Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC(C1C=CC=C(C(C)C)C=1CC([C:16]1[C:17]([CH:30]([CH3:32])[CH3:31])=[C:18]([O:25][S:26](=[O:29])(=[O:28])[NH2:27])[C:19]([CH:22]([CH3:24])[CH3:23])=[CH:20][CH:21]=1)=O)C.C(C1C=CC=C(C(C)C)C=1CC(O)=O)(C)C.[C:49]1([CH:55]([C:60]2[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=2)[CH2:56][C:57](O)=[O:58])[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1>>[O:58]=[C:57]([C:16]1[C:17]([CH:30]([CH3:32])[CH3:31])=[C:18]([O:25][S:26](=[O:29])(=[O:28])[NH2:27])[C:19]([CH:22]([CH3:23])[CH3:24])=[CH:20][CH:21]=1)[CH2:56][CH:55]([C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)[C:60]1[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=1
Reactant: O=C(O)CC(c1ccccc1)c1ccccc1
Reactant: CC(C)c1cccc(C(C)C)c1CC(=O)c1ccc(C(C)C)c(OS(N)(=O)=O)c1C(C)C
Agent: CC(C)c1cccc(C(C)C)c1CC(=O)O
Product: CC(C)c1ccc(C(=O)CC(c2ccccc2)c2ccccc2)c(C(C)C)c1OS(N)(=O)=O

Procedure:
This compound was prepared in the same manner as for the title compound of Example 1, except that 2,6-diisopropylphenylacetic acid was replaced with 3,3-diphenylpropionic acid, mp 149°-152° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][C:7]1[N:8]=[C:9]([S:12][CH2:13][C:14]([NH:16][CH2:17][C@H:18]2[O:23][CH2:22][CH2:21][NH:20][CH2:19]2)=[O:15])[S:10][CH:11]=1)=[O:5])[CH3:2].[Cl:24][C:25]1[CH:32]=[CH:31][C:28]([CH:29]=O)=[CH:27][C:26]=1[C:33]([F:36])([F:35])[F:34]>>[Cl:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29][N:20]2[CH2:21][CH2:22][O:23][C@@H:18]([CH2:17][NH:16][C:14](=[O:15])[CH2:13][S:12][C:9]3[S:10][CH:11]=[C:7]([CH2:6][C:4]([O:3][CH2:1][CH3:2])=[O:5])[N:8]=3)[CH2:19]2)=[CH:27][CH:26]=1.[Cl:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29][N:20]2[CH2:21][CH2:22][O:23][C@@H:18]([CH2:17][NH:16][C:14](=[O:15])[CH2:13][S:12][C:9]3[S:10][CH:11]=[C:7]([CH2:6][C:4]([O:3][CH2:1][CH3:2])=[O:5])[N:8]=3)[CH2:19]2)=[CH:27][C:26]=1[C:33]([F:34])([F:35])[F:36]
Reactant: CCOC(=O)Cc1csc(SCC(=O)NC[C@@H]2CNCCO2)n1
Reactant: O=Cc1ccc(Cl)c(C(F)(F)F)c1
Product: CCOC(=O)Cc1csc(SCC(=O)NC[C@H]2CN(Cc3ccc(Cl)c(C(F)(F)F)c3)CCO2)n1
Product: CCOC(=O)Cc1csc(SCC(=O)NC[C@H]2CN(Cc3ccc(Cl)cc3)CCO2)n1

