Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[NH:10][C:9]([CH2:11][CH2:12][CH3:13])=[CH:8][C:4]([C:5](O)=[O:6])=[CH:3]1.Cl.O>C1COCC1>[OH:6][CH2:5][C:4]1[CH:8]=[C:9]([CH2:11][CH2:12][CH3:13])[NH:10][C:2](=[O:1])[CH:3]=1
Reactant: CCCc1cc(C(=O)O)cc(=O)[nH]1
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: CCCc1cc(CO)cc(=O)[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 46.1 %

Procedure:
27.8 ml and, after 1 hour at room temperature, a further 27.8 ml of a 1M solution of BH3 in THF are added dropwise at 0° C. to a suspension of 3.0 g (16.6 mmol) of 2-oxo-6-propyl-1,2-dihydroisonicotinic acid and the mixture is stirred for a further hour at room temperature. 66.8 ml of 1N hydrochloric acid and 100 ml of water are added to the now clear solution, and it is stirred at room temperature for 1 hour and extracted three times with 75 ml of ethyl acetate each time. The organic phase is discarded, the aqueous phase is adjusted to a pH of about 7 with satd. NaHCO3 solution and the deposited precipitate is filtered off with suction. The aqueous filtrate is concentrated to dryness in a rotary evaporator and recrystallised from about 80 ml of water together with the first precipitate. 1.28 g (46%) of colourless crystals of m.p. 167° C. are obtained.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:14]2[CH2:18][CH2:17][N:16]([C:19]3[CH:20]=[N:21][CH:22]=[CH:23][C:24]=3[CH3:25])[C:15]2=[O:26])[CH:5]=[CH:6][C:7]=1[CH:8]([OH:13])[C:9]([F:12])([F:11])[F:10].CO>C(Cl)Cl.O=[Mn]=O>[F:1][C:2]1[CH:3]=[C:4]([N:14]2[CH2:18][CH2:17][N:16]([C:19]3[CH:20]=[N:21][CH:22]=[CH:23][C:24]=3[CH3:25])[C:15]2=[O:26])[CH:5]=[CH:6][C:7]=1[C:8](=[O:13])[C:9]([F:12])([F:10])[F:11]
Reactant: Cc1ccncc1N1CCN(c2ccc(C(O)C(F)(F)F)c(F)c2)C1=O
Agent: O=[Mn]=O
Solvent: CO
Solvent: ClCCl
Product: Cc1ccncc1N1CCN(c2ccc(C(=O)C(F)(F)F)c(F)c2)C1=O
Temperature: 50 °C
Reaction time: 8 h
Yield: 74.3 %

Procedure:
MnO2 (536 mg, 6.165 mmol) was added to 1-[3-fluoro-4-(2,2,2-trifluoro-1-hydroxy-ethyl)-phenyl]-3-(4-methyl-pyridin-3-yl)-imidazolidin-2-one (I-197a: 325 mg, 0.880 mmol) in DCM (20 mL) under nitrogen atmosphere. The resulting suspension was stirred at 50° C. overnight. The reaction was monitored by TLC (5% MeOH in DCM). The reaction mixture was cooled to room temperature and filtered through celite pad. The filtrate was washed with CHCl3, dried over Na2SO4 and concentrated. The concentrate was washed with hexane and dried to afford 240 mg of the product (74.53% yield).
Reaction SMILES: C(O)C(F)(F)F.Cl.Cl.[NH2:9][C:10]1[CH:11]=[CH:12][C:13]([N:17]2[CH2:22][CH2:21][CH2:20][C@@H:19]([C:23]([N:25]3[CH2:29][CH2:28][CH2:27][CH2:26]3)=[O:24])[CH2:18]2)=[N:14][C:15]=1[NH2:16].[Cl:30][C:31]([Cl:37])([Cl:36])[C:32](=N)OC>C(O)=O>[N:25]1([C:23]([C@@H:19]2[CH2:20][CH2:21][CH2:22][N:17]([C:13]3[N:14]=[C:15]4[NH:16][C:32]([C:31]([Cl:37])([Cl:36])[Cl:30])=[N:9][C:10]4=[CH:11][CH:12]=3)[CH2:18]2)=[O:24])[CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: Nc1ccc(N2CCC[C@@H](C(=O)N3CCCC3)C2)nc1N
Reactant: COC(=N)C(Cl)(Cl)Cl
Agent: Cl
Solvent: O=CO
Solvent: OCC(F)(F)F
Product: O=C([C@@H]1CCCN(c2ccc3nc(C(Cl)(Cl)Cl)[nH]c3n2)C1)N1CCCC1
Temperature: 60 °C
Reaction time: 3 h

