Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[K+].[C:3]1([CH3:13])[CH:8]=[CH:7][C:6]([S:9](Cl)(=[O:11])=[O:10])=[CH:5][CH:4]=1.[O:14]1[C@H:18]([CH2:19][CH2:20][CH3:21])[C@H:15]1[CH2:16][OH:17].O>C(OCC)C>[C:3]1([CH3:13])[CH:8]=[CH:7][C:6]([S:9]([O:17][CH2:16][C@H:15]2[O:14][C@@H:18]2[CH2:19][CH2:20][CH3:21])(=[O:11])=[O:10])=[CH:5][CH:4]=1
Reactant: CCC[C@H]1O[C@@H]1CO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCOCC
Product: CCC[C@H]1O[C@@H]1COS(=O)(=O)c1ccc(C)cc1
Reaction time: 5 h
Yield: 71 %

Procedure:
26 g of powdered potassium hydroxide (0.45 mol) and 14.3 g (75 mmol) of p-toluenesulfonyl chloride were added in succession at −10° C. to a stirred solution of (2R,3R)-2,3-epoxy-1-hexanol (8 g, 69 mmol) in diethyl ether. After 5 hours at 0° C., the reaction mixture was poured into 200 ml of water. The organic layer was separated off and the aqueous phase was extracted twice with 100 ml of diethyl ether in each case. The combined organic phases were washed with concentrated sodium chloride solution and dried over anhydrous sodium sulfate. After removing the solvent, (2-R,3R)-2,3-epoxyhexyl p-toluenesulfonate remained in the form of light yellow crystals which crystallized from diethyl ether/n-hexane as colorless needles (yield: 71%; [α]D20=+36.3°(c=2.0 in trichloromethane)).
Reaction SMILES: Cl.[C:2]12([NH2:12])[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([CH2:5]3)[CH2:3]1)[CH2:9]2.C(N(CC)CC)C.[C:20]([NH:23][C:24]1[CH:29]=[CH:28][C:27]([S:30](Cl)(=[O:32])=[O:31])=[CH:26][CH:25]=1)(=[O:22])[CH3:21]>O1CCOCC1>[C:2]12([NH:12][S:30]([C:27]3[CH:26]=[CH:25][C:24]([NH:23][C:20](=[O:22])[CH3:21])=[CH:29][CH:28]=3)(=[O:32])=[O:31])[CH2:9][CH:8]3[CH2:7][CH:6]([CH2:5][CH:4]([CH2:10]3)[CH2:3]1)[CH2:11]2
Reactant: CC(=O)Nc1ccc(S(=O)(=O)Cl)cc1
Reactant: NC12CC3CC(CC(C3)C1)C2
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CC(=O)Nc1ccc(S(=O)(=O)NC23CC4CC(CC(C4)C2)C3)cc1
Temperature: 80 °C
Yield: 30.3 %

