Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+:2].O.O.[Na+].[OH:6][C:7]1[CH:12]=[CH:11][C:10]([S:13]([O-:16])(=[O:15])=[O:14])=[CH:9][CH:8]=1.O.[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(O)C>[Na+:2].[CH2:18]([O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13]([O-:16])(=[O:14])=[O:15])=[CH:9][CH:8]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=S(=O)([O-])c1ccc(O)cc1
Reactant: BrCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=S(=O)([O-])c1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Aqueous NaOH (40 mL of a 15% aqueous solution, 150 mmol) is added to 20 g (86.2 mmol) of 4-hydroxybenzenesulfonic acid sodium salt dihydrate at RT. An additional 20 mL of water is added, and the mixture is warmed slightly to dissolve the salt. Benzyl bromide (19.2 g, 112.1 mmol) in 8 mL of ethanol is then added in several portions. The mixture is heated to reflux. After 30 min, additional 20 mL of water is added, and heating is continued for 3.5 h, followed by continued stirring at RT overnight. After cooling in the refrigerator for 3 h, the solid product is collected by filtration and washed with water (20 mL), ethanol (40 mL), and ether (40 mL) and then dried overnight under vacuum to give 4-benzyloxybenzenesulfonic acid sodium salt.
Reaction SMILES: [CH2:1]([N:8]1[C:13]2[N:14]=[C:15](Cl)[C:16]([F:18])=[CH:17][C:12]=2[C:11](=[O:20])[N:10]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:9]1=[O:29])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:30]1[CH2:34][CH2:33][CH2:32][CH2:31]1>ClCCl>[CH2:1]([N:8]1[C:13]2[N:14]=[C:15]([N:30]3[CH2:34][CH2:33][CH2:32][CH2:31]3)[C:16]([F:18])=[CH:17][C:12]=2[C:11](=[O:20])[N:10]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:9]1=[O:29])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1CCNC1
Reactant: O=c1c2cc(F)c(Cl)nc2n(Cc2ccccc2)c(=O)n1OCc1ccccc1
Solvent: ClCCl
Product: O=c1c2cc(F)c(N3CCCC3)nc2n(Cc2ccccc2)c(=O)n1OCc1ccccc1
Yield: 78.6 %

Procedure:
Following the procedure of Example X-2, the reaction of 1-benzyl-3-benzyloxy-7-chloro-6-fluoro-1H-pyrido[2,3-d]pyrimidine-2,4-dione (Example P-2, 142 mg, 0.345 mmol) with pyrrolidine (0.070 mL, 0.828 mmol) in dichloromethane (3 mL) afforded 121 mg of the title compound as a solid. mp 171-172° C.
Reaction SMILES: B.[NH2:2][C:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13]([F:16])([F:15])[F:14])=[CH:4][C:5]#[N:6].O>O1CCCC1.CCOCC>[F:14][C:13]([F:15])([F:16])[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[CH:3]([NH2:2])[CH2:4][CH2:5][NH2:6]
Reactant: N#CC=C(N)c1ccccc1C(F)(F)F
Agent: B
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: O
Product: NCCC(N)c1ccccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 21.7 %

Procedure:
Sixty (60) ml of 1 molar borane in tetrahydrofuran is added to a solution of 7.6 g of β-amino-2-trifluoromethylcinnamonitrile (prepared according to Preparation D, Part 1) in 100 ml of ether. The mixture is stirred at room temperature overnight, then treated with 10 ml of water, and stirred for 45 minutes. The resulting mixture is concentrated under reduced pressure and 200 ml of isopropanol and 80 ml of 20% hydrochloric acid are added thereto. This mixture is refluxed for 2 hours, then concentrated to a small volume. The residue is made alkaline by addition of excess of 20% sodium hydroxide and is extracted 3 times with methylene chloride. The extracts are combined, concentrated and distilled to give 1.7 g of 1-(2-trifluoromethylphenyl)-1,3-propanediamine, bp 73°-77° C./0.1 mm.
Reaction SMILES: C[O:2][C:3]([C:5]1[S:9][C:8]([N:10]2[C:14]3[CH:15]=[C:16]([O:21][CH3:22])[C:17]([O:19][CH3:20])=[CH:18][C:13]=3[N:12]=[CH:11]2)=[N:7][C:6]=1Br)=[O:4].[Cl:24][C:25]1[CH:26]=[C:27](B(O)O)[CH:28]=[CH:29][C:30]=1[C:31]([F:34])([F:33])[F:32]>>[Cl:24][C:25]1[CH:26]=[C:27]([C:6]2[N:7]=[C:8]([N:10]3[C:14]4[CH:15]=[C:16]([O:21][CH3:22])[C:17]([O:19][CH3:20])=[CH:18][C:13]=4[N:12]=[CH:11]3)[S:9][C:5]=2[C:3]([OH:2])=[O:4])[CH:28]=[CH:29][C:30]=1[C:31]([F:32])([F:33])[F:34]
Reactant: COC(=O)c1sc(-n2cnc3cc(OC)c(OC)cc32)nc1Br
Reactant: OB(O)c1ccc(C(F)(F)F)c(Cl)c1
Product: COc1cc2ncn(-c3nc(-c4ccc(C(F)(F)F)c(Cl)c4)c(C(=O)O)s3)c2cc1OC
Yield: 15.9 %

