Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.CCN(CC)CC.C[Si]([O:34][C:35]1[CH:40]=[CH:39][CH:38]=[C:37](Br)[CH:36]=1)(C)C.[C:42]1([C:48]#[CH:49])[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[OH:34][C:35]1[CH:36]=[C:37]([C:49]#[C:48][C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[CH:38]=[CH:39][CH:40]=1
Reactant: C[Si](C)(C)Oc1cccc(Br)c1
Reactant: C#Cc1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: O
Product: Oc1cccc(C#Cc2ccccc2)c1
Reaction time: 0.25 h

Procedure:
Palladium acetate (0.20 g, 8.9×10-4 mol) and tri-o-tolylphosphine (0.40 g, 1.31×10-3 mol) as well as 60 ml of NEt3 were placed in a 3-necked 100 ml round-bottomed flask equipped with a reflux condensor, a thermometer and a nitrogen adaptor. The resultant yellow mixture was then heated to reflux under N2. At about 70° C., the mixture turned deep-red but still maintained its homogeneity. While the mixture was still refluxing, 3-bromophenyl trimethylsilyl ether (7.10 g, 28.95 mmol) was introduced via the reflux column, allowing it to flow slowly along the wall of the column, into the reaction mixture. After about 15 minutes, degased phenylacetylene (3.11 g, 30.45 mmol) was added to the reaction mixture in a similar manner. As soon as the reactants were in contact, sudden rise in temperature and concomitant precipitation of white solids occurred. The color of reaction mixture became lighter as the reaction progressed. After about 3 hours, the reaction mixture was dark brown and no further change in color was observed even after 17 hours at 80° C. The cooled reaction mixture was poured into about 300 ml of water and extracted with ethyl ether (100 ml, 3×50 ml). The dark ethereal extract was subjected to rotary evaporation to afford a dark oil. About 20 ml of water was added to the dark oil and the mixture was rota-evaporated, in a 70° C-water bath for about 15 minutes. Then, 150 ml of methanol was added and rotary evaporation was resumed until all solvent was removed at 70° C. The resultant dark oil was then dried in vacuo at room temperature for 24 hrs and solidified into dark brown crude product (about 5.0g). Proton NMR (CDCl3): 5.18 (singlet, --OH), 6.71-7.67 (complex, aromatic H). The hydroxyl proton is readily exchanging with deuterium of D2O. IR(KBr): δ (OH) at 3350 cm-1 (strong and broad); δ (C≡C) at 2210 cm-1 (W). The crude product was used in the subsequent reaction without further purification.
Reaction SMILES: B(Cl)([C@@H]1[C@@H](C)[C@@H]2C(C)(C)[C@@H](C2)C1)[C@@H]1[C@@H](C)[C@@H]2C(C)(C)[C@@H](C2)C1.[CH3:23][C:24]([NH:27][S:28]([C:31]1[S:39][C:38]2[S:37](=[O:41])(=[O:40])[N:36]([CH2:42][CH2:43][CH2:44][CH2:45][O:46][CH3:47])[CH2:35][C:34](=[O:48])[C:33]=2[CH:32]=1)(=[O:30])=[O:29])([CH3:26])[CH3:25].N(CCO)CCO>C1COCC1.C(OCC)(=O)C>[CH3:26][C:24]([NH:27][S:28]([C:31]1[S:39][C:38]2[S:37](=[O:40])(=[O:41])[N:36]([CH2:42][CH2:43][CH2:44][CH2:45][O:46][CH3:47])[CH2:35][C@@H:34]([OH:48])[C:33]=2[CH:32]=1)(=[O:30])=[O:29])([CH3:23])[CH3:25]
Reactant: COCCCCN1CC(=O)c2cc(S(=O)(=O)NC(C)(C)C)sc2S1(=O)=O
Agent: C[C@@H]1[C@@H](B(Cl)[C@H]2C[C@@H]3C[C@H]([C@@H]2C)C3(C)C)C[C@@H]2C[C@H]1C2(C)C
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: OCCNCCO
Product: COCCCCN1C[C@@H](O)c2cc(S(=O)(=O)NC(C)(C)C)sc2S1(=O)=O
Temperature: 25 °C
Reaction time: 40 h
Yield: 88.3 %