Procedure:
1-Adamantanamine hydrochloride (0.0114 mol) and triethylamine (0.0114 mol) are added to a solution of 4-acetamidophenylsulfonyl chloride (1.34 g, 0.0057 mol) in dioxane (5 mL). The mixture is heated for 1 hour at 80° C., then part of the solvent is removed by evaporation at reduced pressure, and water is added until precipitation of the resulting sulfonamide. The product is collected by filtration as a pink solid in 30.3% yield and used without further purification.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14](=[O:24])[NH:15][CH2:16][C:17]3[CH:18]=[N:19][C:20]([CH3:23])=[N:21][CH:22]=3)[CH:11]=[C:10]([C:25](O)=[O:26])[CH:9]=2)=[CH:4][CH:3]=1.Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.[CH3:51][CH:52]1[CH2:54][NH:53]1.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:25]([N:53]3[CH2:54][CH:52]3[CH3:51])=[O:26])[CH:11]=[C:12]([C:14]([NH:15][CH2:16][C:17]3[CH:22]=[N:21][C:20]([CH3:23])=[N:19][CH:18]=3)=[O:24])[CH:13]=2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(-c2cc(C(=O)O)cc(C(=O)NCc3cnc(C)nc3)c2)cc1
Reactant: CC1CN1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(-c2cc(C(=O)NCc3cnc(C)nc3)cc(C(=O)N3CC3C)c2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 4′-methyl-5-((2-methylpyrimidin-5-yl)methylcarbamoyl)-biphenyl-3-carboxylic acid (11 mg, 0.030 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (12 mg, 0.061 mmol), 1-hydroxybenzotriazole hydrate (4.7 mg, 0.030 mmol), CH2Cl2 (2 mL) were added 2-methyl-aziridine (3.5 mg, 0.061 mmol) and N,N-diisopropylethylamine (11 μL, 0.061 mmol). The mixture was stirred at room temperature overnight, and then concentrated in vacuo. The residue was purified by preparative HPLC (100×21.2 mm C18 column, 30-70% MeCN/water[10 mM Et2NH]) to afford a white foam.
Reaction SMILES: C([O:3][CH2:4][CH3:5])C.[CH2:6]([Li])[CH2:7][CH2:8][CH3:9].[C:11]1(=[O:17])[CH2:16][CH2:15][CH2:14][CH:13]=[CH:12]1.C(Cl)(=O)C>CCCCCC>[CH2:6]([CH:13]1[CH2:14][CH2:15][CH2:16][C:11](=[O:17])[CH2:12]1)[CH2:7][CH2:8][CH3:9].[C:4]([CH:12]1[CH:13]([CH2:6][CH2:7][CH2:8][CH3:9])[CH2:14][CH2:15][CH2:16][C:11]1=[O:17])(=[O:3])[CH3:5]
Reactant: [Li]CCCC
Reactant: O=C1C=CCCC1
Reactant: CCOCC
Solvent: CC(=O)Cl
Solvent: CCCCCC
Product: CCCCC1CCCC(=O)C1
Product: CCCCC1CCCC(=O)C1C(C)=O
Reaction time: 0.5 h

Procedure:
To 20 ml of anhydrous diethyl ether was added 1.9 g (10 mmol) of cuprous iodide, and at -78° C in an atmosphere of nitrogen, 12.8 ml (20 mmol) of a 15 % by weight hexane solution of n-butyllithium was added. The mixture was stirred for 30 minutes, and then, 960 mg (10 mmol) of 2-cyclohexenone was added. The mixture was further stirred for one hour. Then, 3.93 g (50 mmol) of acetyl chloride was added, and the mixture was stirred for 2 hours at room temperature. After the reaction, the reaction product was post-treated, extracted, washed, and dried in the same way as in Example 4 to afford 2.662 g of a crude product. The crude product was purified by column chromatography (silica gel) to afford 56 mg (0.4 mmol) of 3-n-butylcyclohexanone as a by-product in a yield of 4% and 1.103 g (5.6 mmol) of 2-acetyl-3-n-butylcyclohexanone as a main product in a yield of 56%.
Reaction SMILES: [ClH:1].[Cl:2][CH2:3][CH2:4][NH:5][C:6]([C:8]1[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=1)=[O:7].[NH:14]1[CH2:19][CH2:18][CH:17]([N:20]2[C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=3[NH:22][C:21]2=[O:29])[CH2:16][CH2:15]1.C(=O)([O-])[O-].[Na+].[Na+]>CC(C)CC(=O)C>[OH2:7].[ClH:2].[ClH:1].[O:29]=[C:21]1[N:20]([CH:17]2[CH2:16][CH2:15][N:14]([CH2:3][CH2:4][NH:5][C:6]([C:8]3[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=3)=[O:7])[CH2:19][CH2:18]2)[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[NH:22]1
Reactant: O=C(NCCCl)c1cccnc1
Reactant: O=c1[nH]c2ccccc2n1C1CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)CC(C)C
Product: O
Product: O=C(NCCN1CCC(n2c(=O)[nH]c3ccccc32)CC1)c1cccnc1
Temperature: 25 °C