Procedure:
In a similar manner as described for Example 26, 4-bromo-2-(5,6-dimethoxy-benzoimidazol-1-yl)-thiazole-5-carboxylic acid methyl ester (40 mg, 0.1 mmol) and 3-chloro-4-trifluoromethylphenylboronic acid (33.7 mg, 0.15 mmol) gave 4-(3-Chloro-4-trifluoromethyl-phenyl)-2-(5,6-dimethoxy-benzoimidazol-1-yl)-thiazole-5-carboxylic acid (7.7 mg, 16%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 13.91 (br.s., 1 H); 8.85 (s, 1 H); 8.48 (d, 1 H); 8.31 (dd, 1 H); 7.89 (d, 1 H); 7.84 (s, 1 H); 7.39 (s, 1 H); 3.86 (s, 3 H), 3.85 (s, 3H). MS 484 m/z (M+1).
Reaction SMILES: [C:1]1([S:7]([C:10]#[N:11])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.ClC(OCC)=[O:14].[C:18]1([CH3:25])[C:19](C)=[CH:20]C=[CH:22][CH:23]=1>>[C:1]1([S:7]([C:10]2[CH:25]=[C:18]3[CH:23]=[CH:22][O:14][C:19]3=[CH:20][N:11]=2)(=[O:8])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: N#CS(=O)(=O)c1ccccc1
Reactant: Cc1ccccc1C
Reactant: CCOC(=O)Cl
Product: O=S(=O)(c1ccccc1)c1cc2ccoc2cn1
Temperature: 130 °C

Procedure:
Benzenesulfonyl cyanide (90.2 g, 0.540 mol) and ethyl chloroformate (29.3 g, 0.270 mol) were mixed at room temperature in xylene (125 mL) and were stirred to reflux at a temperature of 120 to 140° C. A xylene (75 mL) solution of the crude 3-methylfuran-2-carbaldehyde-N-phenylimine (28.1 g) obtained above was added dropwise over 2 hours to the mixture. After all the solution had been added, the reaction mixture was heated to reflux for 3 hours, it was then cooled to room temperature, and the solvent was distilled off to give 81.3 g of crude product. This product was purified by column chromatography on silica gel, giving 17.2 g of 5-benzenesulfonylfuro[2,3-c]pyridine.
Reaction SMILES: [C:1]([NH:4][C:5]1[N:10]=[CH:9][C:8](/[CH:11]=[CH:12]/[C:13]([NH:15][CH2:16][C:17]([N:19]([C:21]2[C:22]([Cl:41])=[C:23]([C:37]([Cl:40])=[CH:38][CH:39]=2)[CH2:24][O:25][C:26]2[C:34]3[N:33]=[C:32]([O:35][CH3:36])[NH:31][C:30]=3[CH:29]=[CH:28][CH:27]=2)[CH3:20])=[O:18])=[O:14])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].Cl.[CH3:43][N:44]([CH3:48])[CH2:45][CH2:46]Cl.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[C:1]([NH:4][C:5]1[N:10]=[CH:9][C:8](/[CH:11]=[CH:12]/[C:13]([NH:15][CH2:16][C:17]([N:19]([C:21]2[C:22]([Cl:41])=[C:23]([C:37]([Cl:40])=[CH:38][CH:39]=2)[CH2:24][O:25][C:26]2[C:34]3[N:33]=[C:32]([O:35][CH3:36])[N:31]([CH2:46][CH2:45][N:44]([CH3:48])[CH3:43])[C:30]=3[CH:29]=[CH:28][CH:27]=2)[CH3:20])=[O:18])=[O:14])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[C:1]([NH:4][C:5]1[N:10]=[CH:9][C:8](/[CH:11]=[CH:12]/[C:13]([NH:15][CH2:16][C:17]([N:19]([C:21]2[C:22]([Cl:41])=[C:23]([C:37]([Cl:40])=[CH:38][CH:39]=2)[CH2:24][O:25][C:26]2[C:34]3[N:33]([CH2:46][CH2:45][N:44]([CH3:48])[CH3:43])[C:32]([O:35][CH3:36])=[N:31][C:30]=3[CH:29]=[CH:28][CH:27]=2)[CH3:20])=[O:18])=[O:14])=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: CN(C)CCCl
Reactant: COc1nc2c(OCc3c(Cl)ccc(N(C)C(=O)CNC(=O)/C=C/c4ccc(NC(C)=O)nc4)c3Cl)cccc2[nH]1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1nc2c(OCc3c(Cl)ccc(N(C)C(=O)CNC(=O)/C=C/c4ccc(NC(C)=O)nc4)c3Cl)cccc2n1CCN(C)C
Product: COc1nc2cccc(OCc3c(Cl)ccc(N(C)C(=O)CNC(=O)/C=C/c4ccc(NC(C)=O)nc4)c3Cl)c2n1CCN(C)C
Reaction time: 28 h

