Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br-].[CH2:2]([Zn+])[CH2:3][CH3:4].O1CCCC1.[Cl:11][C:12]1[N:13]=[C:14]2[CH:19]=[CH:18][C:17](Cl)=[N:16][N:15]2[CH:21]=1.Cl>C1(C)C=CC=CC=1.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.O>[Cl:11][C:12]1[N:13]=[C:14]2[CH:19]=[CH:18][C:17]([CH2:2][CH2:3][CH3:4])=[N:16][N:15]2[CH:21]=1
Reactant: Clc1cn2nc(Cl)ccc2n1
Reactant: CCC[Zn+]
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Agent: [Br-]
Solvent: C1CCOC1
Solvent: O
Solvent: Cc1ccccc1
Product: CCCc1ccc2nc(Cl)cn2n1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
Under a nitrogen stream, a solution of n-propylzinc bromide in tetrahydrofuran (0.5 M, 7.98 ml, 3.99 mmol) was diluted with toluene (5.0 ml), and 2,6-dichloroimidazo[1,2-b]pyridazine (0.50 g, 2.66 mmol) and bis(triphenylphosphine)palladium(II) dichloride (0.19 g, 0.27 mmol) were added thereto, and the reaction mixture was stirred for 2 hours at 80° C. After cooling, to the reaction mixture was added cold water (50 ml), acidified with dilute hydrochloric acid, extracted with ethyl acetate, and the extracts were washed with dilute hydrochloric acid, a saturated saline, an aqueous saturated sodium bicarbonate solution and a saturated saline in this order. The resulting organic layer was dried over anhydrous magnesium sulfate, filtrated and concentrated. The concentrated residue was purified by silica gel column chromatography (ethyl acetate:hexane=3:7) to give the title compound as white crystals. The yield was 0.31 g (59.6%).
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(N(CC)CC)C.[C:21](Cl)(=[O:23])[CH3:22]>ClCCl>[C:21]([N:11]1[CH2:10][CH2:9][N:8]([C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH2:13][CH2:12]1)(=[O:23])[CH3:22]
Reactant: CC(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N1CCN(C(=O)OC(C)(C)C)CC1
Yield: 85 %

Procedure:
A solution of N-Boc-piperazine (300 mg, 1.63 mmol), triethylamine (494 mg, 3 equiv), and acetyl chloride (1.5 equiv) in dichloromethane was stirred overnight at rt. The solution was quenched by the dropwise addition of water. The organic layer was separated, dried over anhydrous Na2SO4, and evaporated in vacuo. The residue was purified by flash chromatography to give the title compound (˜85% yield) as a solid.
Reaction SMILES: [CH3:1][CH:2]1[CH:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:6](=[O:13])[CH2:5][C:4](=O)[CH2:3]1.[CH3:15][C:16]1[CH:17]=[CH:18][C:19]([NH2:23])=[C:20]([SH:22])[CH:21]=1>CS(C)=O>[C:8]([CH:7]1[C:6](=[O:13])[C:5]2[S:22][C:20]3[C:19](=[CH:18][CH:17]=[C:16]([CH3:15])[CH:21]=3)[NH:23][C:4]=2[CH2:3][CH:2]1[CH3:1])([O:10][CH2:11][CH3:12])=[O:9]
Reactant: Cc1ccc(N)c(S)c1
Reactant: CCOC(=O)C1C(=O)CC(=O)CC1C
Solvent: CS(C)=O
Product: CCOC(=O)C1C(=O)C2=C(CC1C)Nc1ccc(C)cc1S2

Procedure:
A mixture of ethyl 6-methyl-2,4-dioxocyclohexane-1-carboxylate, 7b (1.43 g, 7.2 mmole) and 5-methyl-2-aminobenzenethiol, 6 (X=Me, 1.0 g, 7.2 mmole) in DMSO (10 mL) is placed in a preheated heating mantle. The reaction mixture is stirred and refluxed for 0.5 h. Upon cooling, the reaction mixture forms a solid. The crystals are filtered and the remaining mother liquid is poured into cold water, whereupon further precipitation occurs. Each precipitate is separately recrystallized twice from EtOH and proves to be identical. An analytical sample of 4i, (R=Me), mp 224° C. occurs as light orange crystals; yield: 0.50 (21.9%).