Procedure:
By a similar method as in (85-1), the title compound (663 mg) was obtained as a colorless oil from the resultant product (899 mg) of (75-3) and 4-chloro-3-trifluoromethylbenzaldehyde (396 μL).
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3[N:17]=[CH:18][N:19]=[C:20]([C:21]4[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[CH:23][C:22]=4[O:31][CH2:32][CH:33]4[CH2:35][CH2:34]4)[C:15]=3[NH:14][C:13]=2[CH3:36])=[O:11])[CH2:5][CH2:4]1.[C:37](Cl)(=[O:39])[CH3:38]>>[C:37]([NH:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3[N:17]=[CH:18][N:19]=[C:20]([C:21]4[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[CH:23][C:22]=4[O:31][CH2:32][CH:33]4[CH2:34][CH2:35]4)[C:15]=3[NH:14][C:13]=2[CH3:36])=[O:11])[CH2:5][CH2:4]1)(=[O:39])[CH3:38]
Reactant: CC(=O)Cl
Reactant: Cc1[nH]c2c(-c3cc(C(F)(F)F)ccc3OCC3CC3)ncnc2c1C(=O)N[C@H]1CC[C@H](N)CC1
Agent: Cl
Product: CC(=O)N[C@H]1CC[C@H](NC(=O)c2c(C)[nH]c3c(-c4cc(C(F)(F)F)ccc4OCC4CC4)ncnc23)CC1

Procedure:
Starting from N-(trans-4-aminocyclohexyl)-4-[2-(cyclopropylmethoxy)-5-(trifluoromethyl)phenyl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f32) and commercially available acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([Cl:10])[C:5]=1[CH3:11])[CH3:2].C([O:14][CH:15]=[C:16]([C:22](OCC)=O)[C:17]([O:19]CC)=[O:18])C>O>[CH2:1]([N:3]1[C:4]2[C:9](=[CH:8][CH:7]=[C:6]([Cl:10])[C:5]=2[CH3:11])[C:15](=[O:14])[C:16]([C:17]([OH:19])=[O:18])=[CH:22]1)[CH3:2]
Reactant: CCNc1cccc(Cl)c1C
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Solvent: O
Product: CCn1cc(C(=O)O)c(=O)c2ccc(Cl)c(C)c21
Temperature: 110 °C
Yield: 70.2 %

Procedure:
Ten grams of N-ethyl-2-methyl-3-chloroaniline is allowed to react with 15 g of diethyl ethoxymethylenemalonate under heating at 110° C. for 30 minutes. Then, polyphosphoric acid (obtained from 50 g each of phosphoric acid and phosphorus pentaoxide) is added to be subjected to the reaction at 140° C. for 40 minutes. After the reaction, the mixture is poured into 600 g of water and ice, resulting in crystals separated out. The crystals are recovered by filtration, and a 10% sodium hydroxide solution is added to the fitrate and the mixture is refluxed for 1 hour. After refluxing, the mixture is treated with activated carbon and adjusted to pH 2 with concentrated hydrochloric acid, whereby there separate out light yellow crystals. Recrystallization from dimethylformamide yields 11 g of 1-ethyl-7-chloro-8-methyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid as the white, needle-like crystals. mp. 221°-222° C.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH3:6][C:7]1[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][C:10]([C:11](O)=O)=[CH:9][C:8]=1[N+:19]([O-:21])=[O:20].S(N)([NH2:25])(=O)=O.O>S1(CCCC1)(=O)=O>[CH3:6][C:7]1[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][C:10]([C:11]#[N:25])=[CH:9][C:8]=1[N+:19]([O-:21])=[O:20]
Reactant: Cc1c([N+](=O)[O-])cc(C(=O)O)cc1[N+](=O)[O-]
Reactant: NS(N)(=O)=O
Solvent: O=S1(=O)CCCC1
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: Cc1c([N+](=O)[O-])cc(C#N)cc1[N+](=O)[O-]
Temperature: 120 °C
Yield: 91.2 %