Procedure:
To a solution of 4-[3-[N-[(E)-3-(6-acetamidopyridin-3-yl)acryloylglycyl]-N-methylamino]-2,6-dichlorobenzyloxy]-2-methoxy-1H-benzimidazole (100 mg) and 2-dimethylaminoethyl chloride hydrochloride (25.6 mg) in N,N-dimethylformamide (2 ml) was added potassium carbonate (92.5 mg) at ambient temperature, and the mixture was stirred for 28 hours at the same temperature. The reaction mixture was poured into water, and extracted with chloroform. The extract was washed with water and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by preparative thin layer chromatography to give 4-[3-[N-[(E)-3-(6-acetamidopyridin-3-yl)acryloylglycyl]-N-methylamino]-2,6-dichlorobenzyloxy]-2-methoxy-1-(2-dimethylaminoethyl)-1H-benzimidazole (11 mg) and 7-[3-[N-[(E)-3-(6-acetamidopyridin-3-yl)acryloylglycyl]-N-methylamino]-2,6-dichlorobenzyloxy]-2-methoxy-1-(2-dimethylaminoethyl)-1H-benzimidazole (38 mg).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[C:9]([NH2:10])=[CH:8][CH:7]=[N:6][CH:5]=1.C(N(C(C)C)CC)(C)C.[CH2:21]([O:28][C:29](=[O:38])[NH:30][CH:31]([C:35](F)=[O:36])[CH:32]([CH3:34])[CH3:33])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>ClCCl>[CH3:1][O:2][C:3](=[O:11])[C:4]1[C:9]([NH:10][C:35](=[O:36])[CH:31]([NH:30][C:29]([O:28][CH2:21][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)=[O:38])[CH:32]([CH3:34])[CH3:33])=[CH:8][CH:7]=[N:6][CH:5]=1
Reactant: COC(=O)c1cnccc1N
Reactant: CC(C)C(NC(=O)OCc1ccccc1)C(=O)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1cnccc1NC(=O)C(NC(=O)OCc1ccccc1)C(C)C
Reaction time: 8 h
Yield: 90.2 %