Procedure:
Formic acid (2.8 mL) and trifluoroethanol (61 mL) were added to (R)-(1-(5,6-diaminopyridin-2-yl)piperidin-3-yl)(pyrrolidin-1-yl)methanone dihydrochloride. Methyl 2,2,2-trichloroacetimidate (1.65 mL) was added and the reaction mixture was stirred at 60° C. for 3 h. The mixture was used for the next step without further workup or purification.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[O:9][CH:10]([CH3:12])[CH3:11].C(=O)([O-])[O-].[K+].[K+].[CH2:19](I)[CH3:20]>CC(C)=O.C(OCC)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:19][CH3:20])=[CH:4][C:3]=1[O:9][CH:10]([CH3:12])[CH3:11]
Reactant: CCI
Reactant: CC(C)Oc1cc(O)ccc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCOCC
Product: CCOc1ccc(Br)c(OC(C)C)c1
Yield: 85.8 %

Procedure:
To a solution of 4-bromo-3-isopropoxy-phenol (0.50 g, 2.16 mmol) in acetone (3 mL) were added potassium carbonate (0.30 g, 2.16 mmol) and ethyl iodide (0.35 mL, 4.33 mmol). The reaction mixture was heated at gentle reflux for 12 h. The solvent was removed to give a white paste. It was then taken in diethyl ether (50 mL). The white solids were filtered off and the filtrate was concentrated. Purification of the residue by Biotage flash chromatography eluting with 10% ethyl acetate in hexanes gave 1-bromo-4-ethoxy-2-isopropoxy-benzene (0.48 g, 86%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)=[CH:3][CH:2]=1.[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][N:23]([C:26](OC2C=CC([N+]([O-])=O)=CC=2)=[O:27])[CH2:22][CH2:21]1)=[O:19])([CH3:16])([CH3:15])[CH3:14].CCOCC>CN(C)C=O>[C:13]([O:17][C:18]([N:20]1[CH2:21][CH2:22][N:23]([C:26]([N:1]2[CH2:2][CH2:3][CH:4]([C:7]3[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=3)[CH2:5][CH2:6]2)=[O:27])[CH2:24][CH2:25]1)=[O:19])([CH3:16])([CH3:14])[CH3:15]
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)Oc2ccc([N+](=O)[O-])cc2)CC1
Reactant: c1cc(C2CCNCC2)ccn1
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CCN(C(=O)N2CCC(c3ccncc3)CC2)CC1
Temperature: 105 °C
Yield: 46.7 %

