Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[CH:4]=[N:5][OH:6].[Cl:11]CCl>>[F:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([Cl:11])=[N:5][OH:6]
Reactant: ON=Cc1ccccc1F
Reactant: ClCCl
Product: ON=C(Cl)c1ccccc1F
Temperature: -10 °C

Procedure:
In 1 liter dichloromethane was dissolved 55.0 g 2-fluorobenzaldehyde oxime at room temperature with stirring. The resulting solution was cooled to -10° C. and Cl2 was bubbled in at such a rate to maintain the temperature below 15° C. After a dark blue color was generated (2-3 minutes) a solution of triethylamine (50 ml) in dichloromethane (100 ml) was added dropwise concurrently with Cl2 addition. When the reaction mixture had maintained a yellow color, additions of the triethylamine solution and Cl2 were discontinued. Concentration of the reaction mixture left an oil which was dissolved in ether and washed four times with 3N HCl followed by a final wash with brine. The organic layer was dried (MgSO4), filtered and concentrated in vacuo to give 60.0 g of 2-fluoro-N-hydroxybenzenecarboximidoyl chloride as an oil which solidified on standing.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([NH:12][C:13](=[O:22])[CH2:14][C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)=[S:11])[CH:5]=[CH:6][C:7]=1[OH:8].[C:23]([O:29][C:30]1[C:31]([CH3:40])=[C:32]2[N:37]([CH:38]=1)[N:36]=[CH:35][N:34]=[C:33]2Cl)(=[O:28])[C:24]([CH3:27])([CH3:26])[CH3:25].N12CCN(CC1)CC2>CC#N>[C:23]([O:29][C:30]1[C:31]([CH3:40])=[C:32]2[N:37]([CH:38]=1)[N:36]=[CH:35][N:34]=[C:33]2[O:8][C:7]1[CH:6]=[CH:5][C:4]([NH:9][C:10]([NH:12][C:13](=[O:22])[CH2:14][C:15]2[CH:16]=[CH:17][C:18]([F:21])=[CH:19][CH:20]=2)=[S:11])=[CH:3][C:2]=1[F:1])(=[O:28])[C:24]([CH3:27])([CH3:26])[CH3:25]
Reactant: Cc1c(OC(=O)C(C)(C)C)cn2ncnc(Cl)c12
Reactant: O=C(Cc1ccc(F)cc1)NC(=S)Nc1ccc(O)c(F)c1
Agent: C1CN2CCN1CC2
Solvent: CC#N
Product: Cc1c(OC(=O)C(C)(C)C)cn2ncnc(Oc3ccc(NC(=S)NC(=O)Cc4ccc(F)cc4)cc3F)c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.5 %