Procedure:
Phosphorus oxychloride (27.2 kg) is added over 30 minutes to a mixture of 4-methyl-3,5-dinitrobenzoic acid (3) (20.7 kg) and sulfamide (19.9 kg) in sulfolane (118 kg). The mixture is heated to about 120° C. and aged for about 8 hours. After cooling to ambient temperature, water (104 L) is added and the mixture is cooled to about 5° C. to crystallize the product. After aging at least 1.5 hours, the product is isolated via centrifugation, and washed with water (142 L). The product is then removed from the centrifuge and dried in a convection tray dryer at about 60° C. until drying is complete to provide 4-methyl-3,5-dinitrobenzonitrile (4) (17.3 kg, 91% yield) as a tan solid.
Reaction SMILES: [C:1]([S:14]([NH:17][CH3:18])(=[O:16])=[O:15])([C:4]([C:7]([C:10]([F:13])([F:12])[F:11])([F:9])[F:8])([F:6])[F:5])([F:3])[F:2].[CH2:19]([CH:21]1[O:23][CH2:22]1)Cl>>[CH3:18][N:17]([CH2:19][CH:21]1[CH2:22][O:23]1)[S:14]([C:1]([F:3])([F:2])[C:4]([F:6])([F:5])[C:7]([F:9])([F:8])[C:10]([F:13])([F:11])[F:12])(=[O:15])=[O:16]
Reactant: CNS(=O)(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reactant: ClCC1CO1
Product: CN(CC1CO1)S(=O)(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Temperature: 64 °C
Yield: 42 %

Procedure:
A mixture of C4F9SO2NHCH3 (313 g, 1.00 mol), generally made as described in U.S. Pat. No. 6,664,354, Example 1, Part A, and sodium methoxide (216 g of a 25% solution in methanol) was concentrated to a solid, which was dissolved in dry THF (500 mL). Epichlorohydrin (120.2 g, 1.3 mol) was rapidly added to the resulting solution, and the mixture was stirred at reflux (64° C.) for 20 hours. The cooled mixture was washed with about 1 L of water, and dichloromethane was used to help transfer the organic fraction. The organic fraction was dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by one-plate distillation [bp 90° C./0.06 mmHg (8 Pa)] to provide 155.2 g of N-methyl-N-(oxiran-2-ylmethyl)perfluorobutane-1-sulfonamide, which was 98% pure by GLC.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#N)=[C:4]([O:10][CH3:11])[CH:3]=1.[OH-:12].[Na+].[O:14]1CCOCC1>>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]([OH:14])=[O:12])=[C:4]([O:10][CH3:11])[CH:3]=1
Reactant: [OH-]
Reactant: C1COCCO1
Reactant: COc1cc(Br)ccc1C#N
Agent: [Na+]
Product: COc1cc(Br)ccc1C(=O)O
Temperature: 100 °C
Yield: 37 %

Procedure:
4-Bromo-2-methoxybenzonitrile (7.35 g, 35 mmol) was dissolved in dioxane (400 mL). Sodium hydroxide (2.0 N, 200 mL) was added and the suspension was heated at 100° C. for 16 hours. Organic solvent was removed under reduced pressure and the aqueous mixture was filtered and washed with water. The filtrate was neutralized with hydrochloric acid (5.0N) to pH 1. The solid was collected by filtration to give 4-bromo-2-methoxybenzoic acid (3 g, 37%). 1H NMR (DMSO-d6) δ 3.84 (s, 3H), 7.21 (d, J=8.25 Hz, 1H), 7.33 (s, 1H), 7.58 (d, J=8.23 Hz, 1H).
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].[NH2:7][C:8]1[N:12]([C:13]2[C:18]([Cl:19])=[CH:17][C:16]([C:20]([F:23])([F:22])[F:21])=[CH:15][C:14]=2[Cl:24])[N:11]=[C:10]([C:25]([F:28])([F:27])[F:26])[C:9]=1[C:29]#[N:30]>N1C=CC=CC=1>[C:29]([C:9]1[C:10]([C:25]([F:28])([F:26])[F:27])=[N:11][N:12]([C:13]2[C:14]([Cl:24])=[CH:15][C:16]([C:20]([F:22])([F:21])[F:23])=[CH:17][C:18]=2[Cl:19])[C:8]=1[NH:7][C:2]([O:4][CH2:5][CH3:6])=[O:3])#[N:30]
Reactant: CCOC(=O)Cl
Reactant: N#Cc1c(C(F)(F)F)nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c1N
Solvent: c1ccncc1
Product: CCOC(=O)Nc1c(C#N)c(C(F)(F)F)nn1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Reaction time: 8 h