Procedure:
4-(4-Pyridyl)piperidine (2.44 g) was added to a stirred suspension of 1-t-butoxycarbonyl-4-(4-nitrophenoxycarbonyl)piperazine (5.26 g) in dimethylformamide (90 mL) at 25° C. The reaction mixture was heated at 105° C. for 18 hours. The dimethylformamide was evaporated and water (500 mL) added, The aqueous phase was extracted with ethyl acetate. The organic phase was washed with 1M sodium hydroxide solution (5×100 mL) and saturated brine (2×100 mL), dried and evaporated, The residue was purified by chromatography on silica gel using a mixture of dichloromethane: methanol: 0.88 ammonia (94:5:1) as eluent to give a yellow oil. Trituration with ether gave, as a pale yellow solid, 1-t-butoxycarbonyl-4-[4-(4-pyridyl)-1-piperidylcarbonyl]piperazine (2.62 g); mp 143-4° C.; NMR (CDCl3) 1.44(s, 9H), 1.58-1.78(m, 2H), 1.78-1.92(d, 2H), 2.60-2.75(m, 1H), 2.80-2.96 (m, 2H), 3.92-3.25(t, 4H), 3.38-3.50(m, 4H), 3.82(d, 2H), 7.10(d, 2H), 8.51(d, 2H); EI-MS m/z 375(M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([S:11](Cl)(=[O:13])=[O:12])=[C:7]([Cl:15])[C:3]=1[C:4]([OH:6])=[O:5].[NH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1.[Cl-]>>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([S:11]([N:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)(=[O:13])=[O:12])=[C:7]([Cl:15])[C:3]=1[C:4]([OH:6])=[O:5]
Reactant: C1CCNCC1
Reactant: O=C(O)c1c(Cl)ccc(S(=O)(=O)Cl)c1Cl
Agent: [Cl-]
Product: O=C(O)c1c(Cl)ccc(S(=O)(=O)N2CCCCC2)c1Cl

Procedure:
2,6-Dichloro-5-chlorosulfonylbenzoic acid (960 mg.; 3.3 m moles) is added portion-wise to 1.95 g. (0.0165 mole) of piperidine in 15 ml. of drymethylene chloride, and the mixture heated to reflux for 1.5 hrs. The solvent and excess amine are removed under reduced pressure and the residue dissolved in 15 ml. of 2N sodium hydroxide. The aqueous base solution is extracted (2 x 50 ml.) with ether and acidified with 6N hydrochloric acid. The precipitated gum is filtered, dried and allowed to crystallize in hexane, 1.1 g., m.p. 145°-150° C. A small sample is recrystallized from acetonitrile, m.p. 142°-145° C.
Reaction SMILES: BrC1C=CC(O[CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][O:10]2)=C(C(C)(C)C)C=1.[C:19]12([C:29]3[CH:34]=[CH:33][C:32]([Br:35])=[CH:31][C:30]=3[OH:36])[CH2:28][CH:23]3[CH2:24][CH:25]([CH2:27][CH:21]([CH2:22]3)[CH2:20]1)[CH2:26]2.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.O1C=CCCC1>ClCCl>[C:19]12([C:29]3[CH:34]=[CH:33][C:32]([Br:35])=[CH:31][C:30]=3[O:36][CH:9]3[CH2:14][CH2:13][CH2:12][CH2:11][O:10]3)[CH2:20][CH:21]3[CH2:27][CH:25]([CH2:24][CH:23]([CH2:22]3)[CH2:28]1)[CH2:26]2
Reactant: CC(C)(C)c1cc(Br)ccc1OC1CCCCO1
Reactant: Oc1cc(Br)ccc1C12CC3CC(CC(C3)C1)C2
Agent: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: Brc1ccc(C23CC4CC(CC(C4)C2)C3)c(OC2CCCCO2)c1