Procedure:
To a mixture of 1-(3-fluoro-4-hydroxyphenyl)-3-(2-(4-fluorophenyl)acetyl)thiourea (60 mg, 0.19 mmol, Compound A of Example 3), 4-chloro-5-methylpyrrolo[2,1-f][1,2,4]triazin-6-yl pivalate (50 mg, 0.19 mmol, Compound D of Example 1) and 1,4-diazabicyclo[2.2.2]octane (DABCO, 21.3 mg, 0.19 mmol) was added MeCN (5 mL). The reaction was stirred at RT for 1 h and concentrated in vacuo. The residue was purified by flash chromatography (eluted with 1-15% MeOH/CH2Cl2) to give the title compound (91 mg, 86%) as a white solid. 1H NMR (CDCl3) δ 12.40 (s, 1H), 8.54 (s, 1H), 7.87 (m, 3H), 7.29 (m, 4H), 7.12 (m, 2H), 3.71 (s, 2H), 2.43 (s, 3H), 1.39 (s, 9H); MS(ESI+) m/z 554 (M+H)+.
Reaction SMILES: [C:1]([NH:4][CH2:5][CH:6]([C:16]1[CH:24]=[CH:23][C:19]([C:20](O)=[O:21])=[CH:18][CH:17]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:8])(=[O:3])[CH3:2].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[NH2:46][C:47]1[CH:52]=[C:51]([C:53]2[CH:57]=[CH:56][S:55][CH:54]=2)[CH:50]=[CH:49][C:48]=1[NH:58][C:59](=[O:65])[O:60][C:61]([CH3:64])([CH3:63])[CH3:62]>CN(C=O)C.O>[C:61]([O:60][C:59](=[O:65])[NH:58][C:48]1[CH:49]=[CH:50][C:51]([C:53]2[CH:57]=[CH:56][S:55][CH:54]=2)=[CH:52][C:47]=1[NH:46][C:20](=[O:21])[C:19]1[CH:23]=[CH:24][C:16]([CH:6]([CH2:5][NH:4][C:1](=[O:3])[CH3:2])[C:7]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:8])=[CH:17][CH:18]=1)([CH3:62])([CH3:64])[CH3:63]
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccsc2)cc1N
Reactant: CC(=O)NCC(C(=O)Nc1ccccc1)c1ccc(C(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)NCC(C(=O)Nc1ccccc1)c1ccc(C(=O)Nc2cc(-c3ccsc3)ccc2NC(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
4-{1-[(Acetylamino)methyl]-2-anilino-2-oxoethyl}benzoic acid (232 mg, 0.71 mmol), EDCI (176 mg, 0.92 mmol), and HOBT (124 mg, 0.92 mmol) were combined in DMF (8 mL) and stirred for 10 minutes before adding tert-butyl [2-amino-4-(3-thienyl)phenyl]carbamate (227 mg, 0.78 mmol). The reaction was then stirred at 60° C. for 24 h. The solution was cooled to room temperature, poured into water (40 mL), and filtered to collect an orange solid. The crude solid was dissolved in CH2Cl2 (25 mL) and hexanes (20 mL), concentrated to half volume, and filtered to give tert-butyl[2-[(4-{1-[(acetylamino)methyl]-2-anilino-2-oxoethyl}benzoyl)amino]-4-(3-thienyl)phenyl]carbamate as a white solid. MS (ESI) calcd [M+H]+ 599.2, found 599.1.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[N:13]=[CH:12][C:11]([C:14](=[O:34])[NH:15][CH2:16][CH:17]2[CH2:22][CH2:21][N:20]([S:23]([CH2:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)(=[O:25])=[O:24])[CH2:19][CH2:18]2)=[CH:10][N:9]=1)(C)(C)C>Cl.O1CCOCC1>[C:28]1([CH2:27][CH2:26][S:23]([N:20]2[CH2:21][CH2:22][CH:17]([CH2:16][NH:15][C:14]([C:11]3[CH:12]=[N:13][C:8]([NH2:7])=[N:9][CH:10]=3)=[O:34])[CH2:18][CH2:19]2)(=[O:25])=[O:24])[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: CC(C)(C)OC(=O)Nc1ncc(C(=O)NCC2CCN(S(=O)(=O)CCc3ccccc3)CC2)cn1
Agent: Cl
Solvent: C1COCCO1
Product: Nc1ncc(C(=O)NCC2CCN(S(=O)(=O)CCc3ccccc3)CC2)cn1

Procedure:
2-Amino-pyrimidine-5-carboxylic acid [1-(2-phenyl-ethanesulfonyl)-piperidin-4-ylmethyl]-amide was prepared from (5-{[1-(2-phenyl-ethanesulfonyl)-piperidin-4-ylmethyl]-carbamoyl}-pyrimidin-2-yl)-carbamic acid tert-butyl ester by stirring at rt for 3 h in 4N HCl in dioxane. The product was precipitated as the hydrochloride salt by dilution with ether and filtration.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:29]=[CH:30][CH:31]=1)[O:7][C:8]1[C:13]([C:14]([O:16]CC)=[O:15])=[CH:12][CH:11]=[C:10]([O:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26](=[NH:28])[NH2:27])[CH:21]=2)[N:9]=1)(=[NH:3])[NH2:2].[ClH:32]>>[ClH:32].[ClH:32].[C:1]([C:4]1[CH:5]=[C:6]([CH:29]=[CH:30][CH:31]=1)[O:7][C:8]1[C:13]([C:14]([OH:16])=[O:15])=[CH:12][CH:11]=[C:10]([O:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26](=[NH:27])[NH2:28])[CH:21]=2)[N:9]=1)(=[NH:2])[NH2:3]
Reactant: CCOC(=O)c1ccc(Oc2cccc(C(=N)N)c2)nc1Oc1cccc(C(=N)N)c1
Agent: Cl
Product: N=C(N)c1cccc(Oc2ccc(C(=O)O)c(Oc3cccc(C(=N)N)c3)n2)c1
Temperature: 80 °C