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:13][C:12]([CH2:14]O)=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.C(N(CC)CC)C.CS([Cl:29])(=O)=O>C(Cl)Cl>[Cl:29][CH2:14][C:12]1[S:13][C:9]([C:6]2[CH:7]=[CH:8][C:3]([C:2]([F:17])([F:16])[F:1])=[CH:4][CH:5]=2)=[CH:10][CH:11]=1
Reactant: OCc1ccc(-c2ccc(C(F)(F)F)cc2)s1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: FC(F)(F)c1ccc(-c2ccc(CCl)s2)cc1
Temperature: 25 °C

Procedure:
To a mixture of [5-(4-Trifluoromethyl-phenyl)-thiophen-2-yl]-methanol (1.52 g, 5.89 mmole) and triethyl amine (1.64 mL, 11.78 mmole) in DCM (100 mL) at 0° C., is injected methanesulfonyl chloride (0.91 mL, 11.78 mmole) dropwise. The reaction is kept at 0° C. for an hour and warmed up to room temperature for an hour. The reaction mixture is concentrated on rota vapor, and the resulting residue is purified on a silica gel column, eluting with 0-15% ethyl acetate in hexane and concentrated to provide the titled compound as off-white solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][NH2:16])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[S:18]1[CH:22]=[CH:21][N:20]=[C:19]1[C:23]1[CH:30]=[CH:29][C:26]([CH:27]=O)=[CH:25][CH:24]=1>C(N(CC)CC)C>[C:1]([O:5][C:6](=[O:17])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][NH:16][CH2:27][C:26]2[CH:25]=[CH:24][C:23]([C:19]3[S:18][CH:22]=[CH:21][N:20]=3)=[CH:30][CH:29]=2)[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=Cc1ccc(-c2nccs2)cc1
Reactant: CC(C)(C)OC(=O)COc1cccc(CN)c1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)COc1cccc(CNCc2ccc(-c3nccs3)cc2)c1

Procedure:
The title compound of Step A was prepared from (3-aminomethyl-phenoxy)-acetic acid tert-butyl ester, of Preparation 20, and 4-thiazol-2-yl-benzaldehyde, of Preparation 25, following the procedure described in Example 3, Step A except no triethylamine was used. 1H NMR (400 MHz, CDCl3) δ 7.90 (d, 2H), 7.82 (d, 1H), 7.39 (d, 2H), 7.28 (d, 1H), 7.22 (m, 1H), 6.92 (m, 2H), 6.77 (m, 1H), 4.50 (s, 2H), 3.80 (s, 2H), 3.76 (s, 2H), 1.46 (s, 9H); MS 411 (M+1).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](Cl)=[O:7].[Sn](Cl)(Cl)(Cl)Cl.[N:14]1([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])[CH:18]=[CH:17][CH:16]=[CH:15]1>C(Cl)Cl>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([C:15]1[N:14]([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])[CH:18]=[CH:17][CH:16]=1)=[O:7]
Reactant: O=C1c2ccccc2C(=O)N1n1cccc1
Reactant: O=C(Cl)c1cccs1
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: ClCCl
Product: O=C(c1cccs1)c1cccn1N1C(=O)c2ccccc2C1=O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of 2-thiophenecarbonylchloride (10.7 ml) in 500 ml of dry DCM was treated at -10° C. with tin tetrachloride (11.7 ml) and stirred for 30 minutes. 2-(1H-pyrrol-1-yl)-1H-isoindole-1,3(2H)dione (21.2 g) was then added in small portions over a period of 30 minutes at -10° C. After the addition was completed, the reaction mixture was stirred for an additional 30 minutes at -10° C. and subsequently poured into 500 ml of ice water. The precipitate was dissolved by addition of about 1000 ml of DCM and the separated aqueous layer extracted again with DCM. The combined organic layers were washed twice with 2N hydrochloric acid and with water, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by flash column chromatography (silica gel, DCM/ethyl acetate 99:1) and the desired fractions were concentrated. The residue was recrystallized from DCM/ethyl ether affording the product as crystals (17.9 g), m.p. 165°-166° C.