Procedure:
Formula 506 where R1, R3 and R4 are H; R6 is Isopropyl; R6′ is H; W, Y and Z are —C═; and X is —N═: To a solution of dichloromethane (100 mL), 4-amino-nicotinic acid methyl ester (4.60 g, 30.2 mmol) and diisopropylethyl amine (8.25 mL, 46.7 mmol), was added (1-fluorocarbonyl-2-methyl-propyl)-carbamic acid benzyl ester (11.8 g, 46.7 mmol) at room temperature and the mixture stirred overnight. The solvent was removed under reduced pressure and the residue purified by flash silica gel chromatography using hexane-EtOAc (stepwise gradient from 3:1 to 1:1) as eluents to obtain the desired amide of Formula 506, 4-(2-benzyloxycarbonylamino-3-methyl-butyrylamino)-nicotinic acid methyl ester (10.5 g, 90.1%). MS (Cl) M/E: 386.2.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][C:5]([O:9]C(=O)C)=[CH:4][N:3]=1.[CH3:13][O:14][C:15]1[CH:23]=[C:22]([NH:24][S:25]([CH3:28])(=[O:27])=[O:26])[CH:21]=[CH:20][C:16]=1[C:17](O)=O.N>P(Cl)(Cl)(Cl)=O>[CH3:13][O:14][C:15]1[CH:23]=[C:22]([NH:24][S:25]([CH3:28])(=[O:27])=[O:26])[CH:21]=[CH:20][C:16]=1[C:17]1[NH:8][C:7]2[C:2]([N:1]=1)=[N:3][CH:4]=[C:5]([OH:9])[CH:6]=2
Reactant: COc1cc(NS(C)(=O)=O)ccc1C(=O)O
Reactant: CC(=O)Oc1cnc(N)c(N)c1
Agent: N
Solvent: O=P(Cl)(Cl)Cl
Product: COc1cc(NS(C)(=O)=O)ccc1-c1nc2ncc(O)cc2[nH]1
Temperature: 0 °C

Procedure:
0.5 g of 2,3-diamino-5-acetoxy-pyridine and 0.83 g of 2-methoxy-4-methanesulfonylamino-benzoic acid were refluxed for one hour in 20 ml of phosphorus oxychloride. The reaction mixture was combined with ice water and then adjusted to pH 7 with concentrated aqueous ammonia. The product was then extracted with ethyl acetate and purified by column chromatography (silica gel, eluant: methylene chloride/ethanol 1:0.02 to 1:0.1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:10]2[S:11][CH:12]=[CH:13][N:14]=2)[CH3:9])=[CH:4][CH:3]=1.[Br:15][C:16]1[CH:17]=[N:18][C:19]([Cl:22])=[N:20][CH:21]=1.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>O1CCCC1.CCCCC.O=C1O[C@H]([C@H](CO)O)C([O-])=C1O.[Na+].O>[Br:15][C:16]1[C:17]([C:12]2[S:11][C:10]([CH:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)[CH3:9])=[N:14][CH:13]=2)=[N:18][C:19]([Cl:22])=[N:20][CH:21]=1
Reactant: Clc1ncc(Br)cn1
Reactant: CC(c1ccc(F)cc1)c1nccs1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Agent: O=C1O[C@H]([C@@H](O)CO)C([O-])=C1O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCCCC
Product: CC(c1ccc(F)cc1)c1ncc(-c2nc(Cl)ncc2Br)s1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 46 %

Procedure:
A solution of 2-(1-(4-fluorophenyl)ethyl)thiazole (200 mg, 0.966 mmol) in 5 mL of tetrahydrofuran was cooled to −78° C. and treated with tert-butyllithitim (0.622 mL, 1.7 M solution in pentane, 1.06 mmol) added dropwise. 5-Bromo-2-chloropyrimidine (205.5 mg, 1.06 mmol) was added to the reaction mixture and stirred for another 30 min before quenching with 1 mL of acetic acid in 5 mL of methanol. 2,3-Dichloro-5,6-dicyano-1,4-benzoquinone (468 mg, 2.06 mmol) was added to the reaction after cooling to 0° C., stirred for 20 min, diluted with sodium ascorbate (0.5M, 100 mL) and water (300 mL). The crude product was extracted from the aqueous layer with chloroform (3×75 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The crude product was purified by flash chromatography with 0-40% ethyl acetate in hexane to afford the title compound as a yellow amorphous solid (177 mg). MS (M+H)+ 398/400.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][CH:9]=1)[NH2:6].[CH:10]([CH:12]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:13]([O-:15])=[O:14])=O.Cl.[C:23]1(C)C=CC=C[CH:24]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][CH:9]=1)[NH:6]/[CH:10]=[C:12](/[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)\[C:13]([O:15][CH2:23][CH3:24])=[O:14]
Reactant: Cc1ccccc1
Reactant: O=CC(C(=O)[O-])c1ccccc1
Reactant: COc1cccc(N)c1
Agent: Cl
Product: CCOC(=O)/C(=C\Nc1cccc(OC)c1)c1ccccc1
Yield: 56 %

