Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[CH2:16]Cl.[C:21](=[O:24])([O-])[O-].[K+].[K+].O>CN(C=O)C>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[CH2:16][O:24][C:21]1[CH:6]=[C:5]([CH:4]=[CH:3][CH:2]=1)[C:10]#[N:1]
Reactant: ClCc1cccc(OCc2ccc3ccccc3n2)c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1cccc(OCc2cccc(OCc3ccc4ccccc4n3)c2)c1

Procedure:
A solution of 0.65 g (5.4 mmol) 3-hydroxybenzoinitirle, 1.5 g (5.3 mmol) of 3-(2-quinolinylmethyloxy)benzyl chloride, and 0.75 g (5.4 mmol) of potassium carbonate in 15 ml of DMF is heated at 60° C. overnight. The reaction mixture is poured into water. The precipitated product is collected on a filter and purified by dry column chromatography to give 3-[3-(2-quinolinylmethyloxy)benzyloxy]benzonitrile. (M.P. 86°-87° C.)
Reaction SMILES: OC(C(F)(F)F)=O.[NH:8]1[CH2:11][CH:10]([NH:12][C:13](=[O:29])[CH2:14][NH:15][C:16]2[C:20]3[CH:21]=[C:22]([C:25]([F:28])([F:27])[F:26])[CH:23]=[CH:24][C:19]=3[O:18][N:17]=2)[CH2:9]1.[CH2:30]([O:32][C:33]([CH:35]1[CH2:40][CH2:39][C:38](=O)[CH2:37][CH2:36]1)=[O:34])[CH3:31]>>[CH2:30]([O:32][C:33]([CH:35]1[CH2:40][CH2:39][CH:38]([N:8]2[CH2:11][CH:10]([NH:12][C:13](=[O:29])[CH2:14][NH:15][C:16]3[C:20]4[CH:21]=[C:22]([C:25]([F:27])([F:26])[F:28])[CH:23]=[CH:24][C:19]=4[O:18][N:17]=3)[CH2:9]2)[CH2:37][CH2:36]1)=[O:34])[CH3:31]
Reactant: O=C(CNc1noc2ccc(C(F)(F)F)cc12)NC1CNC1
Reactant: CCOC(=O)C1CCC(=O)CC1
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)C1CCC(N2CC(NC(=O)CNc3noc4ccc(C(F)(F)F)cc34)C2)CC1

Procedure:
The title compound was prepared as a white solid from reaction of (N-Azetidin-3-yl-2-(5-trifluoromethyl-benzo[d]isoxazol-3-ylamino)-acetamide TFA salt (as prepared in Example 1, Step D) and 4-oxo-cyclohexanecarboxylic acid ethyl ester using the procedure described in Step E of Example 1.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][C:5]#[C:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1.[Cl:13][C:14]1[CH:22]=[CH:21][CH:20]=[CH:19][C:15]=1[C:16](Cl)=[O:17]>>[Cl:13][C:14]1[CH:22]=[CH:21][CH:20]=[CH:19][C:15]=1[C:16]([N:2]([CH3:1])[CH2:3][CH2:4][C:5]#[C:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1)=[O:17]
Reactant: CNCCC#Cc1ccccn1
Reactant: O=C(Cl)c1ccccc1Cl
Product: CN(CCC#Cc1ccccn1)C(=O)c1ccccc1Cl
Yield: 63.7 %

Procedure:
The title compound was prepared in accordance with the general method of Example 199(D), from N-methyl-4-(pyridin-2-yl)but-3-yn-1-amine (100 mg, 0.62 mmol) and 2-chlorobenzoyl chloride (109 mg, 0.62 mmol). The crude residue was purified over silicagel chromatography (prepacked 10 g silicagel column, DCM/MeOH: 98/2 as eluent) to afford 118 mg of 2-chloro-N-methyl-N-(4-(pyridin-2-yl)but-3-ynyl)benzamide as a brown oil (Yield: 63%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:11])[CH2:9][CH3:10])=[CH:4][CH:3]=1.[C:12](=O)([O-])[O-].[K+].[K+].S(OC)(OC)(=O)=O>C(#N)C>[CH3:12][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](=[O:11])[CH2:9][CH3:10])=[CH:6][CH:7]=1
Reactant: CCC(=O)c1ccc(O)cc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: COS(=O)(=O)OC
Solvent: CC#N
Product: CCC(=O)c1ccc(OC)cc1
Temperature: 25 °C