Reaction SMILES: [CH2:1]([S:3]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[C:16]([C:30]([NH2:32])=[O:31])[CH:17]=[C:18](B4OC(C)(C)C(C)(C)O4)[CH:19]=3)[NH:14][CH:13]=2)[CH2:8][CH2:7]1)(=[O:5])=[O:4])[CH3:2].Br[C:34]1[CH:35]=[C:36]([CH:39]=[CH:40][C:41]=1[F:42])[CH:37]=[O:38].C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.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.[Pd]>[CH2:1]([S:3]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[C:16]([C:30]([NH2:32])=[O:31])[CH:17]=[C:18]([C:34]4[CH:35]=[C:36]([CH:37]=[O:38])[CH:39]=[CH:40][C:41]=4[F:42])[CH:19]=3)[NH:14][CH:13]=2)[CH2:8][CH2:7]1)(=[O:5])=[O:4])[CH3:2]
Reactant: O=Cc1ccc(F)c(Br)c1
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(B4OC(C)(C)C(C)(C)O4)cc23)CC1
Agent: [Pd]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cc(C=O)ccc4F)cc23)CC1
Temperature: 160 °C

Procedure:
To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole-7-carboxamide (200 mg, 0.434 mmol) in dioxane (3.0 mL) and H2O (1.0 mL) was added 3-bromo-4-fluorobenzaldehyde (264 mg, 1.30 mmol), and K2CO3 (360 mg, 2.60 mmol) in microwave tube. The reaction mixture was degassed for 5 min before addition of tetrakis (triphenylphosphosphine) palladium (0) (48 mg, 0.043 mmol). The reaction was heated in a microwave for 30 min at 160° C. The organic layer was separated and concentrated. The residue was dissolved in MeOH until solid precipitated to yield 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(2-fluoro-5-formylphenyl)-1H-indole-7-carboxamide.
Reaction SMILES: Cl.[C:2]([C:4]1[CH:9]=[CH:8][C:7]([NH:10]N)=[CH:6][CH:5]=1)#[N:3].[C:12]([O:20][CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1)(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(O)(=O)C>[C:12]([O:20][CH:21]1[CH2:22][C:23]2[C:8]3[C:7](=[CH:6][CH:5]=[C:4]([C:2]#[N:3])[CH:9]=3)[NH:10][C:24]=2[CH2:25][CH2:26]1)(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C(OC1CCCCC1)c1ccccc1
Reactant: N#Cc1ccc(NN)cc1
Agent: Cl
Solvent: CC(=O)O
Product: N#Cc1ccc2[nH]c3c(c2c1)CC(OC(=O)c1ccccc1)CC3
Yield: 47.8 %

Procedure:
4-Cyanophenyl hydrazine hydrochloride (20.2 g) and 4-benzoyloxy-cyclohexane (25.9 g) were dissolved in glacial acetic acid (400 ml) and the mixture was heated under reflux for 1.5 hr. After allowing to cool, the mixture was filtered, and the filtrate was evaporated to dryness, and neutralized with aqueous sodium bicarbonate solution to give a solid precipitate, which was purified by chromatography (SiO2 ; hexane/ethyl acetate) to give 3-benzoyloxy-6-cyano-1,2,3,4-tetrahydrocarbazole (18 g). This product (11.6 g) was suspended in ethanol (230 ml) and treated with 2.5% aqueous potassium hydroxide solution (120 ml), and heated under reflux for 1 hr. The cooled mixture was neutralized with glacial acetic acid and evaporated to a solid residue which was washed with water, and dried to give 3-hydroxy-6-cyano-1,2,3,4-tetrahydrocarbazole (6.6 g).
