Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](S(C)(=O)=O)[N:5]=[C:4]([N:12]2[C@H:17]([C:18]([F:21])([F:20])[F:19])[CH2:16][CH2:15][C@H:14]([C:22]([NH:24][CH:25]3[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)=[O:23])[CH2:13]2)[CH:3]=1.C[CH2:32][N:33](C(C)C)C(C)C.CN.C1COCC1>O1CCOCC1.CCOC(C)=O>[Cl:1][C:2]1[N:7]=[C:6]([NH:33][CH3:32])[N:5]=[C:4]([N:12]2[C@H:17]([C:18]([F:21])([F:20])[F:19])[CH2:16][CH2:15][C@H:14]([C:22]([NH:24][CH:25]3[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)=[O:23])[CH2:13]2)[CH:3]=1
Reactant: CS(=O)(=O)c1nc(Cl)cc(N2C[C@@H](C(=O)NC3CCCCC3)CC[C@H]2C(F)(F)F)n1
Reactant: CCN(C(C)C)C(C)C
Agent: CN
Solvent: C1CCOC1
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CNc1nc(Cl)cc(N2C[C@@H](C(=O)NC3CCCCC3)CC[C@H]2C(F)(F)F)n1
Temperature: 60 °C
Reaction time: 8 h
Yield: 58.4 %

Procedure:
To cis-1-[6-chloro-2-(methylsulfonyl)-4-pyrimidinyl]-N-cyclohexyl-6-(trifluoromethyl)-3-piperidinecarboxamide (390 mg, 0.832 mmol) in 1,4-dioxane (8 mL) was added Hunig's base (0.29 mL, 1.66 mmol) followed by 2M methylamine in THF (1 mL, 2 mmol), and the reaction mixture was stirred overnight at 60° C. into a sealed tube. The mixture was poured onto water and EtOAc. The organic layer was separated, washed with brine, dried (MgSO4), filtered and concentrated. Flash chromatography on SiO2 (gradient: 100% Hexanes to 50% EtOAc in Hexanes) afforded the title compound (204 mg) as a white foam. LC-MS (ES) m/z=420, 422 [M+H]+.
Reaction SMILES: C([N:8]1[CH2:13][C@H:12]([CH3:14])[O:11][C@H:10]([C:15]([F:18])([F:17])[F:16])[CH2:9]1)C1C=CC=CC=1.[H][H]>CO.[Pd]>[F:18][C:15]([F:16])([F:17])[C@H:10]1[O:11][C@@H:12]([CH3:14])[CH2:13][NH:8][CH2:9]1
Reactant: C[C@H]1CN(Cc2ccccc2)C[C@@H](C(F)(F)F)O1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: C[C@H]1CNC[C@@H](C(F)(F)F)O1
Yield: 76.7 %

Procedure:
N-benzyl-cis-2-trifluoromethyl-6-methylmorpholine [679839-97-5] (6.2 g, 23.91 mmol) was added to a suspension of Pd/C 10% (1 g) in methanol (150 mL). The reaction mixture was stirred at room temperature under a hydrogen atmosphere until 1 equivalent of hydrogen was absorbed. The catalyst was removed by filtration over diatomaceous earth. The solvent was evaporated, yielding 3.1 g (77%) of Intermediate 29 as an oil that was used without further purification.
Reaction SMILES: O.[NH2:2][NH2:3].[C:4]([O:8][C:9]([NH:11][CH2:12][C@H:13]1[CH2:18][CH2:17][C@H:16]([C:19]2[CH:24]=[CH:23][C:22]([NH:25][C:26](=[O:31])[C:27]([O:29]C)=O)=[CH:21][CH:20]=2)[CH2:15][CH2:14]1)=[O:10])([CH3:7])([CH3:6])[CH3:5]>CCO>[NH:2]([C:27](=[O:29])[C:26]([NH:25][C:22]1[CH:21]=[CH:20][C:19]([C@H:16]2[CH2:17][CH2:18][C@H:13]([CH2:12][NH:11][C:9](=[O:10])[O:8][C:4]([CH3:6])([CH3:7])[CH3:5])[CH2:14][CH2:15]2)=[CH:24][CH:23]=1)=[O:31])[NH2:3]
Reactant: COC(=O)C(=O)Nc1ccc([C@H]2CC[C@H](CNC(=O)OC(C)(C)C)CC2)cc1
Reactant: NN
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)NC[C@H]1CC[C@H](c2ccc(NC(=O)C(=O)NN)cc2)CC1