Procedure:
A mixture of 8.8 parts of N-(2-chloroethyl)-3-pyridinecarboxamide hydrochloride, 4.6 parts of 1,3-dihydro-1-(4-piperidinyl)-2H-benzimidazol-2-one, 4.24 parts of sodium carbonate and 120 parts of 4-methyl-2-pentanone is stirred and refluxed for 48 hours. The reaction mixture is cooled to room temperature and poured onto water. The product is extracted five times with trichloromethane. The combined extracts are dried, filtered and evaporated. The residue is purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (90:10 by volume) as eluent. The pure fractions are collected and the eluent is evaporated. The residue is converted into the hydrochloride salt in ethanol and 2-propanol. The salt is filtered off and crystallized from a mixture of methanol and ethanol. It is filtered off again and recrystallized from a mixture of ethanol and 2,2'-oxybispropane, yielding 0.8 parts of N-{2-[4-(2,3-dihydro-2-oxo-1H-benzimidazol-1-yl)-1-piperidinyl]ethyl}-3-pyridinecarboxamide dihydrochloride hydrate; mp. 214.1° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=O.[N:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][NH2:18])[CH:12]=1>>[N:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][NH:18][C:5](=[O:7])[C:4]2[CH:8]=[CH:9][CH:10]=[C:2]([Br:1])[CH:3]=2)[CH:12]=1
Reactant: NCc1cccnc1
Reactant: O=C(O)c1cccc(Br)c1
Product: O=C(NCc1cccnc1)c1cccc(Br)c1
Yield: 73 %

Procedure:
Using Preparation Method 1, 3-bromobenzoic acid was reacted with 3-pyridylmethylamine. The resulting reaction mixture was purified using SiO2 with CH2Cl2/MeOH 95:5 to give N-(3-pyridylmethyl)-3-bromobenzamide as thick yellow oil (73%). NMR 1H (ppm, CDCl3): 8.44 (s, 1H), 8.41 (d, J4=3.9 Hz, 1H), 7.92 (s, 1H), 7.69 (d, J3=7.8 Hz, 1H), 7.64 (d, J3=7.8 Hz, 1H), 7.57-7.54 (m, 2H), 7.24-7.18 (m, 2H), 4.55 (d, J3=5.9 Hz, 2H).
Reaction SMILES: C(OC([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH:17]([OH:22])[CH2:18][C:19]([NH2:21])=[O:20])=O)C1C=CC=CC=1.[ClH:23]>CO.[C].[Pd]>[ClH:23].[NH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH:17]([OH:22])[CH2:18][C:19]([NH2:21])=[O:20]
Reactant: NC(=O)CC(O)CCCCCNC(=O)OCc1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: NCCCCCC(O)CC(N)=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 1.04 g (3.2 mmoles) of 8-benzyloxycarbonylamino-3-hydroxyoctanamide in 20 ml of methanol were added 3.2 ml of 1N hydrochloric acid and 200 mg of 10% palladium-carbon. The mixture was stirred under a hydrogen stream at room temperature for 3 hours. The catalyst was removed by filtration and the filtrate was evaporated to dryness to yield 670 mg of 8-amino-3-hydroxyoctanamide hydrochloride.
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH3:6])=[O:4].[F:7][C:8]([F:32])([F:31])[C:9]1[N:13]2[N:14]=[C:15]([N:18]3[CH2:23][CH2:22][CH:21]([C:24]4[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=4)[CH2:20][CH2:19]3)[CH:16]=[CH:17][C:12]2=[N:11][N:10]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[F:32][C:8]([F:7])([F:31])[C:9]1[N:13]2[N:14]=[C:15]([N:18]3[CH2:23][CH2:22][CH:21]([C:24]4[CH:29]=[CH:28][C:27]([O:30][CH2:2][C:3]([O:5][CH3:6])=[O:4])=[CH:26][CH:25]=4)[CH2:20][CH2:19]3)[CH:16]=[CH:17][C:12]2=[N:11][N:10]=1
Reactant: COC(=O)CBr
Reactant: Oc1ccc(C2CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)COc1ccc(C2CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 100.8 %