Reaction SMILES: C[C@@H]1NCCN(C(OC(C)(C)C)=O)C1.CCN(C(C)C)C(C)C.N1C=CC=CC=1C([Cl:32])=O.[CH3:33][C@@H:34]1[N:39]([C:40]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][N:43]=2)=[O:41])[CH2:38][CH2:37][N:36](C(OC(C)(C)C)=O)[CH2:35]1.[ClH:55]>ClCCl.O.O1CCOCC1>[ClH:32].[ClH:55].[CH3:33][C@H:34]1[CH2:35][NH:36][CH2:37][CH2:38][N:39]1[C:40]([C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][N:43]=1)=[O:41]
Reactant: O=C(Cl)c1ccccn1
Reactant: C[C@H]1CN(C(=O)OC(C)(C)C)CCN1C(=O)c1ccccn1
Agent: C[C@H]1CN(C(=O)OC(C)(C)C)CCN1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: C[C@H]1CNCCN1C(=O)c1ccccn1
Yield: 100.1 %

Procedure:
To a solution 1,1-dimethylethyl (3S)-3-methyl-1-piperazinecarboxylate (140 mg, 0.699 mmol) in dichloromethane (5 ml) was added DIPEA (0.183 ml, 1.049 mmol) at room temperature. 2-pyridinecarbonyl chloride (104 mg, 0.735 mmol) was then added and the resultant mixture stirred for 3 h30. The reaction mixture was then diluted with a further 2 ml DCM and 5 ml of water were added and the layers separated, the organics were then washed with 5 ml 2M HCl solution and 5 ml sat NaHCO3 solution then dried (hydrophobic frit) and concentrated to dryness. To a solution of the resulting 1,1-dimethylethyl (3S)-3-methyl-4-(2-pyridinylcarbonyl)-1-piperazinecarboxylate (78 mg, 0.255 mmol) in 1,4-Dioxane (1 ml) was added HCl (4M in 1,4-Dioxane) (0.319 ml, 1.277 mmol) at room temperature and the resultant mixture stirred overnight at room temperature. Reaction mixture concentrated to dryness and solid triturated with diethylether to give the title compound (71 mg) used without further purification.
Reaction SMILES: [C:1]([CH:3]([C:9]1[CH:14]=[CH:13][C:12]([CH2:15][O:16][Si:17]([CH:24]([CH3:26])[CH3:25])([CH:21]([CH3:23])[CH3:22])[CH:18]([CH3:20])[CH3:19])=[CH:11][CH:10]=1)[C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:2].[BH4-].[Na+]>C1COCC1>[NH2:2][CH2:1][CH:3]([C:9]1[CH:10]=[CH:11][C:12]([CH2:15][O:16][Si:17]([CH:24]([CH3:25])[CH3:26])([CH:18]([CH3:20])[CH3:19])[CH:21]([CH3:22])[CH3:23])=[CH:13][CH:14]=1)[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)C(C#N)c1ccc(CO[Si](C(C)C)(C(C)C)C(C)C)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C(CN)c1ccc(CO[Si](C(C)C)(C(C)C)C(C)C)cc1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
To a suspension of CoCl2.6H2O in THF was added ethyl 2-cyano-2-(4-((triisopropylsilyloxy)methyl)phenyl)acetate (E200). The mixture was cooled to 0° C. and NaBH4 was added to the mixture in several portions over 30 min. The mixture was stirred at room temperature for 4 h. The reaction was quenched with water. The mixture was filtered and the filtrate extracted twice with ether. The organics were dried (MgSO4), filtered, and evaporated. Column chromatography (SiO2, DCM:EtOH=50:1) gave pure ethyl 3-amino-2-(4-((triisopropylsilyloxy)methyl)phenyl)propanoate (E201) as a yellow oil.