Procedure:
Ethyl chloroformate (1.6 g) was added to a stirred solution of 5-amino-4-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-3-trifluoromethylpyrazole (3.9 g) in pyridine (15 ml). After stirring overnight another addition of ethyl chloroformate (1.0 ml) was made, and the mixture was left for a further 12 hours. The solvent was evaporated in vacuo and the residue was acidified with dilute hydrochloric acid, and extracted with dichloromethane. This extract was washed with water (3×), dried over anhydrous magnesium sulphate, filtered, and evaporated in vacuo. Purification by chromatography on silica (Merck, 40-230 mesh, 0.7 kg cm-2) eluting with ethyl acetate--petroleum ether (1:1) gave a white solid, which was recrystallized from a mixture of dichloromethane and hexane to furnish white crystals of 4-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-5-ethoxycarbonylamino-3-trifluoromethylpyrazole, m.p. 177-179° C.
Reaction SMILES: Br[C:2]1[S:22][C:5]2=[N:6][C:7]([CH3:21])=[CH:8][C:9]([NH:10][S:11]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=3)(=[O:13])=[O:12])=[C:4]2[C:3]=1[C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH3:30])[CH:24]=1.CC1(C)C(C)(C)OB([C:39]2[CH:44]=[CH:43][N:42]=[CH:41][CH:40]=2)O1.C(=O)([O-])[O-].[K+].[K+].O>O1CCOCC1.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>[Cl:20][C:16]1[CH:15]=[C:14]([S:11]([NH:10][C:9]2[CH:8]=[C:7]([CH3:21])[N:6]=[C:5]3[S:22][C:2]([C:39]4[CH:44]=[CH:43][N:42]=[CH:41][CH:40]=4)=[C:3]([C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH3:30])[CH:24]=4)[C:4]=23)(=[O:13])=[O:12])[CH:19]=[CH:18][CH:17]=1
Reactant: CC1(C)OB(c2ccncc2)OC1(C)C
Reactant: COc1cccc(-c2c(Br)sc3nc(C)cc(NS(=O)(=O)c4cccc(Cl)c4)c23)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: COc1cccc(-c2c(-c3ccncc3)sc3nc(C)cc(NS(=O)(=O)c4cccc(Cl)c4)c23)c1
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 37.1 %

Procedure:
To a solution of N-{2-bromo-6-methyl-3-[3-(methyloxy)phenyl]thieno[2,3-b]pyridin-4-yl}-3-chlorobenzenesulfonamide (Example 33) (100 mg, 0.191 mmol) in 1,4-dioxane (2 mL) was added 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (58.7 mg, 0.286 mmol), bis(triphenylphosphine)palladium(II) chloride (13.40 mg, 0.019 mmol), potassium carbonate (79 mg, 0.573 mmol) and water (1 mL). The reaction mixture was heated at 100° C. in a microwave for 15 min (×2) and then for 30 min (×1). Another portion of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (58.7 mg, 0.286 mmol) and additional bis(triphenylphosphine)palladium(II) chloride (13.40 mg, 0.019 mmol) were added and heating continued, at 100° C. in a microwave, for another 15 min. The solvent was then removed in vacuo and the residue dissolved in ethyl acetate (30 mL) and washed with water (30 mL). The aqueous phase was re-extracted with ethyl acetate (30 mL×2). All organic phases were combined, dried over MgSO4, filtered and concentrated. The residue was purified on silica, eluting with a gradient of 0-50% ethyl acetate in cyclohexane and then further purified using MDAP (acidic conditions), to give the title compound (37 mg). LCMS (A) m/z: 520 [M−1]−, Rt 1.22 min (acidic).
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[N:8]([C:24]#[N:25])[C:9]3[C:14]([C:15]=2[C:16]2[CH:21]=[CH:20][C:19]([O:22]C)=[CH:18][CH:17]=2)=[CH:13][CH:12]=[CH:11][CH:10]=3)=[C:5]([CH3:26])[S:4][N:3]=1.B(F)(F)F.S(C)C.C([O-])(O)=O.[Na+]>C(Cl)Cl.CO>[CH3:1][C:2]1[C:6]([C:7]2[N:8]([C:24]#[N:25])[C:9]3[C:14]([C:15]=2[C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=2)=[CH:13][CH:12]=[CH:11][CH:10]=3)=[C:5]([CH3:26])[S:4][N:3]=1
Reactant: COc1ccc(-c2c(-c3c(C)nsc3C)n(C#N)c3ccccc23)cc1
Agent: FB(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CSC
Solvent: CO
Solvent: ClCCl
Product: Cc1nsc(C)c1-c1c(-c2ccc(O)cc2)c2ccccc2n1C#N
Temperature: 1 °C
Reaction time: 16 h
Yield: 47.4 %