Procedure:
Methyl 2-bromoacetate (0.418 mL, 4.42 mmol) was added to 4-[1-[3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-yl]phenol (obtained as described in Example 513, preparation of starting materials) (1.07 g, 2.94 mmol) and potassium carbonate (0.814 g, 5.89 mmol) in DMF (20 mL). The resulting suspension was stirred at ambient temperature for 16 hours. The reaction mixture was evaporated to dryness then water (50 mL) added and stirring continued for 20 minutes. The resulting precipitate was collected by filtration, washed with water then ether and dried to afford methyl 2-[4-[1-[3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-yl]phenoxy]acetate (1.290 g, 100%).
Reaction SMILES: [OH:1][CH:2]1[CH2:6][C:5](=[O:7])[C:4]([CH2:8][C:9]#[CH:10])=[CH:3]1.N1C=CN=C1.[CH2:16]([Si:18](Cl)([CH2:21][CH3:22])[CH2:19][CH3:20])[CH3:17]>CN(C)C=O.CCOCC>[CH2:8]([C:4]1[C:5](=[O:7])[CH2:6][CH:2]([O:1][Si:18]([CH2:21][CH3:22])([CH2:19][CH3:20])[CH2:16][CH3:17])[CH:3]=1)[C:9]#[CH:10]
Reactant: C#CCC1=CC(O)CC1=O
Reactant: CC[Si](Cl)(CC)CC
Agent: c1c[nH]cn1
Solvent: CCOCC
Solvent: CN(C)C=O
Product: C#CCC1=CC(O[Si](CC)(CC)CC)CC1=O
Yield: 80.3 %

Procedure:
A solution of 250 mg (1.84 mmole) of the title compound of Example 2 in 4 ml of dimethylformamide was treated successively with 200 mg (3 mmole) of imidazole and 300 mg (2 mmole) of triethylsilyl chloride. After stirring for thirty minutes, the reaction mixture was diluted with ether, washed with water, dried over sodium sulfate, filtered, and concentrated to dryness. The crude material was chromatographed on silica gel to give 0.37 g of the title compound as an oil. Structure assignment was confirmed by the proton nmr spectrum: 2.13 (t, J=2 Hz, ≡C--H), 3.08 (mult, --CH2 --C≡), 4.90 (mult, C-11), 7.35 ppm ##STR7##
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[OH:9].[NH2:10][C:11]1[CH:12]=[C:13]([CH:17]=[CH:18][CH:19]=1)[C:14](O)=O>>[NH2:10][C:11]1[CH:12]=[C:13]([C:14]2[O:9][C:3]3[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=3[N:1]=2)[CH:17]=[CH:18][CH:19]=1
Reactant: Nc1cccc(C(=O)O)c1
Reactant: Nc1cc(Cl)ccc1O
Product: Nc1cccc(-c2nc3cc(Cl)ccc3o2)c1

Procedure:
Prepared by the method of Example 1a), from 2-amino-4-chlorophenol (522 mg, 3.6 mmol) and 3-aminobenzoic acid (500 mg, 3.6 mmol) the subtitle compound was obtained, 114 mg (13%). 1H NMR (CDCl3) δ 7.81(bs, 1H), 7.69–7.60(m, 3H), 7.49(t, J=7.1 Hz), 7.41–7.27(m, 2H), 6.96(dd, J=2.6, 7.9 Hz, 1H). MS 245, 247 m/z (M+H)+.
Reaction SMILES: [N+](C1C=CC(O[C:11]([C:13]2[C:14]3[CH:23]=[C:22]([CH2:24][CH3:25])[O:21][C:15]=3[C:16]([O:19][CH3:20])=[N:17][CH:18]=2)=[O:12])=CC=1)([O-])=O.[NH2:26][C:27]1[C:34]([Cl:35])=[CH:33][C:30]([C:31]#[N:32])=[CH:29][C:28]=1[Cl:36]>>[Cl:35][C:34]1[CH:33]=[C:30]([C:31]#[N:32])[CH:29]=[C:28]([Cl:36])[C:27]=1[NH:26][C:11]([C:13]1[C:14]2[CH:23]=[C:22]([CH2:24][CH3:25])[O:21][C:15]=2[C:16]([O:19][CH3:20])=[N:17][CH:18]=1)=[O:12]
Reactant: N#Cc1cc(Cl)c(N)c(Cl)c1
Reactant: CCc1cc2c(C(=O)Oc3ccc([N+](=O)[O-])cc3)cnc(OC)c2o1
Product: CCc1cc2c(C(=O)Nc3c(Cl)cc(C#N)cc3Cl)cnc(OC)c2o1
Yield: 44.7 %