Procedure:
A solution of 3-methoxyaniline (1.55 ml, 13.79 mol) and ethyl ∀-formylphenylacetate (2.92 g, 1.1 eq) in toluene (20 ml) is refluxed for 18 hours. After cooling, the reaction mixture is diluted with toluene (15 ml) and then acidified with 10% HCl. After extraction, the organic phase obtained is dried over MgSO4 and then evaporated under reduced pressure. The residue is purified by chromatography on a column of silica (eluent: CH2Cl2) to give 2.30 g (56%) of compound 8 (Z isomer) in the form of a yellow solid which crystallizes from methanol.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:19]=[CH:18][C:6]2[CH2:7][CH2:8][C:9]3[CH:10]=[CH:11][N:12]([CH2:14][C@H:15]([NH2:17])[CH3:16])[C:13]=3[C:5]=2[CH:4]=1.C(N(CC)CC)C.[F:27][C:28]([F:35])([F:34])[C:29](OCC)=[O:30].C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N>CO.O1CCOCC1>[CH3:1][O:2][C:3]1[CH:19]=[CH:18][C:6]2=[CH:7][CH:8]=[C:9]3[C:13]([N:12]([CH2:14][C@H:15]([NH:17][C:29](=[O:30])[C:28]([F:35])([F:34])[F:27])[CH3:16])[CH:11]=[CH:10]3)=[C:5]2[CH:4]=1
Reactant: CCOC(=O)C(F)(F)F
Reactant: COc1ccc2c(c1)-c1c(ccn1C[C@@H](C)N)CC2
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: CO
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: COc1ccc2ccc3ccn(C[C@@H](C)NC(=O)C(F)(F)F)c3c2c1
Yield: 59.1 %

Procedure:
A solution of 1.2 g of (R)-2-(4,5-dihydro-8-methoxy-1H-benz[g]indol-1-yl)-1-methyl-ethylamine, 0.52 g of triethylamine and 0.83 g of ethyl trifluoroacetate in 50 ml of anhydrous methanol was stirred at room temperature for 27 hours. After the solvent had been drawn off in a vacuum, the residue was taken up with 70 ml of anhydrous dioxane, 1.8 g of DDQ were added and the mixture was boiled under reflux for 1.5 hours, Subsequently, the reaction mixture was concentrated in a vacuum and the residue was purified by column chromatography on silica gel (dichloromethane/acetone 4:1). 0.97 g (59%) of (R)-N-[2-(8-methoxy-1H-benz[g]indol-1-yl)-1-methyl-ethyl]-trifluoroacetamide was obtained as a pale brown solid which was used in the next reaction without additional recrystallization.
Reaction SMILES: [N:1]1([C:7]2[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[CH:9][CH:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1.[CH3:47][O:48][C:49]1[C:50]2[N:63]=[C:62]([NH2:64])[S:61][C:51]=2[C:52]([N:55]2[CH2:60][CH2:59][O:58][CH2:57][CH2:56]2)=[N:53][CH:54]=1>C1COCC1>[CH3:47][O:48][C:49]1[C:50]2[N:63]=[C:62]([NH:64][C:11](=[O:13])[C:10]3[CH:9]=[CH:8][C:7]([N:1]4[CH2:2][CH2:3][O:4][CH2:5][CH2:6]4)=[CH:15][CH:14]=3)[S:61][C:51]=2[C:52]([N:55]2[CH2:56][CH2:57][O:58][CH2:59][CH2:60]2)=[N:53][CH:54]=1
Reactant: COc1cnc(N2CCOCC2)c2sc(N)nc12
Reactant: O=C(O)c1ccc(N2CCOCC2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: COc1cnc(N2CCOCC2)c2sc(NC(=O)c3ccc(N4CCOCC4)cc3)nc12

Procedure:
From 4-morpholin-4-yl-benzoic acid, HATU and N-methylmorpholine in THF, then treatment with 7-methoxy-4-morpholin-4-yl-thiazolo[5,4-c]pyridin-2-ylamine. ES-MS m/e (%): 456 (M+H+, 100).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[C:7]([O:14][CH3:15])(=[O:13])[CH2:8][CH2:9][C:10]([OH:12])=O.[C:16]([NH:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)(=[O:18])[CH3:17].[Cl-].[Al+3].[Cl-].[Cl-]>CN(C)C=O.ClC(Cl)C>[C:16]([NH:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]1[CH:25]=[CH:26][C:27]([C:10](=[O:12])[CH2:9][CH2:8][C:7]([O:14][CH3:15])=[O:13])=[CH:28][CH:29]=1)(=[O:18])[CH3:17]
Reactant: CC(=O)NCCCCc1ccccc1
Reactant: COC(=O)CCC(=O)O
Agent: O=C(Cl)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: CC(Cl)Cl
Product: COC(=O)CCC(=O)c1ccc(CCCCNC(C)=O)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 84.6 %