Procedure:
Prepared using hydrazine hydrate in EtOH from methyl {[4-(trans-4-{[(tert-butoxycarbonyl)amino]methyl}cyclohexyl)phenyl]amino}(oxo)acetate as described for Intermediate 18.1 1H NMR δ 0.99-1.06 (2H, m), 1.37-1.42 (12H, m), 1.77-1.80 (4H, m), 2.39-2.49 (1H, m), 2.81 (2H, t), 4.60 (2H, s), 6.80 (1H, t), 7.19 (2H, d), 7.68 (2H, d), 10.21 (1H, s), 10.45 (1H, s)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([CH:17]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[CH:18]([CH2:22][CH3:23])[C:19]([OH:21])=O)=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[S:30]1[CH:34]=[N:33][N:32]=[C:31]1[NH2:35]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([CH:17]([C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=4)[CH:18]([CH2:22][CH3:23])[C:19]([NH:35][C:31]4[S:30][CH:34]=[N:33][N:32]=4)=[O:21])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: Nc1nncs1
Reactant: CCC(C(=O)O)C(c1ccccc1)c1ccc2c(cnn2-c2ccc(F)cc2)c1
Product: CCC(C(=O)Nc1nncs1)C(c1ccccc1)c1ccc2c(cnn2-c2ccc(F)cc2)c1
Yield: 35 %

Procedure:
Example 142 was prepared from 2-((1-(4-fluorophenyl)-1H-indazol-5-yl)(phenyl)methyl)butanoic acid (180 mg, 0.26 mmol) and 1,3,4-thiadiazol-2-amine using General Coupling Method B to give 75 mg (35% yield). MS found: (M+H)+=472.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[N:14]([CH2:15][CH2:16][CH2:17][CH2:18][NH:19]C(=O)OC(C)(C)C)[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1.Cl>CO>[NH2:19][CH2:18][CH2:17][CH2:16][CH2:15][N:14]1[C:10]2[C:9]3[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=3[N:3]=[C:2]([NH2:1])[C:11]=2[N:12]=[C:13]1[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: CC(C)(C)OC(=O)NCCCCn1c(-c2ccccc2)nc2c(N)nc3ccccc3c21
Agent: Cl
Solvent: CO
Product: NCCCCn1c(-c2ccccc2)nc2c(N)nc3ccccc3c21
Yield: 75.4 %