Reaction SMILES: C(N(CC)CC)C.[C:8](Cl)(=[O:16])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].[SH:18][CH2:19][CH2:20][CH2:21][SiH2:22][CH:23]([O:26][CH3:27])[O:24][CH3:25]>C1(C)C=CC=CC=1>[C:8]([S:18][CH2:19][CH2:20][CH2:21][SiH2:22][CH:23]([O:26][CH3:27])[O:24][CH3:25])(=[O:16])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: COC(OC)[SiH2]CCCS
Reactant: CCCCCCCC(=O)Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCCCCCCC(=O)SCCC[SiH2]C(OC)OC
Reaction time: 2 h
Yield: 95 %

Procedure:
In a four-necked flask of 1 L, 18.0 g of 3-mercaptopropyl dimethoxymethyl silane and 11.1 g of triethylamine are dissolved in 300 mL of toluene under a nitrogen atmosphere. To this solution is added 16.2 g of octanoic acid chloride dropwise over 30 minutes, which is stirred for 2 hours. Thereafter, the precipitates are filtered off and the solvent is removed by a rotary evaporator at 20 hPa/40° C. to obtain 29.0 g of 3-octanoylthio-propyl dimethoxymethyl silane.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[C:7]([C:12]([F:15])([F:14])[F:13])[CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:23][C:24]([O:26]CC)=[O:25].[OH-].[Na+]>CS(C)=O>[F:14][C:12]([F:15])([F:13])[C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:6]=1[N:5]=[CH:4][CH:3]=[C:2]2[O:1][CH2:23][C:24]([OH:26])=[O:25]
Reactant: CCOC(=O)CBr
Reactant: Oc1ccnc2c(C(F)(F)F)cccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CS(C)=O
Product: O=C(O)COc1ccnc2c(C(F)(F)F)cccc12
Reaction time: 2 h

Procedure:
4-Hydroxy-8-trifluoromethylquinoline (0.50 g, 2.35 mmol) was dissolved in DMSO (2 mL). Potassium carbonate was added (0.32 g, 2.35 mmol) and the mixture was stirred vigorously for 2 h. Ethyl bromoacetate (0.32 mL, 1.2 equiv) was added dropwise and heat was applied at 50° C. for 6 h. At 50° C., 2N NaOH (2 mL) was added and stirring continued for 4 h. The mixture was cooled and quenched with water (4 mL). Glacial acetic acid (1.4 mL) was added to ˜pH 4 resulting in precipitation of product. After stirring the suspension for 6 h, the solid was collected by vacuum filtration, rinsed with water, and dried in a vacuum dessicator over CaCl. The yield of white solid was 0.56 g (87%). 1H-NMR (DMSO-d6) 5.04 (s, 2H), 7.11 (d, J=5.2 Hz, 1H), 7.69 (t, J=8.0 Hz, 1H), 8.15 (d, J=8.0 Hz, 1H), 8.47 (d, J=8.0 Hz, 1H), 8.83 (d, J=5.2 Hz, 1H), 13.3 (br s, 1H); LC/MS (10-99%) M/Z: M+1 obs=333.5; tR=2.63 min.