Procedure:
45.9 g of oxalyl chloride and 5 drops of dimethylformamide were added to a dichloroethane solution (500 ml) containing 45.5 g of methyl hydrogen succinate, and the mixture was stirred at room temperature for 3 hours. Under ice cooling, a dichloroethane solution (60 ml) containing 31.3 g of [4-(acetylamino)butyl]benzene, and 91.9 g of anhydrous aluminum chloride were added thereto, and the mixture was stirred for 1 hour. The reaction mixture was poured into ice water, and the organic layer was collected by separation. After the organic layer was washed with water and dried, the solvent was removed. The resulting crude crystal was recrystallized from ethyl acetate to obtain 42.3 g of 4-[4-(acetylamino)butyl]-l-(3-methoxycarbonylpropionyl)benzene.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:9]([C:16]2[CH:28]=[CH:27][C:19]([C:20]([N:22]([CH2:25][CH3:26])[CH2:23][CH3:24])=[O:21])=[CH:18][CH:17]=2)[N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[CH:6]=[CH:7][CH:8]=1)#[N:2].[O:29]1[CH:33]=[CH:32][CH:31]=[C:30]1[CH:34]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.ClCCl>[CH2:25]([N:22]([CH2:23][CH3:24])[C:20]([C:19]1[CH:27]=[CH:28][C:16]([CH:9]([N:10]2[CH2:11][CH2:12][N:13]([CH2:34][C:30]3[O:29][CH:33]=[CH:32][CH:31]=3)[CH2:14][CH2:15]2)[C:5]2[CH:4]=[C:3]([CH:8]=[CH:7][CH:6]=2)[C:1]#[N:2])=[CH:17][CH:18]=1)=[O:21])[CH3:26]
Reactant: O=Cc1ccco1
Reactant: CCN(CC)C(=O)c1ccc(C(c2cccc(C#N)c2)N2CCNCC2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: ClCCl
Product: CCN(CC)C(=O)c1ccc(C(c2cccc(C#N)c2)N2CCN(Cc3ccco3)CC2)cc1
Yield: 53 %

Procedure:
To a solution of INTERMEDIATE 3 (567 mg) in 1,2-dichloroethane (15 mL) was added 2-furaldehyde (160 μL, 1.3 eq) and sodium triacetoxyborohydride (450 mg, 1.4 eq). After 3 days the reaction was diluted with dichloromethane (50 mL) and washed with saturated aqueous sodium bicarbonate. The aqueous layer was washed with dichloromethane (2×25 mL) and the combined organic extracts were dried (NgSO4), filtered and concentrated. The residue was purified by flash chromatography, eluting 5% methanol in dichloromethane to yield INTERMEDIATE 4b as a colorless foam (367 mg, 53%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([O:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][OH:21])=[CH:15][CH:14]=2)[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[N:22]#[C:23][NH2:24].OS(C(F)(F)F)(=O)=O>C1COCC1>[C:23](=[NH:22])([O:21][CH2:20][CH2:19][C:16]1[CH:17]=[CH:18][C:13]([O:12][C:4]2[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=[C:2]([Cl:1])[CH:3]=2)=[CH:14][CH:15]=1)[NH2:24]
Reactant: N#CN
Reactant: OCCc1ccc(Oc2cc(Cl)cc(C(F)(F)F)c2)cc1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: C1CCOC1
Product: N=C(N)OCCc1ccc(Oc2cc(Cl)cc(C(F)(F)F)c2)cc1
Temperature: 55 °C
Yield: 70.4 %