Procedure:
In a manner similar to Example 2 above, 2,6-bis(3-amidinophenoxy)-pyridine-3-carboxylic acid, ethyl ester (0.20 g, 0.31 mmol) was dissolved in 5 M HCl and heated for 2 hours at 80° C. The solvent was removed in vacuo to give 2,6-bis(3-amidinophenoxy)-pyridine-3-carboxylic acid, dihydrochloride; NMR (DMSO-d6) 9.5 (br s,4), 9.35 (br s,4), 8.45 (d,1), 7.7 (m,2), 7.6 (m,2), 7.5 (m,4), 6.95 (d,1) ppm.
Reaction SMILES: O.[OH-].[Na+].[OH:4][C@H:5]([CH3:12])[CH2:6][C:7]([O:9]CC)=[O:8].[Cl-].[Na+].[CH2:15]([OH:17])[CH3:16]>>[C:15]([O:4][CH:5]([CH3:12])[CH2:6][C:7]([OH:9])=[O:8])(=[O:17])[CH3:16]
Reactant: CCO
Reactant: CCOC(=O)C[C@@H](C)O
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(=O)OC(C)CC(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a liquid mixture comprising 15 ml of water, 15 ml of ethanol and sodium hydroxide was dissolved 4.0 of ethyl (R)-β-hydroxybutanoate, and the solution was refluxed under heating, cooled and passed through an ion exchange resin (Amberlite1/2 IR-120B). The solvent was removed under a reduced pressure, 10 ml of anhydrous pyridine and 3 ml of anhydrous acetic acid were added to the residue, and the mixture was stirred at room temperature overnight. Dilute hydrochloric acid was added to the reaction liquid to adjust the pH value to 1, and the reaction liquid was saturated with sodium chloride and extracted with chloroform. The extract was washed with a saturated aqueous sodium chloride solution and dehydrated on magnesium sulfate. Then, chloroform was removed under a reduced pressure to obtain 3.6 g of the intended compound having [α]24 of -5.7°.
Reaction SMILES: [C:1]1([SH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[CH2:10]([C:14]1[N:15]([CH2:28][CH2:29][CH2:30]Cl)[C:16]2[C:25]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[N:19]=[C:18]([NH2:26])[C:17]=2[N:27]=1)[CH2:11][CH2:12][CH3:13]>CN(C)C=O>[CH2:10]([C:14]1[N:15]([CH2:28][CH2:29][CH2:30][S:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:16]2[C:25]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[N:19]=[C:18]([NH2:26])[C:17]=2[N:27]=1)[CH2:11][CH2:12][CH3:13]
Reactant: Sc1ccccc1
Reactant: CCCCc1nc2c(N)nc3ccccc3c2n1CCCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCc1nc2c(N)nc3ccccc3c2n1CCCSc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 68.1 %