Procedure:
2-(3,5-dimethylisothiazol-4-yl)-3-(4-methoxyphenyl)-1H-indole-1-carbonitrile (38 mg, 0.11 mmol) was dissolved in 10 ml DCM and the mixture was cooled in an ice bath. BF3.SMe2 (0.56 ml, 5.29 mmol) was added drop wise and the mixture was stirred at 0-2° C. for 16 h. A few drops MeOH were added followed by NaHCO3 (aq, sat). The layers were separated and the organic layer was concentrated. The crude product was purified by preparative HPLC. 18.0 mg 2-(3,5-dimethylisothiazol-4-yl)-3-(4-hydroxyphenyl)-1H-indole-1-carbonitrile was obtained.
Reaction SMILES: Br[C:2]1[S:3][C:4]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][N:6]=1.[C:11]1([N:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH:18]2CC)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+].[C:31](#N)[CH3:32]>>[CH3:10][O:9][C:7]([C:4]1[S:3][C:2]([N:20]2[CH2:19][CH2:18][N:17]([CH2:11][CH2:16][C:15]3[CH:14]=[CH:13][CH:12]=[CH:32][CH:31]=3)[CH2:22][CH2:21]2)=[N:6][CH:5]=1)=[O:8]
Reactant: COC(=O)c1cnc(Br)s1
Reactant: CC#N
Reactant: CCC1CNCCN1c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COC(=O)c1cnc(N2CCN(CCc3ccccc3)CC2)s1
Temperature: 80 °C
Yield: 66.4 %

Procedure:
To a solution of methyl 2-bromothiazole-5-carboxylate 1 (222 mg, 1.00 mmol) in acetonitrile (20 mL) were added N-phenyl ethyl piperazine 14e (228 mg, 1.20 mmol) and potassium carbonate (152 mg, 1.10 mmol) under a N2 atmosphere. The reaction mixture was heated to reflux at 80° C. for 10 h. The reaction mixture was filtered through Celite and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography using silica gel to give the compound 15e (245 mg, 66.4%).
Reaction SMILES: [NH2:1][C@H:2]([CH2:25][CH3:26])[C:3]([NH:5][C:6]1[CH:7]=[N:8][C:9]([O:12][C:13]2[C:18]3[C:19]4([CH2:22][O:23][C:17]=3[C:16]([CH3:24])=[CH:15][CH:14]=2)[CH2:21][CH2:20]4)=[N:10][CH:11]=1)=[O:4].Cl[C:28](Cl)([O:30]C(=O)OC(Cl)(Cl)Cl)Cl>C(Cl)Cl>[CH2:25]([C@H:2]1[NH:1][C:28](=[O:30])[N:5]([C:6]2[CH:7]=[N:8][C:9]([O:12][C:13]3[C:18]4[C:19]5([CH2:22][O:23][C:17]=4[C:16]([CH3:24])=[CH:15][CH:14]=3)[CH2:21][CH2:20]5)=[N:10][CH:11]=2)[C:3]1=[O:4])[CH3:26]
Reactant: CC[C@@H](N)C(=O)Nc1cnc(Oc2ccc(C)c3c2C2(CC2)CO3)nc1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: ClCCl
Product: CC[C@H]1NC(=O)N(c2cnc(Oc3ccc(C)c4c3C3(CC3)CO4)nc2)C1=O
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 57.8 %