Reaction SMILES: C[C:2](C)(P(O)(O)=O)[C:3]#[N:4].[Li+].[Cl-].C1CCN2C(=NCCC2)CC1.[C:23]([O:27][C:28]([N:30]1[CH2:35][CH2:34][C:33]([CH:38]2[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]2)([CH:36]=O)[CH2:32][CH2:31]1)=[O:29])([CH3:26])([CH3:25])[CH3:24]>C(#N)C>[C:23]([O:27][C:28]([N:30]1[CH2:35][CH2:34][C:33]([CH:36]=[CH:2][C:3]#[N:4])([CH:38]2[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]2)[CH2:32][CH2:31]1)=[O:29])([CH3:26])([CH3:25])[CH3:24]
Reactant: CC(C)(C)OC(=O)N1CCC(C=O)(C2CCCCC2)CC1
Reactant: CC(C)(C#N)P(=O)(O)O
Agent: [Cl-]
Agent: [Li+]
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)(C)OC(=O)N1CCC(C=CC#N)(C2CCCCC2)CC1
Reaction time: 1 h

Procedure:
To a solution of dimethyl phosphono acetonitrile (0.78 mL, 4.02 mmol), LiCl (184 mg, 4.02 mmol), and DBU (0.55 mL, 4.02 mmol) in anhydrous acetonitrile (25 mL) is added 4-cyclohexyl-4-formylpiperidine-1-carboxylic acid tert-butyl ester, 7, (992 mg, 3.35 mmol) under an atmosphere of argon at room temperature. The mixture is stirred for 1 hour and the solvent removed in vacuo. The resulting crude product is purified over silica gel eluting with dichloromethane/methanol 15:1 to afford the desired product in quantitative yield.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][N:7]([CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:19]=[CH:18][C:17]([CH:20]3[CH2:25][CH2:24][N:23]([C:26]4[CH:27]=[CH:28][C:29]5[N:30]([C:32]([C:35]([F:38])([F:37])[F:36])=[N:33][N:34]=5)[N:31]=4)[CH2:22][CH2:21]3)=[CH:16][CH:15]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].C([O-])=O.[NH4+]>[Pd].C(O)C.C(Cl)Cl>[C:1]([N:4]1[CH2:5][CH2:6][N:7]([CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:15]=[CH:16][C:17]([CH:20]3[CH2:21][CH2:22][N:23]([C:26]4[CH2:27][CH2:28][C:29]5[N:30]([C:32]([C:35]([F:36])([F:37])[F:38])=[N:33][N:34]=5)[N:31]=4)[CH2:24][CH2:25]3)=[CH:18][CH:19]=2)[CH2:8][CH2:9]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCN(CCCOc2ccc(C3CCN(c4ccc5nnc(C(F)(F)F)n5n4)CC3)cc2)CC1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CCO
Product: CC(=O)N1CCN(CCCOc2ccc(C3CCN(C4=Nn5c(nnc5C(F)(F)F)CC4)CC3)cc2)CC1
Temperature: 76 °C
Reaction time: 32 h
Yield: 71.5 %

Procedure:
10% Palladium on carbon (0.276 g, 0.26 mmol) was added to 6-[4-[4-[3-(4-acetylpiperazin-1-yl)propoxy]phenyl]piperidin-1-yl]-3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazine (13.80 g, 25.96 mmol) and ammonium formate (16.37 g, 259.61 mmol) in ethanol (300 mL) at 20° C. The resulting slurry was stirred at 76° C. for 32 hours, regularly adding more ammonium formate and catalyst to force the reaction to completion. The cooled reaction mixture was filtered through diatomaceous earth and the filtrate was concentrated under vacuum to give a colourless gum which was dissolved in DCM (1 L) and the solution washed with water (1 L). The organic layer was washed with brine, dried (Na2SO4), filtered and evaporated to dryness. The crude product was purified by flash silica chromatography, elution gradient 0 to 8% MeOH in DCM. Pure fractions were evaporated to dryness and the resulting oil was triturated with ether to give 6-[4-[4-[3-(4-acetylpiperazin-1-yl)propoxy]phenyl]piperidin-1-yl]-3-(trifluoromethyl)-7,8-dihydro[1,2,4]triazolo[4,3-b]pyridazine (9.90 g, 71.4%) as a white solid.