Procedure:
Using the same general procedure as for the preparation of of 4-bromo-2-t-butyl-1-(2-tetrahydropyranoxy)benzene (Compound H), but instead using 12.56 g (40.9 mmol) of 2-(1-adamantyl)-5-bromophenol (Compound G), 1.03 g (4.1 mmol) of pyridinium p-toluenesulfonate, 5.16 g (5.6 ml, 61.3 mmol) of 3,4-dihydro-2H-pyran and 50 ml of dichloromethane produced a clear, orange solution. During aqueous workup, the organic phase was washed with 3×150 ml-portions of sat. aqueous NaHCO3 solution to produce a light yellow solid. Purification by flash chromatography (silica, 3% ethyl acetate in hexane) yielded the title compound as a white solid. PMR (CDCl3): d 1.6-2.1 (21H, m), 3.65-3.72 (1H, m), 3.8-3.93 (1H, m), 5.45 (1H, t, J=2.8 Hz), 7.04-7.08 (2H, m), 7.32 (1H, br s).
Reaction SMILES: [ClH:1].[OH:2][C@@H:3]1[CH2:8][CH2:7][C@H:6]([N:9]2[CH2:13][CH2:12][C:11]3([CH2:18][CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14]3)[C:10]2=[O:26])[CH2:5][CH2:4]1>C(OCC)(=O)C>[ClH:1].[OH:2][C@@H:3]1[CH2:8][CH2:7][C@H:6]([N:9]2[CH2:13][CH2:12][C:11]3([CH2:18][CH2:17][CH2:16][NH:15][CH2:14]3)[C:10]2=[O:26])[CH2:5][CH2:4]1
Reactant: CC(C)(C)OC(=O)N1CCCC2(CCN([C@H]3CC[C@@H](O)CC3)C2=O)C1
Agent: Cl
Solvent: CCOC(C)=O
Product: O=C1N([C@H]2CC[C@@H](O)CC2)CCC12CCCNC2
Reaction time: 1 h

Procedure:
Hydrogen chloride (2.0 mL, 4.0 M in 1,4-dioxane) was added to a solution of tert-butyl 2-(cis-4-hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]decane-7-carboxylate (0.10 g) in ethyl acetate (0.5 mL) at room temperature and the mixture was stirred for 1 h. The solvent was then removed under vacuum to give the product. LC-MS: 253.2 (M+H)+.
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C)([O-])C.[K+].Br[C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=[O:20])=[CH:17][CH:16]=1>>[C:2]1([S:1][C:15]2[CH:23]=[CH:22][C:18]([C:19]([OH:21])=[O:20])=[CH:17][CH:16]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Sc1ccccc1
Reactant: O=C(O)c1ccc(Br)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Product: O=C(O)c1ccc(Sc2ccccc2)cc1
Yield: 95.7 %

Procedure:
The conditions to prepare Reference Example 32 cl384847 are used with 6.0 g of mercaptobenzene, 12.22 g of potassium t-butoxide and 13.15 g of 4-bromobenzoic acid to give 12.0 g of the desired product as a solid, m.p. 101°-103° C.; M+H=231.
Reaction SMILES: [H-].[Na+].[N:3]1([CH:8]([C:10]2[CH:11]=[C:12]([CH:18]=[CH:19][CH:20]=2)[O:13][CH2:14][CH2:15][CH2:16][NH2:17])[CH3:9])[CH2:7][CH2:6][CH2:5][CH2:4]1.[OH:21][C:22]([CH3:28])([CH3:27])[C:23](OC)=[O:24]>CS(C)=O>[OH:21][C:22]([CH3:28])([CH3:27])[C:23]([NH:17][CH2:16][CH2:15][CH2:14][O:13][C:12]1[CH:18]=[CH:19][CH:20]=[C:10]([CH:8]([N:3]2[CH2:4][CH2:5][CH2:6][CH2:7]2)[CH3:9])[CH:11]=1)=[O:24]
Reactant: COC(=O)C(C)(C)O
Reactant: CC(c1cccc(OCCCN)c1)N1CCCC1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CC(c1cccc(OCCCNC(=O)C(C)(C)O)c1)N1CCCC1
Temperature: 0 °C
Yield: 26.4 %