Procedure:
Starting from 2-ethyl-7-methoxyfuro[2,3-c]pyridine-4-carboxylic acid 4-nitrophenyl ester (0.10 g) and 4-amino-3,5-dichlorobenzonitrile (0.12 g). Purification by column chromatography on silica with 20% then 30% then 50% ethyl acetate in hexane to give the title compound (0.051 g) as a cream solid.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][NH:5][C:6]1[CH:11]=[C:10]([Cl:12])[N:9]=[C:8](Cl)[N:7]=1.C(=O)([O-])[O-:15].[K+].[K+]>O1CCOCC1.O>[Cl:12][C:10]1[CH:11]=[C:6]2[NH:5][CH2:4][CH2:3][CH2:2][N:7]2[C:8](=[O:15])[N:9]=1
Reactant: O=C([O-])[O-]
Reactant: Clc1cc(NCCCBr)nc(Cl)n1
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: O=c1nc(Cl)cc2n1CCCN2
Temperature: 60 °C
Yield: 55.5 %

Procedure:
A suspension of N-(3-bromopropyl)-2,6-dichloropyrimidin-4-amine (47 g, 165 mmol) and potassium carbonate (68.4 g, 495 mmol) in 1,4-dioxane (100 mL) and water (100 mL), was heated to 60° C. overnight. The mixture was evaporated to remove the dioxane solvent and the mixture was adjusted to pH ˜6 with HCl (6M). The mixture was extracted with ethyl acetate to remove by product and aqueous phase was adjusted to pH ˜7 with NaOH (2M), evaporated to afford the title compound (17 g, 55% yield).
Reaction SMILES: F[C:2]1[CH:20]=[CH:19][C:5]([C:6]([N:8]([CH2:14][C:15]([F:18])([F:17])[F:16])[CH2:9][C:10]([F:13])([F:12])[F:11])=[O:7])=[CH:4][C:3]=1[N+:21]([O-:23])=[O:22].[CH:24]1([CH2:30][NH2:31])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1.CCN(CC)CC>CCO>[CH:24]1([CH2:30][NH:31][C:2]2[CH:20]=[CH:19][C:5]([C:6]([N:8]([CH2:14][C:15]([F:17])([F:16])[F:18])[CH2:9][C:10]([F:12])([F:13])[F:11])=[O:7])=[CH:4][C:3]=2[N+:21]([O-:23])=[O:22])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: O=C(c1ccc(F)c([N+](=O)[O-])c1)N(CC(F)(F)F)CC(F)(F)F
Reactant: NCC1CCCCC1
Solvent: CCN(CC)CC
Solvent: CCO
Product: O=C(c1ccc(NCC2CCCCC2)c([N+](=O)[O-])c1)N(CC(F)(F)F)CC(F)(F)F