Procedure:
A round bottom flask was charged with a magnetic stir bar, benzenethiol (0.68 g, 6.21 mmol), sodium hydride (0.25 g, 60% dispersion, 6.21 mmol), and anhydrous dimethyl formamide (28 mL) under a nitrogen atmosphere. After the reaction mixture had stirred at ambient temperature for 30 minutes, 2-butyl-1-(3-chloropropyl)-1H-imidazo[4,5-c]quinolin-4-amine (1.64 g, 5.18 mmol) was added and the resulting cloudy solution was was completely consumed. The hot solution was poured into rapidly stirred water (200 mL). The resulting mixture was extracted with chloroform (2×). The combined organic layers were washed with saturated aqueous sodium bicarbonate and brine, dried over anhydrous sodium sulfate, filtered and then concentrated under reduced pressure to afford a light yellow oil. The material was purified by chromatography over silica gel (95/5 dichloromethane/methanol) to provide 2-butyl-1-[3-(phenylthio)propyl]-1H-imidazo[4,5-c]quinolin-4-amine (1.38 g, 3.53 mmol) as a white solid.
Reaction SMILES: C(O[CH:4]=[C:5]([C:8]#[N:9])[C:6]#[N:7])C.[Br:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([Br:17])[C:12]=1[NH:18][NH2:19]>CO>[NH2:9][C:8]1[N:18]([C:12]2[C:11]([Br:10])=[CH:16][CH:15]=[CH:14][C:13]=2[Br:17])[N:19]=[CH:4][C:5]=1[C:6]#[N:7]
Reactant: NNc1c(Br)cccc1Br
Reactant: CCOC=C(C#N)C#N
Solvent: CO
Product: N#Cc1cnn(-c2c(Br)cccc2Br)c1N
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2-(Ethoxymethylene)malononitrile (197 mg, 1.62 mmol) was added portionwise to a stirred solution of (2,6-dibromophenyl)hydrazine (CAS no. 14763-29-2) (430 mg, 1.62 mmol) in MeOH (8085 μl), under nitrogen at 5° C. The resulting solution was allowed to stir for a further 1 hour. The reaction mixture was then heated to reflux and was stirred for 3 hours. The reaction mixture was allowed to cool to ambient temperature, then was evaporated to afford crude product which was used without further purification.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([S:8]([C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:21])[CH:19]=[CH2:20])=[CH:13][CH:12]=2)(=[O:10])=[O:9])[CH2:4][CH2:3]1.[C:22]1([CH2:28][CH:29]=O)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH2:29]([NH:1][CH:2]1[CH2:7][CH2:6][N:5]([S:8]([C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:21])[CH:19]=[CH2:20])=[CH:13][CH:12]=2)(=[O:9])=[O:10])[CH2:4][CH2:3]1)[CH2:28][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=CCc1ccccc1
Reactant: C=CC(=O)Nc1ccc(S(=O)(=O)N2CCC(N)CC2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: C=CC(=O)Nc1ccc(S(=O)(=O)N2CCC(NCCc3ccccc3)CC2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 3.7 %

Procedure:
To a solution of N-[4-(4-amino-piperidine-1-sulfonyl)-phenyl]-acrylamide (0.2 g, 3.1 mmol) and phenylacetaldehyde (0.06 ml, 0.52 mmol) in DCE (15 ml) was added triethylamine (0.066 ml, 0.47 mmol) in one portion. The resulting mixture was then stirred at room temperature under a nitrogen atmosphere for 30 minutes, after which time sodium triacetoxy borohydride (0.1 g, 0.47 mmol) was added portion wise. The reaction mixture was stirred at room temperature under a nitrogen atmosphere for a further 2 hours before being concentrated under vacuum. The resulting residue was purified by Prep HPLC to afford the title compound (8 mg, 7% yield) as an off-white powder.
Reaction SMILES: [H-].[Na+].[CH:3]1([CH2:6][OH:7])[CH2:5][CH2:4]1.C[O:9][C:10]([C:12]1[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[C:14](Cl)[N:13]=1)=[O:11].Cl>O>[CH:3]1([CH2:6][O:7][C:14]2[N:13]=[C:12]([C:10]([OH:11])=[O:9])[CH:17]=[CH:16][C:15]=2[C:18]([F:21])([F:19])[F:20])[CH2:5][CH2:4]1
Reactant: OCC1CC1
Reactant: COC(=O)c1ccc(C(F)(F)F)c(Cl)n1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: O=C(O)c1ccc(C(F)(F)F)c(OCC2CC2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 85 %