Procedure:
The tert-butyl N-[4-(4-amino-2-phenyl-1H-imidazo[4,5-c]quinolin 1-yl)butyl]carbamate (4.3 g, 10.0 mmol) was dissolved in methanol (15 mL) and 1 N hydrochloric acid (100 mL) and then heated at reflux for 2 hours. The reaction mixture was concentrated under vacuum to a volume of about 50 mL. Addition of concentrated ammonium hydroxide to pH 12 did not produce a precipitate. The pH was adjusted to 7 with 1 N hydrochloric acid. The mixture was extracted with dichloromethane and then with ethyl acetate. The aqueous layer was concentrated to dryness. The residue was dissolved in water (50 mL) and then extracted continuously with refluxing chloroform for 36 hours. The chloroform extract was concentrated under vacuum to provide a light tan solid. This material was recrystallized from acetonitrile to provide 2.5 g of 1-(4-aminobutyl)-2-phenyl-1H-imidazo[4,5-c]quinolin-4-amine as an off white solid, m.p. 175-177° C. Analysis: Calculated for C20H21N5: %C, 72.48; %H, 6.39; %N, 21.13; Found: %C, 72.72; %H, 6.32; %N, 20.71.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:25]=[CH:24][C:6]([CH2:7][NH:8][C:9]2[CH:14]=[C:13]([O:15][C:16]3[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][C:17]=3[F:23])[N:12]=[CH:11][N:10]=2)=[CH:5][CH:4]=1.COC1C=CC(CNC2N=CN=C(OC3C=CC(NC(NC(=O)CC4C=CC(F)=CC=4)=O)=CC=3F)C=2)=CC=1.NC1N=CN=C(OC2C=CC(NC(NC(=O)CC3C=CC(F)=CC=3)=S)=CC=2F)C=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C.[F:124][C:125]1[CH:130]=[CH:129][C:128]([N:131](C2C=CC(OC3C=CN=CC=3)=CC=2)[C:132](=[O:137])[CH2:133][C:134](N)=[O:135])=[CH:127][CH:126]=1>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][NH:8][C:9]2[N:10]=[CH:11][N:12]=[C:13]([O:15][C:16]3[CH:21]=[CH:20][C:19]([NH:22][C:134](=[O:135])[CH2:133][C:132]([NH:131][C:128]4[CH:129]=[CH:130][C:125]([F:124])=[CH:126][CH:127]=4)=[O:137])=[CH:18][C:17]=3[F:23])[CH:14]=2)=[CH:24][CH:25]=1
Reactant: NC(=O)CC(=O)N(c1ccc(F)cc1)c1ccc(Oc2ccncc2)cc1
Reactant: COc1ccc(CNc2cc(Oc3ccc(N)cc3F)ncn2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: COc1ccc(CNc2cc(Oc3ccc(NC(=O)NC(=O)Cc4ccc(F)cc4)cc3F)ncn2)cc1
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc(CNc2cc(Oc3ccc(NC(=O)CC(=O)Nc4ccc(F)cc4)cc3F)ncn2)cc1
Yield: 82 %

Procedure:
The title compound was prepared from N-(4-methoxybenzyl)-6-(4-amino-2-fluorophenoxy)pyrimidin-4-amine. (Compound C of Example 11, 200 mg, 0.59 mmol), 3-(4-fluorophenylamino)-3-oxopropanoic acid (Compound B of Example 1, 128 mg, 0.65 mmol), TBTU (228 mg, 0.71 mmol), and DIPEA (123 μL, 0.71 mmol) in DMF using a similar procedure described for the preparation of Compound C of Example 1. The crude product was purified by trituration with isopropyl ether to give the title compound (250 mg, 82%) as an off-white solid. 1H NMR (DMSO-d6) δ 10.43 (s, 1H), 10.25 (s, 1H), 8.09 (s, 1H), 7.85 (s, 1H), 7.72 (dd, 1H, J=9.1, 5.0 Hz), 7.62 (dd, 2H, J=8.8, 5.0 Hz), 7.31-7.21 (m, 4H), 7.15 (dd, 2H, J=8.8, 8.8 Hz), 6.88 (m, 2H), 5.90 (s, 1H), 4.42 (br s, 2H), 3.71 (s, 3H), 3.46 (s, 2H); MS(ESI+) m/z 520.14 (M+H)+.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH2:27][CH3:28])[C:15]2[C:20]([NH:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[CH:19][CH:18]=[C:17]([Cl:26])[N:16]=2)[CH2:10][CH2:9]1)C1C=CC=CC=1.ClC(OC(Cl)C)=O>C(Cl)Cl>[CH2:27]([N:14]([CH:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1)[C:15]1[C:20]([NH:21][C:22]([CH3:25])([CH3:23])[CH3:24])=[CH:19][CH:18]=[C:17]([Cl:26])[N:16]=1)[CH3:28]
Reactant: CCN(c1nc(Cl)ccc1NC(C)(C)C)C1CCN(Cc2ccccc2)CC1
Agent: CC(Cl)OC(=O)Cl
Solvent: ClCCl
Product: CCN(c1nc(Cl)ccc1NC(C)(C)C)C1CCNCC1