Procedure:
To a solution of (+)-β-chlorodiisopinocamphenylborane (28.01 g, 0.087 mol) in THF (60 mL) at -20° C. was added a solution of the product from Step B (7.4 g, 0.017 mol) in THF (90 mL); this mixture was stirred for 40 hr while maintaining this temperature. Diethanolamine (9.13 g, 0.087 mol) was added to the reaction mixture which was allowed to warm to room temperature and stirred at this temperature for 2 hr. Evaporation of the THF gave a residue which was dissolved in ethyl acetate (100 mL); this solution was washed with water (100 mL). The aqueous layer was separated and extracted with ethyl acetate (3×50 mL). The ethyl acetate extracts were combined, washed with brine (2×20 mL), dried (MgSO4), and evaporated to a residue which was purified by column chromatography (silica, 60% ethyl acetate/hexane) to give an oil (6.4 g, 86%).
Reaction SMILES: [N+](C1C=CC(C([O:10][C@H:11]2[CH2:16][CH2:15][C:14]([CH3:18])([CH3:17])[C@H:13]([N:19]3[C:27](=[O:28])[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[C:20]3=[O:29])[CH2:12]2)=O)=CC=1)([O-])=O.C[O-].[Na+].S([O-])(O)(=O)=O.[K+]>CO.O1CCCC1>[OH:10][C@H:11]1[CH2:12][C@H:13]([N:19]2[C:27](=[O:28])[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:20]2=[O:29])[C:14]([CH3:18])([CH3:17])[CH2:15][CH2:16]1
Reactant: CC1(C)CC[C@H](OC(=O)c2ccc([N+](=O)[O-])cc2)C[C@H]1N1C(=O)c2ccccc2C1=O
Agent: C[O-]
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: C1CCOC1
Solvent: CO
Product: CC1(C)CC[C@@H](O)C[C@@H]1N1C(=O)c2ccccc2C1=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 84.5 %

Procedure:
To a suspension of trans-3-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-4,4-dimethylcyclohexyl 4-nitrobenzoate (420 mg, 1.00 mmol) in a mixture of methanol (0.10 ml) and tetrahydrofuran (10 ml) was added 28%-sodium methoxide (0.24 ml, 1.00 mmol) at 3° C., and stirred at 0° C. for 30 minutes and then at room temperature for 35 minutes. The reaction solution was adjusted to pH 4 with a 0.5M-aqueous potassium hydrogensulfate solution and then distilled under reduced pressure to remove the solvent. The residue was added to water and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and distilled under reduced pressure to remove the solvent, and the resulting residue was purified by a silica gel column chromatography (hexane/ethyl acetate=2/1) to obtain trans-2-(5-hydroxy-2,2-dimethylcyclohexyl)-1H-isoindole-1,3(2H)-dione (231 mg, 85%).
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([C:16]([F:19])([F:18])[F:17])=[N:14][N:15]=3)[N:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[C:20]([C:22]1[CH:29]=[CH:28][C:25]([CH:26]=O)=[CH:24][CH:23]=1)#[CH:21]>>[C:20]([C:22]1[CH:29]=[CH:28][C:25]([CH2:26][N:4]2[CH2:3][CH2:2][N:1]([C:7]3[CH:8]=[CH:9][C:10]4[N:11]([C:13]([C:16]([F:17])([F:18])[F:19])=[N:14][N:15]=4)[N:12]=3)[CH2:6][CH2:5]2)=[CH:24][CH:23]=1)#[CH:21]
Reactant: FC(F)(F)c1nnc2ccc(N3CCNCC3)nn12
Reactant: C#Cc1ccc(C=O)cc1
Product: C#Cc1ccc(CN2CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)cc1

Procedure:
Reductive amination of 6-(piperazin-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine with 4-ethynylbenzaldehyde was carried out according to General Synthetic Method 7. The crude product was purified by hplc using a Waters XBridge Prep C18 OBD column, 5μ silica, 30 mm diameter, 100 mm length eluted with decreasingly polar mixtures of water (containing 0.1% aqueous ammonia) and acetonitrile as eluents to give 6-[4-[(4-ethynylphenyl)methyl]piperazin-1-yl]-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:11]([OH:13])=O)[CH:5]=[C:6]2[C:10]=1[CH2:9][CH2:8][CH2:7]2.C(Cl)(=O)C(Cl)=O.C(Cl)Cl.[NH4+:23].[OH-]>C(O)C.CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([C:11]([NH2:23])=[O:13])[CH:5]=[C:6]2[C:10]=1[CH2:9][CH2:8][CH2:7]2
Reactant: [NH4+]
Reactant: O=C(O)c1cc(Br)c2c(c1)CCC2
Agent: O=C(Cl)C(=O)Cl
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCO
Product: NC(=O)c1cc(Br)c2c(c1)CCC2
Yield: 68 %