Procedure:
Sodium hydride (1.1 g, 31.4 mmol) was added in portions to cyclopropylmethanol (20 mL) and the mixture was stirred at room temperature for 0.5 hours. 6-Chloro-5-(trifluoromethyl)-pyridine-2-carboxylic acid methyl ester (1.5 g, 6.3 mmol) was added and the resulting solution was stirred at 80° C. for 1 h. Water (20 mL) was added; the solution was acidified with 6 N hydrochloric acid and then concentrated to give a residue which was partitioned between water (30 mL) and ethyl acetate (20 mL). The aqueous solution was extracted with ethyl acetate (2×20 mL) and the combined organic phase was washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give the crude target compound. The crude target compound was purified by column chromatography (silica gel, 10 g, 15% ethyl acetate in petroleum ether) to give the title compound (1.4 g, 85%) as white solid; MS (EI): m/e=262.0 [M+H]+.
Reaction SMILES: C([O:3][C:4]([CH2:6][C:7]1([NH:17][C:18]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=2)=[O:19])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[NH:9][C:8]1=[O:16])=[O:5])C.[OH-].[K+]>C(O)C>[OH:5][C:4]([CH2:6][C:7]1([NH:17][C:18]([CH2:20][C:21]2[CH:22]=[CH:23][C:24]([CH3:27])=[CH:25][CH:26]=2)=[O:19])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[NH:9][C:8]1=[O:16])=[O:3]
Reactant: CCOC(=O)CC1(NC(=O)Cc2ccc(C)cc2)C(=O)Nc2ccccc21
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: Cc1ccc(CC(=O)NC2(CC(=O)O)C(=O)Nc3ccccc32)cc1
Reaction time: 4 h

Procedure:
To a solution of 0.29 g of (RS)-3-(ethoxycarbonylmethyl)-3-((4-methylbenzyl)carbonylamino)indolin-2-one in 10 ml of ethanol was added 2 ml of an aqueous solution of 0.16 g of potassium hydroxide (85%) at room temperature, and the mixture was stirred for 4 hours, followed by concentration. The concentrate was diluted with water, and washed with chloroform. The aqueous layer was adjusted to pH 2 by addition of 2N hydrochloric acid and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated to obtain (RS)-3-(hydroxycarbonyl methyl)-3-((4-methylbenzyl )carbonylamino )indolin-2-one.
Reaction SMILES: [F:1][C:2]([F:13])([S:9]([O-:12])(=[O:11])=[O:10])[CH:3]([OH:8])[C:4]([F:7])([F:6])[F:5].[CH2:14]([N+:21]([CH3:24])([CH3:23])[CH3:22])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[C:25]12([C:35](Cl)=[O:36])[CH2:34][CH:29]3[CH2:30][CH:31]([CH2:33][CH:27]([CH2:28]3)[CH2:26]1)[CH2:32]2>>[C:25]12([C:35]([O:8][CH:3]([C:4]([F:6])([F:5])[F:7])[C:2]([F:1])([F:13])[S:9]([O-:12])(=[O:10])=[O:11])=[O:36])[CH2:32][CH:31]3[CH2:30][CH:29]([CH2:28][CH:27]([CH2:33]3)[CH2:26]1)[CH2:34]2.[CH2:14]([N+:21]([CH3:24])([CH3:23])[CH3:22])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C(Cl)C12CC3CC(CC(C3)C1)C2
Reactant: O=S(=O)([O-])C(F)(F)C(O)C(F)(F)F
Agent: C[N+](C)(C)Cc1ccccc1
Product: O=C(OC(C(F)(F)F)C(F)(F)S(=O)(=O)[O-])C12CC3CC(CC(C3)C1)C2