Procedure:
1-Benzyl-4-[N-ethyl-N-(3-(1,1-dimethylethylamino)-6-chloro-2-pyridinyl)amino]piperidine (EXAMPLE 269, 1.5 g) is dissolved in 8 ml of methylene chloride and cooled to 0°. Then 1-chloroethyl chloroformate (0.54 ml) is added dropwise. The reaction is warmed to 20°-25° and refluxed for 30 min. Then the reaction is concentrated under reduced pressure and 15 ml of methanol is added and the reaction is heated to reflux for 2 hr. Then it is poured into saturated aqueous sodium bicarbonate and extracted with chloroform. The organic extracts are dried over potassium carbonate and concentrated under reduced pressure. Purification by flash column chromatography (90:9.5:0.5; chloroform/methanol/concentrated ammonium hydroxide) gives the title compound.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]2[CH:8]=[CH:9][O:10][C:5]2=[CH:4][CH:3]=1.CC(N=NC(C#N)(C)C)(C#N)C.C1C(=O)N([Br:30])C(=O)C1>>[Br:30][CH2:1][C:2]1[N:7]=[C:6]2[CH:8]=[CH:9][O:10][C:5]2=[CH:4][CH:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc2occc2n1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Product: BrCc1ccc2occc2n1
Temperature: 75 °C
Reaction time: 1 h

Procedure:
To a solution of 1.46 g (11.0 mmol) of 5-methylfuro[3,2b]pyridine (from Step 2) and 100 mg AIBN in 35 mL of CC14 was added 2.1 g (11.6 mmol) of NBS. The mixture was stirred at 75° C. under radiation from a 150 W spot light for 1 hr. Another portion of NBS was added (1.0 g) and the reaction was allowed to proceed for another 1.5 hr. The reaction was allowed to cool to r.t., diluted with aqueous NH4OAc 25% w/v (150 mL) and the mixture was extracted with EtOAc. The organic layer was dried over MgSO4 and concentrated. The resulting residue was purified by chromatography on silica gel eluted with 20-25 % EtOAc in hexane to give the title compound as a colorless oil.
Reaction SMILES: [ClH:1].[Cl-].O[CH2:4][CH2:5][CH2:6][N:7]([CH2:9][CH2:10][CH2:11][N+:12]([CH3:15])([CH3:14])[CH3:13])[CH3:8].S(Cl)([Cl:18])=O>>[ClH:18].[Cl-:1].[Cl:18][CH2:4][CH2:5][CH2:6][N:7]([CH2:9][CH2:10][CH2:11][N+:12]([CH3:15])([CH3:14])[CH3:13])[CH3:8]
Reactant: O=S(Cl)Cl
Reactant: CN(CCCO)CCC[N+](C)(C)C
Agent: Cl
Agent: [Cl-]
Product: CN(CCCCl)CCC[N+](C)(C)C

Procedure:
The process, according to claim 1, which comprises reacting N,N,N-trimethyl-[3-(methylamino)]-1-propanaminium bromide with oxetane in aqueous solution at a temperature of about 100° C., thereby forming 3[N'-(3-hydroxypropyl)-N'-methylamino]-N,N,N-trimethyl-1-propanaminium bromide, reacting the latter compound with aqueous hydrochloric acid to form 3-[N'-(3-hydroxypropyl)-N'-methylamino]-N,N,N-trimethyl-1-propanaminium chloride hydrochloride, and reacting the said 3-[N'-(3-hydroxypropyl)-N'-methylamino]-N,N,N-trimethyl-1-propanaminium chloride hydrochloride with thionyl chloride to form 3-[N'-(3-chloropropyl)-N'-methylamino]-N,N,N-trimethyl-1-propanaminium chloride hydrochloride.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]3[CH:15]=[C:14]([O:16][CH2:17][CH2:18][N:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)[C:13]([O:25][CH3:26])=[CH:12][C:9]=3[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:27]#[N:28].[Cl:29][C:30]1[CH:31]=[C:32]([NH2:43])[CH:33]=[CH:34][C:35]=1[S:36][C:37]1[N:38]([CH3:42])[CH:39]=[CH:40][N:41]=1.Cl.N1C=CC=CC=1>C(OCCO)C.CCOCC>[Cl:29][C:30]1[CH:31]=[C:32]([NH:43][C:2]2[C:11]3[C:6](=[CH:7][C:8]4[CH:15]=[C:14]([O:16][CH2:17][CH2:18][N:19]5[CH2:20][CH2:21][O:22][CH2:23][CH2:24]5)[C:13]([O:25][CH3:26])=[CH:12][C:9]=4[CH:10]=3)[N:5]=[CH:4][C:3]=2[C:27]#[N:28])[CH:33]=[CH:34][C:35]=1[S:36][C:37]1[N:38]([CH3:42])[CH:39]=[CH:40][N:41]=1
Reactant: Cn1ccnc1Sc1ccc(N)cc1Cl
Reactant: COc1cc2cc3c(Cl)c(C#N)cnc3cc2cc1OCCN1CCOCC1
Agent: Cl
Solvent: CCOCCO
Solvent: c1ccncc1
Solvent: CCOCC
Product: COc1cc2cc3c(Nc4ccc(Sc5nccn5C)c(Cl)c4)c(C#N)cnc3cc2cc1OCCN1CCOCC1
Temperature: 120 °C
Reaction time: 0.75 h
Yield: 59.1 %