Procedure:
7-Bromoindane-5-carboxylic acid (2.9 g, 12 mmol) and oxalylchloride (2.0 g, 16 mmol) were mixed with CH2Cl2 (50 mL) whereupon DMF (100 mg) was added. After 1 h at room temperature the mixture was poured into a mixture of concentrated NH4OH aq (20 mL) and ethanol (100 mL). The volatiles were removed by evaporation and the residue partitioned between ethyl acetate (100 mL) and water (50 mL). The organic layer was washed with brine and then dried over Na2SO4. The solvent was removed by evaporation and the solid residue was treated with cold CH2Cl2, then filtered off and dried. There was obtained 2.0 g (68%) of 7-bromoindane-5-carboxamide as a solid material. 1H NMR (300 MHz, CD3CO CD3): 2.0-2.2 (m, 2H), 2.8-2.9 (d, 2H), 2.9-3.0 (t, 1H), 3.0-3.1 (t, 1H), 6.5 (b, 1H), 7.4 (b, 1H), 7.7 (s, 1H), 7.9 (s,1H).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:23]=[CH:22][C:8]2[N:9]([CH3:21])[C:10]([NH:12][C:13]3[C:18]([Cl:19])=[CH:17][CH:16]=[CH:15][C:14]=3[Cl:20])=[N:11][C:7]=2[CH:6]=1)=[O:4].[OH-].[Na+]>C(O)C>[Cl:20][C:14]1[CH:15]=[CH:16][CH:17]=[C:18]([Cl:19])[C:13]=1[NH:12][C:10]1[N:9]([CH3:21])[C:8]2[CH:22]=[CH:23][C:5]([C:3]([OH:4])=[O:2])=[CH:6][C:7]=2[N:11]=1
Reactant: COC(=O)c1ccc2c(c1)nc(Nc1c(Cl)cccc1Cl)n2C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cn1c(Nc2c(Cl)cccc2Cl)nc2cc(C(=O)O)ccc21

Procedure:
Prepared analogously to example 3b from 2-(2,6-Dichloro-phenylamino)-1-methyl-1H-benzimidazole-5-carboxylic acid-methyl ester and NaOH in ethanol.
Reaction SMILES: [CH2:1]([Zn]CC)C.[CH2:6]=[C:7]1[CH2:12][CH2:11][CH:10]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:9][CH2:8]1.[Cl-].[NH4+]>C(Cl)Cl>[CH2:1]1[C:7]2([CH2:12][CH2:11][CH:10]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:17])([CH3:19])[CH3:18])[CH2:9][CH2:8]2)[CH2:6]1
Reactant: C=C1CCC(NC(=O)OC(C)(C)C)CC1
Reactant: CC[Zn]CC
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC1CCC2(CC1)CC2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 37.4 %

Procedure:
Diethyl zinc (40 mL, 1 M solution in hexane) was slowly added to 300 mL of anhydrous DCM at −78° C. under nitrogen, further dimethyl iodide (15 g, 56 mmol) was added slowly. After 30 minutes, warmed to room temperature and maintained for 30 minutes, cooled with an ice-water bath. Then a solution of Compound 7-2 (2 g, 9.5 mmol) dissolved in 10 mL of methylene chloride was added and reacted overnight. To the reaction mixture was poured 100 mL of saturated aqueous solution of ammonium chloride, and liquid separated, the organic phase was extracted with ethyl acetate (100 mL) twice, the organic phases were combined and dried over anhydrous sodium sulfate. Suction filtered to remove desiccant, and rotary evaporated to remove solvents. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=10:1) to give Compound 7-3 as a white solid (0.8 g, 37.4% yield).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@@H:12]([CH2:13][NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[N:16]=2)[CH2:11][O:10][C:9]1([CH3:23])[CH3:22])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:24](=O)[CH3:25].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClCCCl.C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[C@@H:12]([CH2:13][N:14]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[N:16]=2)[CH2:24][CH3:25])[CH2:11][O:10][C:9]1([CH3:23])[CH3:22])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1[C@@H](CNc2cccc(Cl)n2)COC1(C)C
Reactant: CC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CCN(C[C@H]1COC(C)(C)N1C(=O)OC(C)(C)C)c1cccc(Cl)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 43 %