Procedure:
43 mg of 50% sodium hydride was suspended in 0.5 ml of dry dimethylsulfoxide, and with stirring under ice cooling, a solution of 200 mg of 3-[3-[1-(1-pyrrolidinyl)ethyl]phenoxy]propylamine in 0.5 ml of dimethylsulfoxide was added dropwise. The mixture was stirred at room temperature for 20 minutes. Then, 105 mg of methyl α-hydroxyisobutyrate was added dropwise, and the mixture was stirred at room temperature for 1 hour. Ice water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with water, and dried over anhydrous sodium sulfate. The solvent was distilled off, and the resulting crude oil was separated and purified by TLC (developing solvent: chloroform/methanol=9/l) to afford 71 mg of N-(2-hydroxy-2-methylpropionyl)-3-[3-[1-(1-pyrrolidinyl)ethyl]phenoxy]propylamine as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[CH:9][C:3]=1[O:4][CH2:5][C:6]([OH:8])=O.[Br:17][C:18]1[CH:19]=[C:20]([NH2:32])[CH:21]=[CH:22][C:23]=1[O:24][CH2:25][CH2:26][N:27]([CH2:30][CH3:31])[CH2:28][CH3:29]>>[Br:17][C:18]1[CH:19]=[C:20]([NH:32][C:6](=[O:8])[CH2:5][O:4][C:3]2[CH:9]=[CH:10][C:11]([C:13]([F:16])([F:15])[F:14])=[CH:12][C:2]=2[Cl:1])[CH:21]=[CH:22][C:23]=1[O:24][CH2:25][CH2:26][N:27]([CH2:30][CH3:31])[CH2:28][CH3:29]
Reactant: O=C(O)COc1ccc(C(F)(F)F)cc1Cl
Reactant: CCN(CC)CCOc1ccc(N)cc1Br
Product: CCN(CC)CCOc1ccc(NC(=O)COc2ccc(C(F)(F)F)cc2Cl)cc1Br

Procedure:
Prepared analogously to Example 143 starting from (2-chloro-4-trifluoromethyl-phenoxy)-acetic acid (Z2b) and 3-bromo-4-(2-diethylamino-ethoxy)-phenylamine (Z30b).
Reaction SMILES: [AlH4-].[Li+].[O:3]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[O:6][CH2:5][CH:4]1[CH:13]([N:16]1[CH2:21][CH2:20][CH:19]([C:22]([NH2:24])=O)[CH2:18][CH2:17]1)[CH2:14][OH:15]>O1CCCC1>[O:3]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[O:6][CH2:5][CH:4]1[CH:13]([N:16]1[CH2:17][CH2:18][CH:19]([CH2:22][NH2:24])[CH2:20][CH2:21]1)[CH2:14][OH:15]
Reactant: NC(=O)C1CCN(C(CO)C2COc3ccccc3O2)CC1
Agent: [AlH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: NCC1CCN(C(CO)C2COc3ccccc3O2)CC1
Temperature: 25 °C