Procedure:
Benzyltrimethylammonium 1,1,3,3,3-pentafluoro-2-hydroxypropane-1-sulfonate in Synthesis Example 1-1 and 1-adamantanecarboxylic acid chloride were reacted in accordance with the teaching of JP-A 2008-106045, yielding the desired compound, benzyltrimethylammonium 2-(adamantane-1-carbonyloxy)-1,1,3,3,3-pentafluoropropane-1-sulfonate as white crystals.
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[C:9]([CH3:10])=[C:8]([O:11][CH3:12])[C:7]([CH3:13])=[CH:6][N:5]=1.[SH:14][C:15]1[NH:16][C:17]2[C:23]([S:24]([C:27]3[C:38]([CH3:39])=[CH:37][C:30]([O:31][CH2:32][C:33]([O:35][CH3:36])=[O:34])=[CH:29][C:28]=3[CH3:40])(=[O:26])=[O:25])=[C:22]([O:41][CH3:42])[CH:21]=[CH:20][C:18]=2[N:19]=1.C(=O)([O-])[O-].[K+].[K+].Cl>CN(C)C=O>[CH3:42][O:41][C:22]1[CH:21]=[CH:20][C:18]2[N:19]=[C:15]([S:14][CH2:3][C:4]3[C:9]([CH3:10])=[C:8]([O:11][CH3:12])[C:7]([CH3:13])=[CH:6][N:5]=3)[NH:16][C:17]=2[C:23]=1[S:24]([C:27]1[C:28]([CH3:40])=[CH:29][C:30]([O:31][CH2:32][C:33]([O:35][CH3:36])=[O:34])=[CH:37][C:38]=1[CH3:39])(=[O:25])=[O:26]
Reactant: COC(=O)COc1cc(C)c(S(=O)(=O)c2c(OC)ccc3nc(S)[nH]c23)c(C)c1
Reactant: COc1c(C)cnc(CCl)c1C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)COc1cc(C)c(S(=O)(=O)c2c(OC)ccc3nc(SCc4ncc(C)c(OC)c4C)[nH]c23)c(C)c1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 80 %

Procedure:
2-Chloromethyl-3,5-dimethyl-4-methoxypyridine hydrochloride (4.4 g, 0.020 mol) was added to a mixture of methyl {4-[(2-mercapto-5-methoxybenzimidazolyl)sulfonyl]-3,5-dimethylphenoxy}acetate (Intermediate A4, 8.2 g, 0.019 mol), potassium carbonate (5.7 g, 0.041 mol), and dimethylformamide (80 mL). The mixture was stirred for 1.5 hr and was then poured in 150 mL of rapidly stirring ice water containing 40 mL of 1.2 M hydrochloric acid. The resulting solid was collected and washed with several portions of water. After partial air-drying, the 10 g of solid was dissolved in 100 mL of dichloromethane. This solution was washed with saturated aqueous sodium bicarbonate, filtered through 1PS paper, and concentrated. The residue was mixed with boiling methanol and collected, yielding 8.9 g (80%) of the title compound.
Reaction SMILES: [CH3:1][N:2]([CH3:22])[C:3](=[O:21])[O:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([NH:11][C:12]([C:14]2([CH3:20])[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)=[O:13])[CH:6]=1.Cl[C:24]1[C:25]2[C:32]([CH3:33])=[CH:31][NH:30][C:26]=2[N:27]=[CH:28][N:29]=1.C(N(CC)C(C)C)(C)C>C(O)(C)C>[CH3:22][N:2]([CH3:1])[C:3](=[O:21])[O:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([NH:11][C:12]([C:14]2([CH3:20])[CH2:15][CH2:16][N:17]([C:24]3[C:25]4[C:32]([CH3:33])=[CH:31][NH:30][C:26]=4[N:27]=[CH:28][N:29]=3)[CH2:18][CH2:19]2)=[O:13])[CH:6]=1
Reactant: Cc1c[nH]c2ncnc(Cl)c12
Reactant: CN(C)C(=O)Oc1cccc(NC(=O)C2(C)CCNCC2)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: Cc1c[nH]c2ncnc(N3CCC(C)(C(=O)Nc4cccc(OC(=O)N(C)C)c4)CC3)c12
Temperature: 100 °C
Yield: 53 %