Procedure:
To a solution of (2R)-2-amino-N-[2-(7-methylspiro[2H-benzofuran-3,1′-cyclopropane]-4-yl)oxypyrimidin-5-yl]butanamide (Intermediate 164, 24 mg, 0.068 mmol) in dry DCM (3 ml) TEA (0.028 ml, 0.2 mmol) was added and the reaction mixture was cooled to 0° C. A solution of triphosgene (15 mg, 0.05 mmol) in dry DCM (1.5 ml) was slowly added and the reaction mixture was stirred for 15 minutes at the same temperature. The reaction was quenched with water (10 ml) and two phases were separated. The organic layer was dried (Na2SO4), filtered and evaporated and the residue was purified by flash chromatography (Biotage system) on silica gel using a 10 g SNAP column and cyclohexane/ethyl acetate 75:25 to cyclohexane/ethyl acetate 25:75 as eluents affording the title compound (11 mg) as a white solid.
Reaction SMILES: [CH2:1]([N:3](C(OC(C)(C)C)=O)[CH2:4][CH2:5][CH2:6][N:7](C(OC(C)(C)C)=O)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][N:16](C(OC(C)(C)C)=O)[CH2:17][CH2:18][CH2:19][N:20]([CH2:28][CH3:29])C(OC(C)(C)C)=[O:22])[CH3:2].[ClH:51]>C(O)C.C(OCC)C>[OH2:22].[ClH:51].[ClH:51].[ClH:51].[ClH:51].[CH2:28]([NH:20][CH2:19][CH2:18][CH2:17][NH:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][NH:7][CH2:6][CH2:5][CH2:4][NH:3][CH2:1][CH3:2])[CH3:29].[CH2:28]([NH:20][CH2:19][CH2:18][CH2:17][NH:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][NH:7][CH2:6][CH2:5][CH2:4][NH:3][CH2:1][CH3:2])[CH3:29].[ClH:51].[ClH:51].[ClH:51].[ClH:51]
Reactant: CCN(CCCN(CCCCCCCCN(CCCN(CC)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCO
Solvent: CCOCC
Product: CCNCCCNCCCCCCCCNCCCNCC
Product: O

Procedure:
Dissolve 3.3 g (0.0046 mol) of the product of Step A in 7 ml ethanol and treat with 70 ml of 2N HCl in diethyl ether stirring overnight. Filter the mixture and dry the residue at 70° C. at reduced pressure to yield 1.95 g of the title compound, mp>300° C. Elemental analysis: Calculated, C-46.09, H-10.10, N-11.95, Cl-30.24; Found C-46.23, H-9.94, N-12.11, Cl-29.99.
Reaction SMILES: CS[C:3]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[CH:9]=2)[S:5][N:4]=1.Cl[C:16]1C=C(C=CC=1)C(OO)=O.[S:26]([O-:29])([O-])=[O:27].[Na+].[Na+]>C(Cl)(Cl)Cl>[CH3:16][S:26]([C:3]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[CH:9]=2)[S:5][N:4]=1)(=[O:29])=[O:27]
Reactant: O=S([O-])[O-]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1nsc(-c2cccc(Cl)c2)n1
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CS(=O)(=O)c1nsc(-c2cccc(Cl)c2)n1
Reaction time: 0.5 h