Procedure:
A suspension of 30 g lithium aluminohydride in 1000 ml tetrahydrofuran is prepared under stirring and at room temperature. To this suspension 66 g of previously ground 1-[1-(2,3-dihydro[4H]1,4-benzodioxin-2 yl)2-hydroxy ethyl]piperidine 4-carboxamide are added portionwise.
Reaction SMILES: O[CH2:2][CH2:3][C:4]1[CH:8]=[CH:7][O:6][C:5]=1[CH2:9][CH2:10]O.C(N(CC)C(C)C)(C)C.CS(Cl)(=O)=O.[CH2:26]([NH2:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(N(CC)CC)C>ClCCl.O>[CH2:26]([N:33]1[CH2:2][CH2:3][C:4]2[CH:8]=[CH:7][O:6][C:5]=2[CH2:9][CH2:10]1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: OCCc1ccoc1CCO
Reactant: NCc1ccccc1
Agent: CS(=O)(=O)Cl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCN(CC)CC
Product: c1ccc(CN2CCc3ccoc3CC2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 1.208 g (7.735 mmol) of 2-[3-(2-hydroxyethyl)furan-2-yl]ethanol and 4.04 ml (23.2 mmol) of N,N-diisopropylethylamine in 50 ml of dichloromethane, 1.32 ml (17.0 mmol) of methanesulfonyl chloride was added dropwise under ice-cooling, followed by stirring at room temperature for 1 hour. The reaction mixture was poured into water and extracted with diethyl ether 3 times. The combined organic layer was dried over anhydrous magnesium sulfate; the solvent was distilled off under reduced pressure. The resulting residue was dissolved in 100 ml of ethanol; 0.83 g (7.7 mmol) of benzylamine and 2.37 ml (17.0 mmol) of triethylamine were added, followed by stirring at 80° C. for 3 days. After the solvent was distilled off from the reaction mixture under reduced pressure, aqueous sodium hydroxide was added, followed by 3 extractions with ethyl acetate. The combined organic layer was dried over anhydrous magnesium sulfate; the solvent was distilled off under reduced pressure. The resulting crude product was purified by silica gel column chromatography (hexane/ethyl acetate=9/1) to yield the desired product.
Reaction SMILES: [NH2:1][C@:2]12[CH2:37][CH2:36][C@@H:35]([C:38]([CH3:40])=[CH2:39])[C@@H:3]1[C@@H:4]1[C@@:17]([CH3:20])([CH2:18][CH2:19]2)[C@@:16]2([CH3:21])[C@@H:7]([C@:8]3([CH3:34])[C@@H:13]([CH2:14][CH2:15]2)[C:12]([CH3:23])([CH3:22])[C:11]([C:24]2[CH:33]=[CH:32][C:27]([C:28]([O:30]C)=[O:29])=[CH:26][CH:25]=2)=[CH:10][CH2:9]3)[CH2:6][CH2:5]1.Cl[CH2:42][CH2:43][NH:44][CH:45]1[CH2:49][CH2:48][S:47](=[O:51])(=[O:50])[CH2:46]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[I-].[K+]>C(#N)C>[O:50]=[S:47]1(=[O:51])[CH2:48][CH2:49][CH:45]([NH:44][CH2:43][CH2:42][NH:1][C@:2]23[CH2:37][CH2:36][C@@H:35]([C:38]([CH3:40])=[CH2:39])[C@@H:3]2[C@@H:4]2[C@@:17]([CH3:20])([CH2:18][CH2:19]3)[C@@:16]3([CH3:21])[C@@H:7]([C@:8]4([CH3:34])[C@@H:13]([CH2:14][CH2:15]3)[C:12]([CH3:23])([CH3:22])[C:11]([C:24]3[CH:25]=[CH:26][C:27]([C:28]([OH:30])=[O:29])=[CH:32][CH:33]=3)=[CH:10][CH2:9]4)[CH2:6][CH2:5]2)[CH2:46]1
Reactant: O=S1(=O)CCC(NCCCl)C1
Reactant: C=C(C)[C@@H]1CC[C@]2(N)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: O=P([O-])([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: C=C(C)[C@@H]1CC[C@]2(NCCNC3CCS(=O)(=O)C3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 120 °C
Yield: 62.9 %