Procedure:
To a stirred solution of (S)-4-[(6-chloro-pyridin-2-ylamino)-methyl]-2,2-dimethyl-oxazo-lidine-3-carboxylic acid tert-butyl ester (528 mg) at r.t. in 1,2-dichloroethane (20 ml) under an argon atmosphere were added molecular sieves 4 A (˜2 g) and acetaldehyde (044 ml). After 30 min stirring at r.t., sodium triacetoxyborohydride (1.02 g) was added, followed by acetic acid (0.13 ml). The mixture was stirred for at r.t. over night, then diluted with CH2Cl2 and washed with sat. aq. Na2CO3. The biphasic mixture was filtered. The aqueous phase of the filtrate was back extracted with CH2Cl2. The combined organics were washed with brine, dried over MgSO4, filtered and concentrated. The crude product was purified by column chromatography (SiO2; gradient:cyclohexane->cyclohexane/EtOAc 85:15) to give (S)-4-{[(6-chloro-pyridin-2-yl)-ethyl-amino]-methyl}-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (244 mg, 43%) as viscous yellow oil. MS (ISP): 370.3 ([M+H]+)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:11]=[C:12]=[O:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[C:14]([NH2:18])(=[O:17])[CH2:15][CH3:16]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]([NH:18][C:14](=[O:17])[CH2:15][CH3:16])=[O:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(N=C=O)cc1OC
Reactant: CCC(N)=O
Product: CCC(=O)NC(=O)Nc1ccc(OC)c(OC)c1
Reaction time: 0.25 h

Procedure:
A mixture of 3,4-dimethoxyphenylisocyanate (26.0 g, 145 mM) and propionamide (10.61 g, 145 mM) is heated at 160°-165° C. for 11/2 hours. A homogeneous pale yellow solution forms which after 15 minutes solidifies. The heating is discontinued and the flask is allowed to cool slowly. The mixture is triturated with acetone and this resulting white solid is filtered and dried. Yield: 32.45 g, mp 193°-197° C.
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][C:5]([O:6][C:7]([CH3:12])([CH3:11])[C:8]([NH2:10])=O)=[C:4]([F:15])[CH:3]=1.C(N(CC)CC)C.FC(F)(F)C(OC(=O)C(F)(F)F)=O.CO>ClCCl>[Cl:1][C:2]1[CH:14]=[CH:13][C:5]([O:6][C:7]([CH3:12])([CH3:11])[C:8]#[N:10])=[C:4]([F:15])[CH:3]=1
Reactant: CC(C)(Oc1ccc(Cl)cc1F)C(N)=O
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: CO
Solvent: CCN(CC)CC
Product: CC(C)(C#N)Oc1ccc(Cl)cc1F
Temperature: 25 °C

Procedure:
To a solution of Example 53C (8 g, 34.5 mmol) in dichloromethane (100 mL) and triethylamine (19.25 mL, 138 mmol) was added trifluoroacetic anhydride (slow addition, 14.63 mL, 104 mmol) at 0° C. After the addition, the solution was allowed to warm to room temperature and stirred for 2 hours before methanol (20 mL) was added to quench the reaction. The solution was washed with saturated NaHCO3 solution, dried (Na2SO4), and concentrated. The residue was purified by column chromatography using an Analogix® Intelliflash280™ (SiO2, 0-60% ethyl acetate in hexanes) to provide titled product. MS (DCI+) m/z 214 (M+H)+.
Reaction SMILES: [Si:1]([O:8][C@H:9]([C:33]1[CH:34]=[N:35][C:36](Cl)=[CH:37][CH:38]=1)[C@H:10]1[CH2:14][CH2:13][C@@H:12]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]([O:24][CH3:25])=[O:23])=[CH:18][CH:17]=2)[N:11]1[C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C([O-])(=O)C.[K+]>C(O)C.[Pd]>[Si:1]([O:8][C@H:9]([C:33]1[CH:34]=[N:35][CH:36]=[CH:37][CH:38]=1)[C@H:10]1[CH2:14][CH2:13][C@@H:12]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]([O:24][CH3:25])=[O:23])=[CH:18][CH:17]=2)[N:11]1[C:26]([O:28][C:29]([CH3:30])([CH3:32])[CH3:31])=[O:27])([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:2])[CH3:3]
Reactant: COC(=O)c1ccc(C[C@@H]2CC[C@H]([C@H](O[Si](C)(C)C(C)(C)C)c3ccc(Cl)nc3)N2C(=O)OC(C)(C)C)cc1
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CCO
Product: COC(=O)c1ccc(C[C@@H]2CC[C@H]([C@H](O[Si](C)(C)C(C)(C)C)c3cccnc3)N2C(=O)OC(C)(C)C)cc1
Temperature: 50 °C
Reaction time: 14 h
Yield: 92.1 %