Procedure:
Following the general procedure for Intermediate 2 using 4-fluoro-3-nitro-N,N-bis(2,2,2-trifluoroethyl)benzamide (100 mg, 0.287 mmol) and cyclohexylmethyl amine (0.041 mL, 0.315 mmol) in 3 mL of EtOH containing Et3N (0.080 mL, 0.574 mmol). The product was purified by flash chromatography on silica gel using 4:1/hexanes:EtOAc as eluent. Yield: 107 mg (85%); 1H NMR (CDCl3) 1.05 (m, 2H), 1.24 (m, 4H), 1.69 (m, 2H), 1.75 (m, 2H), 1.83 (m, 1H), 3.17 (t, J=6.64 Hz, 2H), 4.23 (q, J=8.53 Hz, 4H), 6.91 (d, J=8.98 Hz, 1H), 7.51 (d, J=8.89 Hz, 1H), 8.28 (s, 1H), 8.39 (s, 1H); MS (ESI) 442.29 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]([CH2:18][CH2:19][CH:20]([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)O)[C:11](=[O:17])[O:12]C(C)(C)C)[CH3:9])=[CH:4][CH:3]=1.[H-].[Na+].CCOC(C)=O>C1COCC1.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C@@H:8]([N:10]2[CH2:18][CH2:19][CH:20]([C:22]3[CH:23]=[CH:24][C:25]([F:28])=[CH:26][CH:27]=3)[O:12][C:11]2=[O:17])[CH3:9])=[CH:6][CH:7]=1
Reactant: C[C@@H](c1ccc(Br)cc1)N(CCC(O)c1ccc(F)cc1)C(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: C[C@@H](c1ccc(Br)cc1)N1CCC(c2ccc(F)cc2)OC1=O

Procedure:
To a stirred solution of tert-butyl (S)-1-(4-bromophenyl)ethyl(3-(4-fluorophenyl)-3-hydroxypropyl)carbamate (474 mg, 1.05 mmol) in dry THF (10 mL) was added 60% NaH in oil (250 mg, 10.4 mmol). The mixture was heated at reflux for 3 h. The mixture was diluted with water (20 mL) and. EtOAc (80 mL). The organic layer was separated, washed with 5% aq HCl (20 mL), satd aq NaHCO3 (20 mL) and brine (20 mL), and dried over Na2SO4. Removal of the solvent left an oil (348 mg). A portion of the crude product was purified by preparative HPLC to afford 3-((1S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-1,3-oxazinan-2-one as a 2:1 mixture of diastereomers based on 1H NMR. LC-MS (3 min) tR=1.92 min, m/z=380, 378. 1H NMR (CDCl3) S [selected resonances of major and minor diastereomers] 1.52 (d, major), 1.59 (d, minor), 3.06 (m, major), 3.31 (m, minor), 5.20 (dd, major), 5.25 (dd, minor).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8](F)[C:5]([CH:6]=O)=[C:4]([F:11])[CH:3]=1.C(=O)(O)O.C(=O)(O)O.[NH2:20][C:21]([NH2:23])=[NH:22].O>CC(N(C)C)=O>[Cl:1][C:2]1[CH:9]=[C:8]2[C:5]([CH:6]=[N:20][C:21]([NH2:23])=[N:22]2)=[C:4]([F:11])[CH:3]=1
Reactant: O=Cc1c(F)cc(Cl)cc1F
Reactant: N=C(N)N
Agent: O=C(O)O
Solvent: CC(=O)N(C)C
Solvent: O
Product: Nc1ncc2c(F)cc(Cl)cc2n1
Temperature: 140 °C
Yield: 62.7 %

Procedure:
To a stirred suspension of 4-chloro-2,6-difluorobenzaldehyde (45 g, 255 mmol) in DMA (360 mL), at room temperature under nitrogen was added guanidine bis(carbonate) (70.0 g, 382 mmol). The mixture was heated to 140° C. for 3 hours. The reaction was then cooled to room temperature followed by addition of 400 mL water with stirring. The mixture was then filtered. The solids were then collected and triturated in 200 mL methanol for 10 minutes, then filtered. These solids were then dried in vacuo to obtain 31.6 g (63%) of 7-chloro-5-fluoroquinazolin-2-amine (82a) as a brown solid.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[C:6](=O)[CH2:7][CH2:8][C:2]1=2.[N:10]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:19]([F:22])([F:21])[F:20])=[C:11]=S.C[Si](C)(C)[Si](C)(C)C.[Li].O.[NH2:33][NH2:34]>C1COCC1.O.C(O)(=O)C>[S:1]1[CH:5]=[CH:4][C:3]2[C:6]3[NH:33][N:34]=[C:11]([NH:10][C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=4[C:19]([F:22])([F:21])[F:20])[C:7]=3[CH2:8][C:2]1=2
Reactant: FC(F)(F)c1ccccc1N=C=S
Reactant: O=C1CCc2sccc21
Reactant: NN
Agent: C[Si](C)(C)[Si](C)(C)C
Agent: [Li]
Solvent: O
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: FC(F)(F)c1ccccc1Nc1n[nH]c2c1Cc1sccc1-2
Reaction time: 8 h
Yield: 33 %