Procedure:
A mixture of 1.98 g (4.98 mmol) of 4-chloro-7-methoxy-8-(2-morpholin-4-yl-ethoxy)benzo[g]quinoline-3-carbonitrile, 1.31 g (5.47 mmol) of 3-chloro-4-(1-methyl-1H-imidazol-2-ylsulfanyl)phenylamine and 0.6 g (5.2 mmol) of pyridine hydrochloride in 2-ethoxyethanol is heated at 120° C. for 1.25 hours, then cooled. The crude mixture is poured into a solution of saturated sodium bicarbonate/ice and stirred for 45 minutes. The resulting solid is collected by filtration, then washed with water, ether and ethyl acetate successively. After drying in vacuo, the solid is purified by silica gel chromatography, using a 94:6 to 9:1 gradient of methylene chloride/methanol to provide a yellow solid. This solid is suspended in ether, filtered, and further washed with ether. After drying in vacuo, 1.77 g of 4-[3-chloro-4-(1-methyl-1H-imidazol-2-ylsulfanyl)phenylamino]-7-methoxy-8-(2-morpholin-4-yl-ethoxy)benzo[g]quinoline-3-carbonitrile is obtained as a yellow solid, mp. >300° C.
Reaction SMILES: [CH3:1][CH:2]([NH2:9])[CH2:3][C:4]1[S:5][CH:6]=[CH:7][CH:8]=1.[CH:10](OCC)=[O:11]>>[CH3:1][CH:2]([NH:9][CH:10]=[O:11])[CH2:3][C:4]1[S:5][CH:6]=[CH:7][CH:8]=1
Reactant: CC(N)Cc1cccs1
Reactant: CCOC=O
Product: CC(Cc1cccs1)NC=O

Procedure:
A solution of 5.9 g (33.4 mmol) 1-methyl-2-thiophen-2-yl-ethylamine in 34.8 ml (417.7 mmol) ethyl formate is refluxed for 16 hours. Then the mixture is cooled and evaporated to dryness i. vac.
Reaction SMILES: Cl[CH2:2][C:3]([C:14]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=1[F:21])([OH:13])[CH:4]([O:6]C(=O)C(C)(C)C)[CH3:5].C[O-].[Na+].Cl>C1COCC1.CO>[O:13]1[C:3]([C:14]2[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=2[F:21])([CH:4]([OH:6])[CH3:5])[CH2:2]1
Reactant: CC(OC(=O)C(C)(C)C)C(O)(CCl)c1cc(F)ccc1F
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CC(O)C1(c2cc(F)ccc2F)CO1
Reaction time: 5 h
Yield: 79 %