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([CH:10]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:11]([CH3:16])([CH3:15])[C:12]([OH:14])=O)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[NH2:23][C:24]1[S:25][CH:26]=[CH:27][N:28]=1.C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([CH:10]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:11]([CH3:15])([CH3:16])[C:12]([NH:23][C:24]3[S:25][CH:26]=[CH:27][N:28]=3)=[O:14])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: Nc1nccs1
Reactant: CC(C)(C(=O)O)C(c1ccccc1)c1ccc2[nH]ccc2c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C(=O)Nc1nccs1)C(c1ccccc1)c1ccc2[nH]ccc2c1
Temperature: 80 °C
Reaction time: 6 h
Yield: 72.7 %

Procedure:
To a stirred solution of 3-(1H-indol-5-yl)-2,2-dimethyl-3-phenylpropanoic acid (0.31 g, 1.1 mmol), 2-aminothiazole (0.2 g, 2 mmol), and diisopropylethylamine (0.5 mL) in anhydrous DMF (3 mL) was added HATU (1 g, 2.7 mmol) under argon. After the reaction mixture was stirred at rt for 14 hr and 80° C. for 6 hr, it was concentrated, dissolved in ethyl acetate (20 mL), washed with saturated aqueous sodium bicarbonate solution (10 mL), brine (10 mL), dried (Na2SO4), and concentrated. Silica gel flash chromatography gave 3-(1H-indol-5-yl)-2,2-dimethyl-3-phenyl-N-(thiazol-2-yl)propanamide (Example 107, 0.3 g, 0.8 mmol, 75% yield) as a yellow solid. MS found: (M+H)+=376. 1H-NMR (400 MHz, MeOD) δ ppm 7.60 (1H, s) 7.43 (2H, d, J=7.12 Hz) 7.38 (1H, d, J=3.56 Hz) 7.20-7.29 (3H, m) 7.12-7.20 (2H, m) 7.10 (1H, d) 7.04 (1H, d, J=3.56 Hz) 6.38 (1H, d, J=3.05 Hz) 4.70 (1H, s) 4.62 (1H, s) 1.43 (6H, d, J=4.07 Hz).
Reaction SMILES: [OH:1][C@H:2]1[CH2:19][CH2:18][C@@:17]2([CH3:20])[C@@H:4]([CH2:5][CH2:6][C@:7]3([CH3:38])[C@@H:16]2[CH2:15][CH2:14][C@H:13]2[C@@:8]3([CH3:37])[CH2:9][CH2:10][C@@:11]3([C:27]([O:29][CH2:30][C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)=[O:28])[CH2:23][CH2:22][C@@H:21]([C:24]([CH3:26])=[CH2:25])[C@@H:12]32)[C:3]1([CH3:40])[CH3:39].C1C=C[NH+]=CC=1.[O-][Cr](Cl)(=O)=O>ClCCl>[CH3:37][C@:8]12[C@@:7]3([CH3:38])[C@@H:16]([C@:17]4([CH3:20])[C@@H:4]([CH2:5][CH2:6]3)[C:3]([CH3:39])([CH3:40])[C:2](=[O:1])[CH2:19][CH2:18]4)[CH2:15][CH2:14][C@@H:13]1[C@H:12]1[C@H:21]([C:24]([CH3:26])=[CH2:25])[CH2:22][CH2:23][C@:11]1([C:27]([O:29][CH2:30][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)=[O:28])[CH2:10][CH2:9]2