Procedure:
A mixture of 5,6-Dihydro-cyclopenta[b]thiophen-4-one (1.0 g, 7.4 mmol) and 1-Isothiocyanato-2-trifluoromethyl-benzene (1.5 g, 7.2 mmol) in THF (2.0 mL) was added to lithium hexamethyl disilane (7.0 mL, 7.2 mmol) dropwise at room temperature. The reaction mixture was stirred for 8 hr. Hydrazine monohydrate (0.4 mL, 7.9 mmol) and glacial acetic acid (0.5 mL) were added to the reaction mixture, which was then heated at the reflux temperature for 24 hr. The resulting mixture was added to water (30 mL) and then extracted with ethyl acetate. The target product was purified by gravity column chromatography (50% EtOAc in hexane) to give a (4,7-Dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalen-6-yl)-(2-trifluoromethyl-phenyl)-amine as brown solid in 33% yield.
Reaction SMILES: C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=[O:8])C=CC=CC=1.C([N:20]([CH2:23]C)CC)C.[CH2:25]([C@:32]1([CH2:38]C(O)=O)[CH2:36][CH2:35][C@@H:34]([CH3:37])[CH2:33]1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C1(C)C=CC=CC=1.C(OCC)(=O)C>[N:20]([CH2:38][C@@:32]1([CH2:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH2:36][CH2:35][C@@H:34]([CH3:37])[CH2:33]1)=[C:23]=[O:8]
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: C[C@@H]1CC[C@@](CC(=O)O)(Cc2ccccc2)C1
Reactant: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: C[C@@H]1CC[C@@](CN=C=O)(Cc2ccccc2)C1
Yield: 100.6 %

Procedure:
Diphenylphosphoryl azide (4.48 g, 16 mmol), triethylamine (1.69 g, 16.8 mmol), and acid ((1S,3R)-1-benzyl-3-methyl-cyclopentyl)-acetic acid (3.74 g, 16 mmol) were refluxed in toluene (40 mL) for 17 hours. The mixture was allowed to cool and then taken up in ethyl acetate (150 mL), washed with saturated aqueous sodium hydrogen carbonate (200 mL), brine (150 mL), and dried (MgSO4). The solvent was removed under reduced pressure to give 3.69 g (100%) of ((1S,3R)-1-isocyanatomethyl-3-methyl-cyclopentylmethyl)-benzene, which was used without further purification;
Reaction SMILES: [H-].[Na+].[CH3:3][S:4][C:5]1[CH:6]=[C:7]([NH:11][C:12]#[N:13])[CH:8]=[CH:9][CH:10]=1.I[CH3:15]>C1COCC1>[CH3:15][N:11]([C:7]1[CH:8]=[CH:9][CH:10]=[C:5]([S:4][CH3:3])[CH:6]=1)[C:12]#[N:13]
Reactant: CSc1cccc(NC#N)c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CSc1cccc(N(C)C#N)c1
Temperature: 70 °C
Yield: 72.6 %