Procedure:
A solution of 1.70 g (5.3 mmol) of 1-chloro-2-(2,5-difluorophenyl)-3-(pivaloyloxy)butan-2-ol ((2S,3R)/(2R,3R)=94/6) in 20 mL of THF was cooled to 0° C., and 3.5 g (17.8 mmol) of a 28% solution of NaOMe in methanol was added thereto. The reaction was performed for 5 hours, and 20 mL of 1 M hydrochloric acid was added to stop the reaction. Then, extraction was performed with ethylacetate (30 mL). After drying over anhydrous sodium sulfate, concentration was performed under reduced pressure to obtain 1.51 g of a crude product. The resulting product was purified by column on silica gel to obtain 0.838 g of the title compound (yield: 79%) ((2R,3R)/(2S,3R)=98/2 (the diastereomeric ratio was measured by HPLC under the same HPLC measurement conditions as those in Example 10, (2R,3R) 32 minutes, (2S,3R) 30 minutes). 1H-NMR (400 MHz, CDCl3) (2R,3R) δ: 1.70 (d, 3H, J=6.6 Hz), 2.80 (d, 1H, J=5.1 Hz), 3.34 (d, 1H, J=5.1 Hz), 4.17 (q, 1H, 6.6 Hz), 6.98-7.00 (m, 2H), 7.14-7.26 (m, 1H)
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[CH:11]/[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[NH2:18])=[N:2]1.C(N(CC)CC)C.[F:26][C:27]1[CH:35]=[CH:34][C:30]([C:31](Cl)=[O:32])=[CH:29][CH:28]=1.C(=O)([O-])[O-].[K+].[K+]>C1COCC1>[F:26][C:27]1[CH:35]=[CH:34][C:30]([C:31]([NH:18][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2/[CH:11]=[CH:10]/[C:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[NH:1][N:2]=2)=[O:32])=[CH:29][CH:28]=1
Reactant: Nc1ccccc1/C=C/c1n[nH]c2ccccc12
Reactant: O=C(Cl)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(Nc1ccccc1/C=C/c1n[nH]c2ccccc12)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 61.3 %

Procedure:
(E)-2-[2-(1H-indazol-3-yl)vinyl]phenylamine (60 mg, 0.26 mmol) obtained in Example 2 was dissolved in THF (1.5 mL) and the solution was added with triethylamine (71 μL, mmol) and p-fluorobenzoylchloride (45 μL, 0.38 mmol), followed by stirring at room temperature for 30 minutes. Further, the reaction mixture was added with potassium carbonate and stirred for a while. Then, the solid precipitated by adding water to the mixture was collected by filtration and the solid was triturated in ethanol to obtain Compound 3 (57 mg, 62%).
Reaction SMILES: [OH:1][C@H:2]1[CH2:22][C@@:21]2([CH3:23])[C@@H:13]([CH2:14][CH2:15][C@:16]2([OH:24])[C:17](=[O:20])[CH2:18][OH:19])[C@H:12]2[C@H:3]1[C@:4]1([CH3:27])[C:9]([C@@H:10]([CH3:25])[CH2:11]2)=[CH:8][C:7](=[O:26])[CH:6]=[CH:5]1.[CH3:28][O:29][CH2:30][CH2:31][C:32](Cl)=[O:33]>>[OH:1][C@H:2]1[CH2:22][C@@:21]2([CH3:23])[C@@H:13]([CH2:14][CH2:15][C@:16]2([OH:24])[C:17](=[O:20])[CH2:18][O:19][C:32](=[O:33])[CH2:31][CH2:30][O:29][CH3:28])[C@H:12]2[C@H:3]1[C@:4]1([CH3:27])[C:9]([C@@H:10]([CH3:25])[CH2:11]2)=[CH:8][C:7](=[O:26])[CH:6]=[CH:5]1
Reactant: C[C@H]1C[C@@H]2[C@H]([C@@H](O)C[C@@]3(C)[C@H]2CC[C@]3(O)C(=O)CO)[C@@]2(C)C=CC(=O)C=C12
Reactant: COCCC(=O)Cl
Product: COCCC(=O)OCC(=O)[C@@]1(O)CC[C@H]2[C@@H]3C[C@H](C)C4=CC(=O)C=C[C@]4(C)[C@H]3[C@@H](O)C[C@@]21C

Procedure:
Under the conditions of Example 3(a), 15.0 g of 11β,17,21-trihydroxy-6α-methyl-1,4-pregnadiene-3,20-dione is reacted with 3-methoxypropionic acid chloride, worked up, and purified, thus isolating 14.3 g of 11β,17-dihydroxy-6α-methyl-21-(3-methoxypropionyloxy)-1,4-pregnadiene-3,20-dione, mp 230° C.
Reaction SMILES: [OH2:1].[OH:2][CH2:3][CH2:4][CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[NH:8][C:7]1=[O:15].[CH3:16][S:17](Cl)(=[O:19])=[O:18]>N1C=CC=CC=1>[CH3:16][S:17]([OH:19])(=[O:1])=[O:18].[OH:2][CH2:3][CH2:4][CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[NH:8][C:7]1=[O:15]
Reactant: O
Reactant: CS(=O)(=O)Cl
Agent: O=c1[nH]c2ccccc2n1CCCO
Solvent: c1ccncc1
Product: CS(=O)(=O)O