Procedure:
In 12 ml of chloroform, 1.5 g of 3-methylthio-5-(3-chlorophenyl)-1,2,4-thiadiazole was dissolved, to the resulting solution was slowly added 5.85 g of 3-chloroperoxybenzoic acid (65%<) with ice-cooling, and the mixture was stirred for 30 minutes with ice-cooling, and at room temperature for 2 hours. The reaction mixture was poured into an aqueous sodium sulfite solution, and the layers were separated. The organic layer was washed with an aqueous sodium bicarbonate solution, dried over anhydrous sodium sulfate, and concentrated to obtain 1.44 g of 3-methylsulfonyl-5-(3-chlorophenyl)-1,2,4-thiadiazole.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:18]([OH:21])([CH3:20])[CH3:19])[CH:5]=[C:6]([F:17])[C:7]=1B1OC(C)(C)C(C)(C)O1.Br[C:23]1[N:28]=[C:27]([C:29]([O:31][CH3:32])=[O:30])[CH:26]=[CH:25][C:24]=1[F:33].CCN(C(C)C)C(C)C>O1CCOCC1.O.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[F:17][C:6]1[CH:5]=[C:4]([C:18]([OH:21])([CH3:19])[CH3:20])[CH:3]=[C:2]([F:1])[C:7]=1[C:23]1[N:28]=[C:27]([C:29]([O:31][CH3:32])=[O:30])[CH:26]=[CH:25][C:24]=1[F:33]
Reactant: COC(=O)c1ccc(F)c(Br)n1
Reactant: CC(C)(O)c1cc(F)c(B2OC(C)(C)C(C)(C)O2)c(F)c1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)c1ccc(F)c(-c2c(F)cc(C(C)(C)O)cc2F)n1
Temperature: 120 °C

Procedure:
To a nitrogen purged mixture of 2-[3,5-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]propan-2-ol (1.53 g, 5.13 mmol), methyl 6-bromo-5-fluoropyridine-2-carboxylate (1.20 g, 5.13 mmol) and DIPEA (2.7 mL, 15 mmol) in 1,4-dioxane (20 mL) and water (1.2 mL), bis(tri-tert-butylphosphine)palladium (262 mg, 0.513 mmol) was added. The reaction mixture was heated at 120° C. for 40 min., then cooled and filtered through a pad of diatomaceous earth. The filtrate was concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography (0-50% EtOAc in hexanes) to give methyl 6-[2,6-difluoro-4-(1-hydroxy-1-methylethyl)phenyl]-5-fluoropyridine-2-carboxylate as a white powder, which was used without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].Br[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([O:22][CH2:23][C:24]1[O:25][CH:26]=[CH:27][CH:28]=1)=[O:21].C(#N)C>O>[OH:1][C:2]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][C:3]=1[C:4]([O:6][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([O:22][CH2:23][C:24]1[O:25][CH:26]=[CH:27][CH:28]=1)=[O:21])=[O:5]
Reactant: O=C(O)c1cc(O)ccc1O
Reactant: O=C(CCCCCCCBr)OCc1ccco1
Solvent: O
Solvent: CC#N
Product: O=C(CCCCCCCOC(=O)c1cc(O)ccc1O)OCc1ccco1