Procedure:
3-(4-methylpiperidine-4-carboxamido)phenyl dimethylcarbamate from step B (47 mg, 0. 14 mmol) 4-chloro-5-methyl-7H-pyrrolo[2,3-d]pyrimidine (23 mg, 0.138 mmol), N,N-diisopropylethylamine (54 mg, 0.41 mmol), and isopropanol (1.0 mL) were combined in a pressure rated sealed tube and heated at 100° C. for 18 hours. The mixture was concentrated, and the residue was purified by preparative HPLC to give the title compound in 53% yield.
Reaction SMILES: [C:1]1([CH2:7][C:8](=[O:12])[C:9]([OH:11])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:13]Br>C(O)(=O)C>[Br:13][CH:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[C:8](=[O:12])[C:9]([OH:11])=[O:10]
Reactant: BrBr
Reactant: O=C(O)C(=O)Cc1ccccc1
Solvent: CC(=O)O
Product: O=C(O)C(=O)C(Br)c1ccccc1
Reaction time: 0.25 h
Yield: 69.1 %

Procedure:
12.31 g of phenyl-pyruvic acid and 50 ml of acetic acid were mixed together and then a solution of 12.34 g of bromine in 4 ml of acetic acid was added drop by drop over 1 hour. After the introduction was finished, stirring was continued for 15 minutes, followed by concentration to dryness under reduced pressure. The residue was taken up in 40 ml of dichloroethane and concentrated to dryness under reduced pressure, 30 ml of dichloroethane were added, and crystallization was allowed for 2 hours at 20° C. to obtain 12.6 g of 3-bromo-3-phenyl-pyruvic acid melting at 110° C.
Reaction SMILES: [CH3:1][CH:2]([CH2:4][CH2:5][CH2:6][C@H:7]([C@@H:9]1[C@:26]2([CH3:27])[C@H:12]([C@H:13]3[C@H:23]([CH2:24][CH2:25]2)[C@:21]2([CH3:22])[C:16]([CH2:17][C@@H:18]([O:28][CH2:29][CH2:30]Cl)[CH2:19][CH2:20]2)=[CH:15][CH2:14]3)[CH2:11][CH2:10]1)[CH3:8])[CH3:3].[I-:32].[Na+]>CC(=O)CC>[CH3:1][CH:2]([CH2:4][CH2:5][CH2:6][C@H:7]([C@@H:9]1[C@:26]2([CH3:27])[C@H:12]([C@H:13]3[C@H:23]([CH2:24][CH2:25]2)[C@:21]2([CH3:22])[C:16]([CH2:17][C@@H:18]([O:28][CH2:29][CH2:30][I:32])[CH2:19][CH2:20]2)=[CH:15][CH2:14]3)[CH2:11][CH2:10]1)[CH3:8])[CH3:3]
Reactant: [I-]
Reactant: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](OCCCl)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: [Na+]
Solvent: CCC(C)=O
Product: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](OCCI)CC[C@]4(C)[C@H]3CC[C@]12C
Yield: 76.9 %

Procedure:
A solution of 2-(5-cholesten-3β-yloxy)ethyl chloride (17 g, 38 mmol) and sodium iodide (8.5 g, 57 mmol) in 2-butanone (200 ml) is heated for 5 hours under reflux. The mixture is concentrated to a residue which is partitioned between chloroform and water. The organic layer is washed with sodium thiosulfate, water, dried and evaporated to dryness. Crystallization from ether-methanol affords 2-(5-cholesten-3β-yloxy)ethyl iodide (15.8 g, 77%), m.p. 86°-88°.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH:8]=O)=[N:4][N:5]([CH3:7])[CH:6]=1.C(O)(=O)[CH2:11][C:12]([OH:14])=[O:13].N1CCCCC1.Cl>N1C=CC=CC=1>[Br:1][C:2]1[C:3](/[CH:8]=[CH:11]/[C:12]([OH:14])=[O:13])=[N:4][N:5]([CH3:7])[CH:6]=1
Reactant: Cn1cc(Br)c(C=O)n1
Reactant: O=C(O)CC(=O)O
Agent: Cl
Solvent: C1CCNCC1
Solvent: c1ccncc1
Product: Cn1cc(Br)c(/C=C/C(=O)O)n1