Procedure:
To a solution of 52.5 parts of 1,3-dihydro-1-(3-hydroxypropyl)-2H-benzimidazol-2-one hydrate in 200 parts of pyridine is added dropwise 63 parts of methanesulfonyl chloride. The mixture is stirred and cooled on the air for 2 hours. The pyridine is evaporated. To the residue is added 500 parts of water and the formed precipitate is filtered off. It is dissolved in 350 parts of trichloromethane. This solution is dried over magnesium sulfate and evaporated. The residue is crystallized from 40 parts of methylbenzene, yielding 25.5 parts of 1,3-dihydro-1-(3-hydroxypropyl)-2H-benzimidazol-2-one methanesulfonate; mp. 118°-120° C.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([CH3:11])[CH:3]=1.[CH3:12][S:13]([C:16]1[N:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=1)(=[O:15])=[O:14].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:11][C:4]1[CH:3]=[C:2]([CH:7]=[CH:6][C:5]=1[N+:8]([O-:10])=[O:9])[O:22][C:19]1[CH:18]=[CH:17][C:16]([S:13]([CH3:12])(=[O:15])=[O:14])=[N:21][CH:20]=1
Reactant: CS(=O)(=O)c1ccc(O)cn1
Reactant: Cc1cc(F)ccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(Oc2ccc(S(C)(=O)=O)nc2)ccc1[N+](=O)[O-]
Temperature: 60 °C
Reaction time: 24 h
Yield: 46.5 %

Procedure:
A mixture of 4-fluoro-2-methyl-1-nitrobenzene (9.4 g), 6-(methylsulfonyl)pyridin-3-ol (10.0 g), potassium carbonate (8.8 g), and N,N-dimethylformamide (100 mL) was stirred at 60° C. for 24 hr. The reaction solution was concentrated under reduced pressure, and the obtained residue was added to a mixture of ethyl acetate-water. The precipitated solid was collected by filtration, washed with water and ethyl acetate and dried to give the title compound (8.28 g) as a pale-yellow solid. The filtrate was extracted with ethyl acetate, washed successively with aqueous citric acid solution, water and brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The obtained solid was washed with ethyl acetate to give the title compound (4.30 g) as a pale-yellow solid.
Reaction SMILES: [CH2:1]([Li])[C:2]([CH3:5])([CH3:4])[CH3:3].[CH3:7][N-:8][CH3:9].[CH3:10][N-:11][CH3:12].[CH3:13][N-:14][CH3:15].C[N-]C.[Zr+4:19]>CCCCCC.CCCCC>[CH3:7][N-:8][CH3:9].[CH3:10][N-:11][CH3:12].[CH3:13][N-:14][CH3:15].[CH2:1]([Zr+3:19])[C:2]([CH3:5])([CH3:4])[CH3:3]
Reactant: [Li]CC(C)(C)C
Reactant: [Zr+4]
Agent: C[N-]C
Solvent: CCCCC
Solvent: CCCCCC
Product: CC(C)(C)C[Zr+3]
Reaction time: 48 h