Procedure:
A mixture of 2,5-dihydroxybenzoic acid (4.8 g), 1,8-diazobicyclo[5.5.0]undec-7-ene (4.7 g), 2-furylmethyl 8-bromooctanoate (7.8 g) and acetonitrile (150 ml) was heated, under reflux for 18 h. The cooled reaction mixture was added to water (500 ml) and extracted with ethyl acetate (3×200 ml). The combined organic layers were washed with 1N-hydrochloric acid (150 ml) and water (2×20 ml), dried over magnesium sulphate and filtered. The solvent was removed in vacuum. The residue (8.4 g) was purified by column flash chromatography on silica gel using toluene/ethyl acetate (5:1) as eluent, to give 8-(2-furylmethoxy)-8-oxooctyl 2,5-dihydroxybenzoate as colourless oil.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[CH:4][C:3]=1[O:11][CH3:12].[C-]#N.[Na+].[C:16]1([C:22]#[C:23][CH2:24]OS(C2C=CC(C)=CC=2)(=O)=O)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.O>CN(C)C=O>[CH3:12][O:11][C:3]1[CH:4]=[C:5]([CH2:8][C:9]#[N:10])[CH:6]=[CH:7][C:2]=1[O:1][CH2:24][C:23]#[C:22][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Cc1ccc(S(=O)(=O)OCC#Cc2ccccc2)cc1
Reactant: COc1cc(CC#N)ccc1O
Agent: [C-]#N
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(CC#N)ccc1OCC#Cc1ccccc1
Reaction time: 3 h

Procedure:
A mixture of (4-hydroxy-3-methoxy-phenyl)-acetonitrile (17.4 g) and sodium cyanide (6.6 g) in dimethylformamide (250 ml) is stirred under an atmosphere of nitrogen for 3 hours at +120° C. The mixture is then cooled to +60° C. and toluene-4-sulfonic acid 3-phenyl-prop-2-ynyl ester (39 g) in dimethylformamid (50 ml)is added during 5 minutes. It is stirred at +65° C. for another 4 hours. Upon cooling water (800 ml) is added. The mixture is extracted with ethyl acetate (2×500 ml). The organic phases are washed with brine (2×500 ml), dried (MgSO4) and evaporated. The residue is purified by flash column chromatography on silica gel (ethyl acetate/hexane 1:3) and recrystallised from ethyl acetate/hexane. [3-Methoxy-4-(3-phenyl-prop-2-ynyloxy)-phenyl]-acetonitrile is obtained, m.p. 74-75° C.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.C(O)(=O)C.[CH:18](N)=[NH:19]>C(O)C>[N+:11]([C:9]1[CH:10]=[C:2]2[C:3]([C:4]([OH:6])=[N:19][CH:18]=[N:1]2)=[CH:7][CH:8]=1)([O-:13])=[O:12]
Reactant: N=CN
Reactant: Nc1cc([N+](=O)[O-])ccc1C(=O)O
Solvent: CCO
Solvent: CC(=O)O
Product: O=[N+]([O-])c1ccc2c(O)ncnc2c1
Temperature: 25 °C
Yield: 88.9 %

Procedure:
To a solution of 2-amino-4-nitrobenzoic acid (6.00 g, 32.94 mmol) in ethanol (40 mL) was added formamidin acetate (6.80 g, 65.32 mmol). The reaction mixture was refluxed for 5 h. The reaction mixture was cooled to room temperature and refrigerated. The precipitate was filtered out, washed with several portions of cooled ethanol, and then dried in vacuo to give 5.60 g (89%) of 7-nitroquinazolin-4-ol as a yellow solid.
Reaction SMILES: [N+:1]([C:4]1[CH:17]=[CH:16][C:15]2[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH2:8][CH2:7][C:6]=2[CH:5]=1)([O-:3])=[O:2].ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>O1CCOCC1>[N+:1]([C:4]1[CH:17]=[CH:16][C:15]2[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH:8]=[CH:7][C:6]=2[CH:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc2c(c1)CCc1ccccc1-2
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: C1COCCO1
Product: O=[N+]([O-])c1ccc2c(ccc3ccccc32)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 60.1 %

Procedure:
Under an argon atmosphere, 22.5 g of 2-nitro-9,10-dihydrophenanthrene, 22.7 g of 2,3-dichloro-5,6-dicyano-p-benzoquinone, and 240 mL of 1,4-dioxane were added, and then the mixture was stirred for 24 hours under heating reflux. After having been cooled to room temperature, the reaction solution was concentrated. The residue was purified by silica gel column chromatography, and was then washed with methanol. Thus, 13.4 g of a white crystal were obtained (in 60% yield).