Procedure:
A flame-dried Schlenk flask under a nitrogen atmosphere was charged with sodium hydride (60% in mineral oil, 0.14 g, 3.5 mmol), 3-Methylsulfanyl-phenyl-cyanamide (0.493 g, 3.00 mmol) and anhydrous THF (5 ml). The mixture was stirred rapidly and heated to 70° C. for circa 0.5 hours. On cooling to room temperature, iodomethane (0.37 ml, 6.00 mmol) was added drop wise and the mixture stirred at room temperature over night. The resulting clear, colourless solution was concentrated under vacuum before water (30 ml) and diethylether (40 ml) were added. The organic phase was separated, dried over Na2SO4 and the diethylether solvent removed under vacuum to yield a crude residue. Purification by column chromatography on silica gel using dichloromethane as mobile phase afforded the title compound as a pale yellow oil (0.388 g, 73%).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[C:8]([CH2:10][C:11]2[C:12]([NH2:18])=[N:13][C:14]([NH2:17])=[N:15][CH:16]=2)[CH:7]=[C:6]([O:19][CH2:20][CH3:21])[C:5]=1[C:22]1[CH:27]=[CH:26][C:25](SC)=[CH:24][CH:23]=1)[CH3:2].F[C:31](F)(F)C(O)=O.ClC1C=CC=C(C(OO)=O)C=1.[O-:48][S:49]([O-:52])(=S)=O.[Na+].[Na+]>C(Cl)Cl>[CH2:1]([O:3][C:4]1[CH:9]=[C:8]([CH2:10][C:11]2[C:12]([NH2:18])=[N:13][C:14]([NH2:17])=[N:15][CH:16]=2)[CH:7]=[C:6]([O:19][CH2:20][CH3:21])[C:5]=1[C:22]1[CH:23]=[CH:24][C:25]([S:49]([CH3:31])(=[O:52])=[O:48])=[CH:26][CH:27]=1)[CH3:2]
Reactant: O=S([O-])([O-])=S
Reactant: O=C(O)C(F)(F)F
Reactant: CCOc1cc(Cc2cnc(N)nc2N)cc(OCC)c1-c1ccc(SC)cc1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Solvent: ClCCl
Product: CCOc1cc(Cc2cnc(N)nc2N)cc(OCC)c1-c1ccc(S(C)(=O)=O)cc1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
5-(2,6-Diethoxy-4′-methylsulphanyl-biphenyl-4-ylmethyl)-pyrimidine-2,4-diamine (616 mg; 1.5 mmol) is suspended in methylene chloride (12 ml), and trifluoroacetic acid (0.276 ml; 3.6 mmol) is added. After cooling to 0° C., m-chloroperbenzoic acid (456 mg; 2.25 mmol) is added. After 40 minutes a 10% aqueous Na2S2O3 solution (15 ml) is added and the mixture is stirred at room temperature for 15 minutes. It is then extracted with methylene chloride (60 ml) and the extract is washed with an aqueous saturated sodium bicarbonate solution, dried over magnesium sulphate, filtered with suction and concentrated. The crude product is chromatographed over silica gel (100 g) with methylene chloride/methanol/NH4OH (conc.) (19/1/0.05).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([S:9][CH3:10])[CH:4]=1.C1OCCOCCOCCOCCOCCOC1.[C-:29]#[N:30].[K+].ClCCl>C(#N)C>[CH3:10][S:9][C:5]1[CH:4]=[C:3]([CH2:2][C:29]#[N:30])[CH:8]=[CH:7][CH:6]=1
Reactant: CSc1cccc(CCl)c1
Reactant: [C-]#N
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Solvent: ClCCl
Solvent: CC#N
Product: CSc1cccc(CC#N)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 91 %

Procedure:
To a solution of 1-chloromethyl-3-methylsulfanyl-benzene (26.9 g, 0.156 mol) and 18-crown-6 (2 g, 7.8 mmol) in dry acetonitrile (100 mL) was added potassium cyanide and stirred at room temperature for 48 hours. A precipitate was formed while adding dichloromethane (400 mL). The suspension was filtered, washed with water (2×150 mL), dried (Na2SO4) concentrated and distilled under reduced pressure to give a colorless oil (22.9 g, 91%). MS: 161.9 (M+1−).