Procedure:
A solution of 0.50 g of neopentyllithium in hexane was added to a hot solution of zirconium tetrakis(dimethylamide) in hot hexane with stirring. Lithium dimethylamide precipitated immediately. The total amount of hexane in the reaction mixture was about 50-100 ml. The mixture was cooled and filtered, and the filtrate was evaporated to give a sticky solid. The latter was dissolved in pentane, and the solution was kept at -40° C. for 2 days. During this time yellow crystals of neopentylzirconium tris(dimethylamide) separated. They were isolated by filtration and dried; yield 0.5 g. Nmr in C6D6 : δ (NMe) 2.92, δ (CH2) 0.9, δ (CMe3) 1.20 ppm downfield from tetramethylsilane.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[NH:10][C:11]2[CH:17]=[C:16]([C:18]([NH:20][NH2:21])=[O:19])[CH:15]=[CH:14][C:12]=2[N:13]=1.[CH3:22][O:23][C:24]1[CH:25]=[C:26]([N:30]=[C:31]=S)[CH:27]=[CH:28][CH:29]=1.CCN=C=NCCCN(C)C.CCOC(C)=O>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[NH:10][C:11]2[CH:17]=[C:16]([C:18]3[O:19][C:31]([NH:30][C:26]4[CH:27]=[CH:28][CH:29]=[C:24]([O:23][CH3:22])[CH:25]=4)=[N:21][N:20]=3)[CH:15]=[CH:14][C:12]=2[N:13]=1
Reactant: COc1cccc(N=C=S)c1
Reactant: NNC(=O)c1ccc2nc(-c3c(Cl)cccc3Cl)[nH]c2c1
Agent: CCN=C=NCCCN(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1cccc(Nc2nnc(-c3ccc4nc(-c5c(Cl)cccc5Cl)[nH]c4c3)o2)c1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of 2-(2,6-dichloro-phenyl)-3H-benzoimidazole-5-carboxylic acid hydrazide (150 mg, 0.466 mmol) in DMF (3 mL) add 3-methoxy phenyl isothiocyanate (69 uL, 0.512 mmol) and stir for 1.5 hr. Add EDCI (179 mg, 0.932 mmol) and heat to 80° C. for 50 min. Upon cooling to room temp, dilute the reaction with EtOAc (75 mL) and extract with water (15 mL). Evaporate the organic phase and suspend the solid in 1 N NaOH. Collect the solid wash with water and Et2O, Suspend the solid in boiling toluene/EtOAc. Cool the suspension to 4° C. and filter. Wash the solid with Et2O. Again suspend the solid in 1 N NaOH and stir for 1 hr. Collect the solid and wash with water and Et2O. Dry to afford the title compound: 1H NMR (400 MHz, DMSO-d6) δ ppm 3.78 (s, 3H) 6.61 (dd, J=8.15, 1.83 Hz, 1H) 7.14-7.19 (m, 1H) 7.28 (t, J=8.15 Hz, 1H) 7.34 (t, J=2.15 Hz, 1H) 7.64 (dd, J=9.35, 6.69 Hz, 1H) 7.70 (s, 1H) 7.84 (br. s., 2H) 7.72 (d, J=1.89 Hz, 1H) 8.11 (br. s., 1H) 10.67 (br. s., 1H) 13.29 (br. s., 1H); MS m/z=452.1 (M+1).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[O:7][CH:8]([C:10]1[CH:19]=[CH:18][C:13]([C:14]([O:16]C)=[O:15])=[CH:12][CH:11]=1)[CH3:9].O.[OH-].[Li+].O.CO>O1CCCC1>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[O:7][CH:8]([C:10]1[CH:19]=[CH:18][C:13]([C:14]([OH:16])=[O:15])=[CH:12][CH:11]=1)[CH3:9]
Reactant: COC(=O)c1ccc(C(C)Oc2ccccn2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CC(Oc1ccccn1)c1ccc(C(=O)O)cc1
Temperature: 20 °C
Reaction time: 5 h
Yield: 92.9 %

Procedure:
A mixture of methyl 4-(1-(pyridin-2-yloxy)ethyl)benzoate (590 mg, 2.3 mmol), lithium hydroxide monohydrate (482 mg, 11.5 mmol), water (4 mL) and methanol (4 mL) in tetrahydrofuran (12 mL) was stirred at 20° C. for 5 hours. The reaction mixture was concentrated. The residue was acidified to pH=2 with concentrated hydrochloride solution. The mixture was extracted with ethyl acetate (20 mL×2). The organic phase was dried over sodium sulfate and filtered. The filtrate was concentrated. The residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=2:1) to give 4-(1-(pyridin-2-yloxy)ethyl)benzoic acid as a white solid (520 mg, 93%). LRMS (M+H+) m/z: 243.09. found 243.