Procedure:
To a solution of tert-butyl (2R,5S)-2-[(R)-{[tert-butyl(dimethyl)silyl]oxy}(6-chloropyridin-3-yl)methyl]-5-[4-(methoxycarbonyl)benzyl]pyrrolidine-1-carboxylate from Step C (14.0 g, 24.3 mmol) in ethanol (200 mL) was added potassium acetate (3.58, 36.5 mmol) and 10% palladium on carbon (4.0 g) under argon. The reaction mixture was heated to 50° C. and agitated under an atmosphere of hydrogen at 50 psi for 14 h. The mixture was cooled to RT and filtered. The filtrate was concentrated to afford 12.1 g (92%) of the title compound as yellow foam. 1H NMR (400 MHz, CDCl3): δ 8.62 (s, 1H), 8.58 (s, 1H), 7.89 (d, J=7.9 Hz, 2H), 7.36-7.32 (m, 1H), 7.02-6.99 (m, 2H), 5.62 (s, 1H), 4.20-4.11 (m, 2H), 3.94 (s, 3H), 2.99-2.96 (m, 1H), 2.64-2.60 (m, 1H), 2.02-1.88 (m, 2H), 1.61 (s, 9H), 1.56-1.43 (m, 2H), 0.96 (s, 9H), 0.17 (s, 3H), 0.00 (s, 3H). MS: m/z (ESI) 541 (M+1).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][N:8]([CH3:37])[C:9](=O)[CH2:10][CH2:11][C@H:12]([C@@H:14]1[C@:31]2([CH3:32])[C:17]([C:18]3[CH2:19][CH2:20][C@@H:21]4[C@:26]([C:28]=3[CH2:29][CH2:30]2)([CH3:27])[CH2:25][CH2:24][C@H:23]([OH:33])[C:22]4([CH3:35])[CH3:34])=[CH:16][CH2:15]1)[CH3:13]>C1COCC1>[CH3:35][C:22]1([CH3:34])[C@@H:23]([OH:33])[CH2:24][CH2:25][C@@:26]2([CH3:27])[C@H:21]1[CH2:20][CH2:19][C:18]1[C:17]3[C@:31]([CH3:32])([CH2:30][CH2:29][C:28]=12)[C@@H:14]([C@H:12]([CH3:13])[CH2:11][CH2:10][CH2:9][N:8]([CH3:37])[CH3:7])[CH2:15][CH:16]=3
Reactant: C[C@H](CCC(=O)N(C)C)[C@H]1CC=C2C3=C(CC[C@@]21C)[C@@]1(C)CC[C@H](O)C(C)(C)[C@@H]1CC3
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: C[C@H](CCCN(C)C)[C@H]1CC=C2C3=C(CC[C@@]21C)[C@@]1(C)CC[C@H](O)C(C)(C)[C@@H]1CC3