Procedure:
A mixture of methyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-amino-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate (50 mg, 0.092 mmol), 3-((2-chloroethyl)amino)tetrahydrothiophene 1,1-dioxide (45.4 mg, 0.230 mmol), potassium phosphate (58.5 mg, 0.276 mmol) and potassium iodide (30.5 mg, 0.184 mmol) in acetonitrile (1 mL) was heated up at 120° C. for 18 hours. The reaction mixture was quenched with distilled water (3 mL), extracted with dichloromethane (3×3 mL), the organic phases were combined, dried over sodium sulfate, filtered and concentrated under reduced pressure to provide the crude product as a white solid (40 mg, 62%). LCMS: m/e 705.48 (M+H)+, 2.44 min (method 11).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]([CH3:26])=[C:8]([C:10]2[N:15]=[C:14]3[N:16]([CH3:25])[C:17](=[O:24])[N:18]([CH2:19][C:20]([CH3:23])([CH3:22])[CH3:21])[C:13]3=[CH:12][CH:11]=2)[CH:9]=1)(=O)[CH3:2].[NH:27]1[CH2:32][CH2:31][S:30](=[O:34])(=[O:33])[CH2:29][CH2:28]1.C([BH3-])#N.[Na+]>C1(C)C=CC=CC=1.CO.[Ti](Cl)(Cl)(Cl)Cl>[CH3:22][C:20]([CH3:23])([CH3:21])[CH2:19][N:18]1[C:13]2[C:14](=[N:15][C:10]([C:8]3[CH:9]=[C:4]([C@H:1]([N:27]4[CH2:32][CH2:31][S:30](=[O:34])(=[O:33])[CH2:29][CH2:28]4)[CH3:2])[CH:5]=[CH:6][C:7]=3[CH3:26])=[CH:11][CH:12]=2)[N:16]([CH3:25])[C:17]1=[O:24]
Reactant: O=S1(=O)CCNCC1
Reactant: CC(=O)c1ccc(C)c(-c2ccc3c(n2)n(C)c(=O)n3CC(C)(C)C)c1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CO
Product: Cc1ccc([C@@H](C)N2CCS(=O)(=O)CC2)cc1-c1ccc2c(n1)n(C)c(=O)n2CC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a microwave vial was added 5-(5-acetyl-2-methylphenyl)-1-(2,2-dimethylpropyl)-3-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (15-7) (30 mg, 0.085 mmol) and thiomorpholine 1,1-dioxide (17 mg, 0.13 mmol) were added under nitrogen and dissolved in toluene (0.43 ml). Titanium(IV) chloride (10 mg, 0.05 mmol) was added to the solution and the reaction was allow to stir at room temperature overnight. Sodium cyanoborohydride (8 mg, 0.12 mmol) was then added and allowed to stir for 1 hour. The reaction was diluted with methanol, and passed through a syringe filter. The solution was purified using reverse phase chromatography (10-100%, 0.1% TFA in H2O/Acetonitrile) and the desired fractions were collected and concentrated to produce 1-(2,2-dimethylpropyl)-5-{5-[(1R)-1-(1,1-dioxidothiomorpholin-4-yl)ethyl]-2-methylphenyl}-3-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (36-1). HRMS (M+H)+: observed=471.2421, calculated=471.2424.
Reaction SMILES: [F:1][C:2]1[C:10]([O:11][C:12]2[C:21]3[C:16](=[CH:17][C:18]([O:24][CH2:25][CH2:26][CH2:27][N:28]4[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]4)=[C:19]([O:22][CH3:23])[CH:20]=3)[N:15]=[CH:14][N:13]=2)=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH3:34])[NH:6]2.I[CH2:36][C:37]([NH2:39])=[O:38]>C(#N)C>[C:37]([CH2:36][N:31]1[CH2:32][CH2:33][N:28]([CH2:27][CH2:26][CH2:25][O:24][C:18]2[CH:17]=[C:16]3[C:21]([C:12]([O:11][C:10]4[C:2]([F:1])=[C:3]5[C:7](=[CH:8][CH:9]=4)[NH:6][C:5]([CH3:34])=[CH:4]5)=[N:13][CH:14]=[N:15]3)=[CH:20][C:19]=2[O:22][CH3:23])[CH2:29][CH2:30]1)(=[O:38])[NH2:39]
Reactant: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3F)ncnc2cc1OCCCN1CCNCC1
Reactant: NC(=O)CI
Solvent: CC#N
Product: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3F)ncnc2cc1OCCCN1CCN(CC(N)=O)CC1
Temperature: 25 °C
Yield: 31.6 %

Procedure:
A mixture of 4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]-6-methoxy-7-(3-piperazin-1-ylpropoxy)quinazoline (370 mg, 0.8 mmol), (prepared as described for the starting material in Example 15), iodoacetamide (162 mg, 0.88 mmol) and N,N-diisopropylethylanmine (230 mg, 1.80 mmol) in acetonitrile (10 ml) was stirred at reflux for 1 hour and allowed to cool to ambient temperature. The solvent was removed under vacuum and the residue purified by column chromatography eluting with methylene chloride/methanol (saturated with ammonia) (92/8) solvent. The relevant fractions were combined and evaporated under vacuum to give a solid which was triturated with acetone, filtered and dried to give 7-[3-(4-carbamoylmethylpiperazin-1-yl)propoxy]-4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]-6-methoxyquinazoline (132 mg, 32%).
Reaction SMILES: Cl.[CH3:2][NH:3][CH3:4].C(N(CC)CC)C.[C:12]([NH:19][C@H:20]([C:28]([OH:30])=O)[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>CN(C=O)C.C(OCC)(=O)C>[CH3:2][N:3]([CH3:4])[C:28](=[O:30])[C@H:20]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[NH:19][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13]
Reactant: CNC
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CN(C)C(=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Reaction time: 16 h