Procedure:
To a solution of 2-(4-{[3-chloro-5-(trifluoromethyl)phenyl]oxy}phenyl)ethanol (2 g, 6.32 mmol) and cyanamide (0.4 g, 9.51 mmol) in dry THF (20 mL) under nitrogen was added triflic acid (0.8 mL, 9.01 mmol). The mixture was heated at 55° C. for 4 h. Purification via reverse phase flash chromatography afforded the title compound (2.1 g, 4.45 mmol, 70.5% yield) as a brown oil. LCMS: rt=2.95 min, [M+H+]=359
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[C:23]3[C:18](=[CH:19][C:20]([O:24][CH3:25])=[CH:21][CH:22]=3)[CH:17]=[C:16]2[CH2:26][O:27][CH3:28])=[CH:11][CH:10]=1)C1C=CC=CC=1.C([O-])=O.[NH4+]>CO.O1CCCC1.[Pd]>[CH3:25][O:24][C:20]1[CH:19]=[C:18]2[C:23](=[CH:22][CH:21]=1)[N:15]([C:12]1[CH:13]=[CH:14][C:9]([OH:8])=[CH:10][CH:11]=1)[C:16]([CH2:26][O:27][CH3:28])=[CH:17]2
Reactant: COCc1cc2cc(OC)ccc2n1-c1ccc(OCc2ccccc2)cc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Solvent: C1CCOC1
Product: COCc1cc2cc(OC)ccc2n1-c1ccc(O)cc1
Temperature: 25 °C

Procedure:
1-(4-Benzyloxyphenyl)-5-methoxy-2-methoxymethyl-1H-indole (0.16 g, 0.43 mmol) was dissolved in methanol (3 mL) and tetrahydrofuran (1 mL). Palladium on carbon (0.32 g, 10% wet) and ammonium formate (0.14 g, 2.14 mmol) were added, and the reaction was stirred at reflux for 2 hours. The mixture was cooled to room temperature and filtered through a pad of Celite. The filtrate was concentrated, and the crude material taken on without purification. LC-MS (C17H17NO3 calc'd 283) m/z 284 (M+H).
Reaction SMILES: [OH:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[Cl:18][C:19]1[C:24]([Cl:25])=[CH:23][C:22]([N+:26]([O-:28])=[O:27])=[C:21](F)[CH:20]=1>CS(C)=O>[Cl:25][C:24]1[C:19]([Cl:18])=[CH:20][C:21]([O:1][C:2]2[N:6]([CH3:7])[N:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[CH:3]=2)=[C:22]([N+:26]([O-:28])=[O:27])[CH:23]=1
Reactant: Cn1nc(C(F)(F)F)cc1O
Reactant: O=[N+]([O-])c1cc(Cl)c(Cl)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: Cn1nc(C(F)(F)F)cc1Oc1cc(Cl)c(Cl)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 18 h
Yield: 41.4 %

Procedure:
5-Hydroxy-1-methyl-3-trifluoromethylpyrazole (7.0 g, 40 mmol) and powdered potassium carbonate (11.4 g, 80 mmol) were stirred together in dimethylsulfoxide (40 ml) for 30 minutes. 4,5-Dichloro-2-fluoronitrobenzene (7.9 g, 50 mmol) was added and the mixture stirred at room temperature for 18 h. The mixture was partitioned between diethyl ether and water, the ethereal extract washed with water and brine, dried over magnesium sulfate, filtered and the filtrate evaporated. The residue was further purified by flash column chromatography over silica gel, to give the desired product (5.9 g) as a light yellow solid, m.p. 99°-100° C.
Reaction SMILES: S(Cl)([Cl:3])=O.[CH2:5]([O:7][C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][C:15]=1[O:16][CH2:17][C:18]1[N:19]=[C:20]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[O:21][C:22]=1[CH3:23])[CH2:11]O)[CH3:6].O1CCCC1.C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1>[Cl:3][CH2:11][C:10]1[CH:13]=[CH:14][C:15]([O:16][CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[O:21][C:22]=2[CH3:23])=[C:8]([O:7][CH2:5][CH3:6])[CH:9]=1
Reactant: CCOc1cc(CO)ccc1OCc1nc(-c2ccccc2)oc1C
Reactant: O=S(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCOc1cc(CCl)ccc1OCc1nc(-c2ccccc2)oc1C
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 91 %

Procedure:
Thionyl chloride (0.73 ml) was added slowly to a mixture of 3-ethoxy-4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyl alcohol (3.05 g), tetrahydrofuran (25 ml) and toluene (50 ml) at room temperature, which was stirred at 80° C. for 30 minutes. After cooling, the reaction mixture was poured into an aqueous saturated sodium bicarbonate solution, which was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium bicarbonate solution, dried (MgSO4) and concentrated to obtain 4-(4-chloromethyl-2-ethoxyphenoxymethyl)-5-methyl-2-phenyloxazole (2.94 g, yield 91%) as colorless crystals. This was recrystallized from tetrahydrofuran-hexane. Melting point: 138–139° C.