Procedure:
The compound is synthesised by lithium aluminium hydride reduction in THF of 3β-hydroxy-4,4-dimethyl-5α-chola-8,14-dien-24-oic acid-N,N-dimethyl amide. 1H-NMR (CDCl3, 400 MHz): δ=5.35 (1H, s); 3.23 (1H, m); 2.85 (2H, m); 2.72 (6H, s).
Reaction SMILES: [Br:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([C:10]2[O:11][CH:12]=[CH:13][CH:14]=2)=[CH:4][C:3]=1[O:15][CH3:16].CON(C)[C:20](=[O:36])[CH:21]([O:34][CH3:35])[C:22]1[CH:27]=[CH:26][C:25]([C:28]2[O:29][C:30]([CH3:33])=[CH:31][CH:32]=2)=[CH:24][CH:23]=1>>[Br:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([C:10]2[O:11][C:12]([C:20](=[O:36])[CH:21]([O:34][CH3:35])[C:22]3[CH:27]=[CH:26][C:25]([C:28]4[O:29][C:30]([CH3:33])=[CH:31][CH:32]=4)=[CH:24][CH:23]=3)=[CH:13][CH:14]=2)=[CH:4][C:3]=1[O:15][CH3:16]
Reactant: COC(C(=O)N(C)OC)c1ccc(-c2ccc(C)o2)cc1
Reactant: COc1cc(-c2ccco2)cc(OC)c1Br
Product: COc1cc(-c2ccc(C(=O)C(OC)c3ccc(-c4ccc(C)o4)cc3)o2)cc(OC)c1Br
Yield: 47 %

Procedure:
2-(4-Bromo-3,5-dimethoxyphenyl)furan was coupled with N,2-dimethoxy-N-methyl-2-(4-(5-methylfuran-2-yl)phenyl)acetamide following the method used for the final coupling step of Example 12. Purification by chromatography (30-60% EtOAc-hexanes) provided 1-(5-(4-bromo-3,5-dimethoxyphenyl)furan-2-yl)-2-methoxy-2-(4-(5-methylfuran-2-yl)phenyl)ethanone as a pale orange colored solid (0.172 g, 47% yield). MS: m/z 511.0 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[C@@H:16]3[C@@H:14]([CH2:15]3)[C@@H:13]([OH:17])[C@H:12]2[OH:18])=[C:4]([NH:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([C:27]#[C:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][C:34]#[CH:35])[CH:22]=2)[N:3]=1.ClC1N=C2C(N=CN2[C@@H]2[C@@H]3[C@@H](C3)[C@@H](O)[C@H]2O)=C(NCC2C=CC=C(C#CCCCC3[N:68]=[N:69][N:70]([C:72]4[CH:77]=[CH:76][C:75]([F:78])=[C:74]([N+:79]([O-:81])=[O:80])[CH:73]=4)C=3)C=2)N=1>>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[C@@H:16]3[C@@H:14]([CH2:15]3)[C@@H:13]([OH:17])[C@H:12]2[OH:18])=[C:4]([NH:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([C:27]#[C:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][C:34]3[N:68]=[N:69][N:70]([C:72]4[CH:77]=[CH:76][C:75]([F:78])=[C:74]([N+:79]([O-:81])=[O:80])[CH:73]=4)[CH:35]=3)[CH:22]=2)[N:3]=1
Reactant: O=[N+]([O-])c1cc(-n2cc(CCCC#Cc3cccc(CNc4nc(Cl)nc5c4ncn5[C@H]4[C@H](O)[C@H](O)[C@@H]5C[C@@H]54)c3)nn2)ccc1F
Reactant: C#CCCCCCC#Cc1cccc(CNc2nc(Cl)nc3c2ncn3[C@H]2[C@H](O)[C@H](O)[C@@H]3C[C@@H]32)c1
Product: O=[N+]([O-])c1cc(-n2cc(CCCCCC#Cc3cccc(CNc4nc(Cl)nc5c4ncn5[C@H]4[C@H](O)[C@H](O)[C@@H]5C[C@@H]54)c3)nn2)ccc1F
Yield: 91 %