Procedure:
A solution of 4-bromo-1-methyl-1H-pyrazole-3-carbaldehyde (1.00 g, 5.29 mmol), malonic acid (825 mg, 7.94 mmol) and piperidine (0.12 mL, 1.2 mmol) in pyridine (0.60 mL) was heated to reflux for 3 hours. The mixture was then poured into 10% HCl and extracted with ethyl acetate (3×). The combined extracts were dried (Na2SO4) and concentrated in vacuo to afford (2E)-3-(4-bromo-1-methyl-1H-pyrazol-3-yl)prop-2-enoic acid as a colorless solid.
Reaction SMILES: C([N:8]1[CH2:12][CH:11]2[CH2:13][N:14]([C:16]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][C:19]=3[N:26]3[N:30]=[CH:29][CH:28]=[N:27]3)=[O:17])[CH2:15][CH:10]2[CH2:9]1)C1C=CC=CC=1>CCO.CC(O)=O.[OH-].[OH-].[Pd+2]>[CH2:13]1[CH:11]2[CH2:12][NH:8][CH2:9][CH:10]2[CH2:15][N:14]1[C:16]([C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][C:19]=1[N:26]1[N:27]=[CH:28][CH:29]=[N:30]1)=[O:17]
Reactant: COc1ccc(C(=O)N2CC3CN(Cc4ccccc4)CC3C2)c(-n2nccn2)c1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Solvent: CC(=O)O
Product: COc1ccc(C(=O)N2CC3CNCC3C2)c(-n2nccn2)c1

Procedure:
(5-Benzylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(4-methoxy-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone in EtOH (20 mL) and AcOH (1 mL) was continuously flowed through a 20 wt % Pd(OH)2/C cartridge at a rate of 1 mL/min for 2 h at 50° C. and 50 bar using a H-cube apparatus. Then the reaction was concentrated and neutralized with 5% Na2CO3 (aq), and extracted with CH2Cl2 (3×). Combined organics and dried (Na2SO4) to give (hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(4-methoxy-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone as a clear oil that was used without further purification. 1H NMR (CDCl3): 7.83-7.80 (m, 2H), 7.50 (d, J=2.5 Hz, 1H), 7.32 (d, J=8.5 Hz, 1H), 6.96 (dd, J=8.5, 2.5 Hz, 1H), 3.89 (s, 3H), 3.75-3.63 (m, 2H), 3.27 (s, 1H), 3.08 (dd, J=11.9, 8.1 Hz, 1H), 2.94 (dt, J=11.4, 5.7 Hz, 2H), 2.88-2.75 (m, 2H), 2.69 (dd, J=17.8, 14.3 Hz, 1H), 2.56 (dd, J=11.4, 3.9 Hz, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8](O)[CH3:9])[CH:5]=[N:6][CH:7]=1.P(Br)(Br)[Br:12].C([O-])(O)=O.[Na+]>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[N:6][CH:5]=[C:4]([CH:8]([Br:12])[CH3:9])[CH:3]=1
Reactant: CC(O)c1cncc(Br)c1
Reactant: BrP(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(Br)c1cncc(Br)c1
Reaction time: 4 h
Yield: 43.4 %

Procedure:
1-(5-Bromo-pyridin-3-yl)-ethanol (1.5 g, 7.4 mmol) is dissolved in DCM (70 mL) and phosphorus tribromide (0.73 mL, 7.4 mmol) is added. The mixture is stirred for 4 hrs and saturated NaHCO3 aqueous solution is used to adjust the pH to about 7. The mixture is then extracted with DCM (3×50 mL). The organic layers are combined and concentrated to give the crude product. Purification by flash column chromatography affords 850 mg of 3-bromo-5-(1-bromo-ethyl)-pyridine.