtration, washed with water, with ethyl acetate and dried giving 3-ethyl-6-methyl-5-(thiophen-2-yl)-1H-pyridin-2-one as a yellow solid (90% yield).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[Cl:15][C:16]1[CH:17]=[N:18][C:19]2[NH:20][C:21]3[CH:22]=[N:23][CH:24]=[C:25]([CH:47]=3)[CH2:26][CH2:27][C:28]3[CH:36]=[C:32]([NH:33][C:34]=1[N:35]=2)[CH:31]=[CH:30][C:29]=3[NH:37][C:38](=[O:46])[CH2:39][CH:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1.[C:48](Cl)(=[O:55])[C:49]1[CH:54]=[CH:53][CH:52]=[N:51][CH:50]=1>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Cl:15][C:16]1[CH:17]=[N:18][C:19]2[NH:20][C:21]3[CH:22]=[N:23][CH:24]=[C:25]([CH:47]=3)[CH2:26][CH2:27][C:28]3[CH:36]=[C:32]([NH:33][C:34]=1[N:35]=2)[CH:31]=[CH:30][C:29]=3[NH:37][C:38](=[O:46])[CH2:39][CH:40]1[CH2:45][CH2:44][N:43]([C:48]([C:49]2[CH:50]=[N:51][CH:52]=[CH:53][CH:54]=2)=[O:55])[CH2:42][CH2:41]1
Reactant: O=C(Cl)c1cccnc1
Reactant: O=C(CC1CCNCC1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Solvent: O=C(O)C(F)(F)F
Product: O=C(CC1CCN(C(=O)c2cccnc2)CC1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Yield: 37 %

Procedure:
The desired compound was prepared according to the procedure of Example A20 using of N-[6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-piperidin-4-ylacetamide bis(trifluoroacetate) and nicotinoyl chloride as starting materials in 37% yield. LCMS for C30H30ClN8O2 (M+H)+: m/z=569.2.