Procedure:
Compound 216 (91%) was synthesized from compound 213 following the same procedure as for compound 214. 1H NMR (CD3OD, 400 MHz) δ 8.56-8.54 (m, 1H), 8.40 (s, 1H), 8.13-8.18 (m, 2H), 7.60 (t, J=8.8 Hz, 1H), 7.37 (s, 1H), 7.30 (d, J=6.8 Hz, 1H), 7.24-7.21 (m, 2H), 4.79 (s, 1H), 4.72-4.69 (m, 3H), 3.90 (d, J=6.4 Hz, 1H), 2.84 (t, J=7.2 Hz, 2H), 2.45 (t, J=6.8 Hz, 2H), 2.01-1.95 (m, 1H), 1.86-1.79 (m, 2H), 1.68-1.58 (m, 5H), 1.33-1.30 (m, 1H), 0.82-0.72 (m, 1H). HRMS calculated for C33H32ClFN9O4 (M+H)+: 672.2250. Found 672.2245.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:16]2([C:19]([NH2:21])=[O:20])[CH2:18][CH2:17]2)[C:5]([Cl:22])=[CH:4][N:3]=1.[CH3:23][N:24]1[CH2:28][CH2:27][CH:26]([N:29]2[CH:33]=[C:32]([NH2:34])[CH:31]=[N:30]2)[CH2:25]1.CC1C=CC(S(O)(=O)=O)=CC=1>O1CCOCC1>[Cl:22][C:5]1[C:6]([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:16]2([C:19]([NH2:21])=[O:20])[CH2:18][CH2:17]2)=[N:7][C:2]([NH:34][C:32]2[CH:31]=[N:30][N:29]([CH:26]3[CH2:27][CH2:28][N:24]([CH3:23])[CH2:25]3)[CH:33]=2)=[N:3][CH:4]=1
Reactant: CN1CCC(n2cc(N)cn2)C1
Reactant: NC(=O)C1(c2ccccc2CCc2nc(Cl)ncc2Cl)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1COCCO1
Product: CN1CCC(n2cc(Nc3ncc(Cl)c(CCc4ccccc4C4(C(N)=O)CC4)n3)cn2)C1
Reaction time: 2 h
Yield: 7 %

Procedure:
A stirred solution of 1-(2-(2-(2,5-dichloropyrimidin-4-yl)ethyl)phenyl)cyclopropanecarboxamide A14 (0.085 g, 0.25 mmol), 1-(1-methylpyrrolidin-3-yl)-1H-pyrazol-4-amine A24 (0.046 g, 0.278 mmol) and TsOH (0.003 g, 0.02 mmol) in 1,4-dioxane (4 mL) was stirred at 120° C. in the microwave for 60 minutes followed by 150° C. for 2 hours and then 160° C. for 2 hours. After cooling, the solvent was removed to afford a crude red oil that was purified by flash chromatography (0-30% MeOH in DCM) followed by HPLC (Gradient: 20-100%, Acetonitrile 0.1% formic acid in water 0.1% formic acid, 12 min) to give the title compound 21 as a clear gum (0.008 g, 7% yield). LCMS-C: rt 4.34 min; m/z 466 [M+H]+.
Reaction SMILES: [Li]C(C)(C)C.[CH2:6]([O:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][O:22][CH3:23])=[CH:16][N:15]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[I:24]I>C1COCC1>[CH2:6]([O:13][C:14]1[CH:19]=[C:18]([I:24])[C:17]([O:20][CH2:21][O:22][CH3:23])=[CH:16][N:15]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: II
Reactant: COCOc1ccc(OCc2ccccc2)nc1
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: COCOc1cnc(OCc2ccccc2)cc1I
Reaction time: 0.5 h
Yield: 47.6 %

Procedure:
tBuLi (27 mL, 46.2 mmol) was added drop wise to a stirring solution of 2-(benzyloxy)-5-(methoxymethoxy)pyridine (5.4 g, 22.06 mmol) in THF (110 mL) at −78° C. The light yellow solution was allowed to stir for 30 min then treated with a solution of iodine (8.4 g, 33.1 mmol) in THF (55 mL) dropwise (the purple color per drop dissipated until after 1.05 equiv was added, then it turned progressively purple). It was allowed to stir for 1 hour and then quenched with H2O and diluted with EtOAc washed with sodium thiosulfate sat. soln and sat NaCl. The organic phase was dried over Na2SO4, filtered and concentrated and was purified on silica gel (Biotage, EtOAc/hexanes gradient, fraction collection at λ=254 nm) to give the expected product 2-(benzyloxy)-4-iodo-5-(methoxymethoxy)pyridine (3.90 g, 10.5 mmol, 48% yield) by LCMS and NMR. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.87 (1H, s), 7.28-7.44 (6H, m), 5.28 (2H, s), 5.21 (2H, s), 3.43 (3H, s). LC-MS retention time: 2.36 min; m/z (MH+): 372. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Waters SunFire 5u C18 4.6×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 10% acetonitrile/90% H2O/0.1% trifluoroacetic acid and solvent B was 10% H2O/90% acetonitrile/0.1% trifluoroacetic acid. MS data was determined using a Micromass Platform for LC in electrospray mode.