Reactant: C=C(C)[C@@H]1CC[C@]2(C(=O)OCc3ccccc3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: C=C(C)[C@@H]1CC[C@]2(C(=O)OCc3ccccc3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CCC(=O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Reaction time: 0.08 h
Yield: 97.9 %

Procedure:
To a solution of (1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-benzyl 9-hydroxy-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysene-3a-carboxylate (7.1 g, 12.98 mmol) in dichloromethane (100 mL) was added PCC (4.20 g, 19.48 mmol). After stirring for five minutes, the mixture turned a deep crimson color. The mixture was further stirred for 5.5 h. The mixture was filtered through a pad of celite and silica gel which was washed with dichloromethane and then with a 1:1 mixture of ethyl acetate:hexanes. The filtrate was concentrated under reduced pressure to give (1R,3aS,5aR,5bR,7aR,11aR,11bR,13aR,13bR)-benzyl 5a,5b,8,8,11a-pentamethyl-9-oxo-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysene-3a-carboxylate (6.92 g, 98% yield) as a white foam. 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 7.38-7.28 (m, 5H), 5.17-5.06 (m, 2H), 4.72 (d, J=1.83 Hz, 1H), 4.59 (s, 1H), 3.01 (td, J=10.99, 4.88 Hz, 1H), 2.51-2.43 (m, 1H), 2.42-2.34 (m, 1H), 2.28 (dt, J=12.59, 3.17 Hz, 1H), 2.21 (td, J=12.28, 3.51 Hz, 1H), 1.94-1.82 (m, 3H), 1.67 (s, 3H), 1.05 (s, 3H), 1.01 (s, 3H), 1.73-0.95 (m, 17H), 0.94 (s, 3H), 0.89 (s, 3H), 0.78 (s, 3H).
Reaction SMILES: Cl[C:2]1[O:3][C:4]([C:7]2[CH:8]=[C:9]([C:13]3[C:14]([O:19]C)=[N:15][CH:16]=[CH:17][CH:18]=3)[CH:10]=[CH:11][CH:12]=2)=[CH:5][N:6]=1.[CH3:21][O:22][C:23]1[CH:24]=[C:25]([CH:27]=[C:28]([O:30][CH3:31])[CH:29]=1)[NH2:26].Cl>CC(O)C>[CH3:31][O:30][C:28]1[CH:27]=[C:25]([NH:26][C:2]2[O:3][C:4]([C:7]3[CH:8]=[C:9]([C:13]4[C:14](=[O:19])[NH:15][CH:16]=[CH:17][CH:18]=4)[CH:10]=[CH:11][CH:12]=3)=[CH:5][N:6]=2)[CH:24]=[C:23]([O:22][CH3:21])[CH:29]=1
Reactant: COc1cc(N)cc(OC)c1
Reactant: COc1ncccc1-c1cccc(-c2cnc(Cl)o2)c1
Agent: Cl
Solvent: CC(C)O
Product: COc1cc(Nc2ncc(-c3cccc(-c4ccc[nH]c4=O)c3)o2)cc(OC)c1

Procedure:
3-{3-[2-(3,5-Dimethoxy-phenylamino)-oxazol-5-yl]-phenyl}-1H-pyridin-2-one 219 was prepared as for intermediate I-f above from 3-[3-(2-chloro-oxazol-5-yl)-phenyl]-2-methoxy-pyridine VI-c (40 mg, 0.150 mmol) with 3,5-dimethoxyaniline (29 mg, 0.190 mmol) and HCl (2M in ether, 120 μL, 0.23 mmol) in iPrOH (4 mL). The crude reaction mixture was evaporated under reduced pressure and the residue treated with a saturated solution of NaHCO3 and EtOAc. A precipitate formed from the biphasic mixture and was filtered off and dried to give the compound 219 product as a beige solid (19 mg, 33%). 1H NMR (300 MHz, DMSO-d6) δ 11.86 (s, 1H), 10.35 (s, 1H), 7.96 (s, 1H), 7.70 (dd, J=2.0, 6.9 Hz, 1H), 7.60-7.41 (m, 5H), 6.89 (d, J=2.0 Hz, 2H), 6.32 (t, J=6.7 Hz, 1H), 6.13 (s, 1H), 3.73 (s, 6H). ESI+ MS m/z 390 (M+H)+. Retention time=3.45 min (method 1).