Procedure:
A solution of dimethylamine hydrochloride (1.45 g, 17.8 mmol) in DMF (46 mL) was cooled to −10° C. and triethylamine (2.7 mL, 19.4 mmol) was added. N-Boc-L-phenylalanine (4.59 g, 17.3 mmol, Aldrich) and HOBt (3.49 g, 26 mmol) were then added and the reaction stirred for 5 min before addition of EDCI (3.33 g, 17.4 mmol). The reaction mixture was left to stir for 16 h then diluted with ethyl acetate (400 mL), washed sequentially with aqueous sodium hydroxide solution (2M, 2×100 mL), hydrochloric acid (2N, 2×100 mL), brine (250 mL) and then dried (MgSO4). Evaporation in vacuo gave the title compound as a pale yellow oil. δH (CDCl3): 1.41 (9H, s), 2.61, 2.85 (6H, 2s), 2.91–2.99 (2H, m), 4.83 (1H, m), 5.40 (1H, br d), 7.18–7.29 (5H, m).
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[NH:11][C:12]([C:14]1[CH:15]=[N:16][N:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:18]=1Cl)=[O:13])[CH2:8]2.[NH:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1>>[CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[NH:11][C:12]([C:14]1[CH:15]=[N:16][N:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:18]=1[N:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1)=[O:13])[CH2:8]2
Reactant: C1COCCN1
Reactant: O=C(NC1C2CC3CC(C2)CC1C3)c1cnn(-c2ccccc2)c1Cl
Product: O=C(NC1C2CC3CC(C2)CC1C3)c1cnn(-c2ccccc2)c1N1CCOCC1

Procedure:
5-Morpholin-4-y1-1-phenyl-1H-pyrazole-4-carboxylic acid adamantan-2-ylamide was prepared using Procedure A from 5-chloro-1-phenyl-1H-pyrazole-4-carboxylic acid adamantan-2-ylamide (Intermediate 3) and morpholine. Mass spectrum (ES) MH+=407.
Reaction SMILES: [C:1]([O:9][C@H:10]1[C@H:14]([OH:15])[CH2:13][N:12]([C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:17])[C@@H:11]1[CH2:26][O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.O>C(Cl)Cl>[C:1]([O:9][C@H:10]1[C@@H:14]([OH:15])[CH2:13][N:12]([C:16]([O:18][CH2:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)=[O:17])[C@@H:11]1[CH2:26][O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O[C@H]1[C@H](O)CN(C(=O)OCc2ccccc2)[C@@H]1COCc1ccccc1)c1ccccc1
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: O
Solvent: c1ccncc1
Product: O=C(O[C@@H]1[C@@H](COCc2ccccc2)N(C(=O)OCc2ccccc2)C[C@@H]1O)c1ccccc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 49.8 %

Procedure:
The compound (183 mg, 0.40 mmol) synthesized in Example 9 (9a) was dissolved in methylene chloride (4 mL) and pyridine (96 μL, 1.20 mmol) and trifluoromethanesulfonic acid anhydride (0.10 mL, 0.60 mmol) were added thereto, followed by stirring of the mixture at 0° C. for 20 minutes. After water (10 mL) was added thereto at 0° C. and the mixture was extracted with methylene chloride, the organic layer was washed with saturated brine (10 mL) and dried with anhydrous sodium sulfate, followed by distilling off of the solvent under reduced pressure. The residue was purified using silica gel flash column chromatography (hexane:ethyl acetate, 2:1, V/V) to obtain the desired title compound (92 mg, yield 50%) as a pale yellow oil.