Procedure:
To a solution of 4′-hydroxypropiophenone (1.0 g, 6.67 mmol) in acetonitrile (50.0 mL) was added potassium carbonate (7.17 g, 66.7 mmol) and the mixture heated to reflux for 90 min. After this time the reaction mixture was allowed to cool to room temperature and dimethyl sulphate (1.05 mL, 11.1 mmol) was added and the reaction mixture was heated to reflux for a further 19 h. After cooling the acetonitrile was evaporated under reduced pressure and the residue taken up in water and extracted with dichloromethane. The dichloromethane extract was dried (MgSO4) and evaporated under reduced pressure to give 4′-methoxypropiophenone as a yellow oil, (970 mg, 89%) 1H nmr (d6-DMSO, 300 MHz) 1.06, t (7.2 Hz), CH3; 2.95, q (7.2 Hz), CH2; 3.83, s, OMe; 7.02, d (6.9 Hz), H3′,5′; 7.93, d (6.9 Hz), H2′,6′. ESI (+ve) MS m/z 165 (M+H, 100%).
Reaction SMILES: C(N(CC)CC)C.[C:8]([O:12][C:13]([NH:15][C@@H:16]([CH2:39][CH3:40])[C:17]([N:19]1[C:27]2[C:22](=[CH:23][C:24]([O:28][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:25][CH:26]=2)[CH2:21][C@H:20]1[C:36](O)=[O:37])=[O:18])=[O:14])([CH3:11])([CH3:10])[CH3:9].Cl.[F:42][C:43]([F:47])([F:46])[CH2:44][NH2:45].O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1>ClCCl>[F:42][C:43]([F:47])([F:46])[CH2:44][NH:45][C:36]([CH:20]1[CH2:21][C:22]2[C:27](=[CH:26][CH:25]=[C:24]([O:28][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH:23]=2)[N:19]1[C:17](=[O:18])[C@@H:16]([NH:15][C:13]([O:12][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:14])[CH2:39][CH3:40])=[O:37]
Reactant: CC[C@H](NC(=O)OC(C)(C)C)C(=O)N1c2ccc(OCc3ccccc3)cc2C[C@H]1C(=O)O
Reactant: NCC(F)(F)F
Agent: Cl
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC[C@H](NC(=O)OC(C)(C)C)C(=O)N1c2ccc(OCc3ccccc3)cc2CC1C(=O)NCC(F)(F)F
Temperature: 25 °C

Procedure:
Triethylamine (4.9 mL, 33 mmol) was added to the solution of 1-(N-t-butoxycarbonyl-2(S)-aminobutyryl)-5-benzyloxyindoline-2(S)-carboxylic acid (2.6 g, 5.72 mmol) and 2,2,2-trifluoroethylamine hydrochloride (1.55 g, 11.4 mmol) in dried dichloromethane (50 mL) at 0° C. under nitrogen, followed by bis(2-oxo-3-oxazolidinyl)phosphinic chloride (2.902 g, 11.4 mmol). The temperature was allowed to rise to room temperature and the mixture was stirred at room temperature for twenty-four hours, then filtered. The filtrate was concentrated under vacuum to give a brown solid which was purified by column chromatography (silica gel, 8:2 diethyl ether: petroleum spirit) to provide a white solid as the desired product.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[O:8][C:7]([CH3:15])([CH3:14])[CH:6]=[C:5]2[C:16]([CH3:19])([CH3:18])[CH3:17].C([Sn](CCCC)(CCCC)[C:25]([O:27]CC)=[CH2:26])CCC>C1COCC1>[C:16]([C:5]1[C:4]2[C:9](=[CH:10][C:11]([O:12][CH3:13])=[C:2]([C:25](=[O:27])[CH3:26])[CH:3]=2)[O:8][C:7]([CH3:15])([CH3:14])[CH:6]=1)([CH3:19])([CH3:18])[CH3:17]
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: COc1cc2c(cc1Br)C(C(C)(C)C)=CC(C)(C)O2
Solvent: C1CCOC1
Product: COc1cc2c(cc1C(C)=O)C(C(C)(C)C)=CC(C)(C)O2

Procedure:
Following General Procedure H, a solution of 6-bromo-4-tert-butyl-7-methoxy-2,2-dimethyl-2H-chromene (Compound 15, 280 mg, 0.86 mmol) in THF was treated with tributyl(1-ethoxyvinyl)tin (0.58 mL, 1.7 mmol) to give the title compound as a colorless oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9](Cl)[CH:10]([C:14]3[C:19]([F:20])=[CH:18][CH:17]=[CH:16][C:15]=3[F:21])[N:11]=[CH:12][CH:13]=2)=[CH:4][CH:3]=1.[C-:23]#[N:24].[K+].C1(C)C=CC=CC=1S([O-])=O.[Na+]>CN(C)C=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([C:23]#[N:24])[CH:10]([C:14]3[C:19]([F:20])=[CH:18][CH:17]=[CH:16][C:15]=3[F:21])[N:11]=[CH:12][CH:13]=2)=[CH:4][CH:3]=1
Reactant: Fc1cccc(F)c1C1N=CC=C(c2ccc(Br)cc2)N1Cl
Reactant: [C-]#N
Agent: Cc1ccccc1S(=O)[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#CN1C(c2ccc(Br)cc2)=CC=NC1c1c(F)cccc1F
Temperature: 80 °C
Reaction time: 3 h

Procedure:
6 g of 4-(4-bromophenyl)-2-(2,6-difluorophenyl)-3-chloropyrimidine, 80 ml of dimethylformamide, 1.53 g of KCN and 0.93 g of sodium tolylsulfinate are mixed together, stirred for 3 hours at 80° C., mixed with ice water and filtered. After dissolving the precipitate in ethyl acetate, drying with magnesium sulfate, filtering and concentrating, the title compound is obtained with a melting point 146-148° C. (compound 3.355).
Reaction SMILES: [CH:1]1([S:4][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH2:3][CH2:2]1.C([Li])CCC.[I:16]N1C(=O)CCC1=O.C(=O)([O-])O.[Na+]>O1CCCC1>[I:16][C:1]1([S:4][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH2:3][CH2:2]1
Reactant: O=C1CCC(=O)N1I
Reactant: c1ccc(SC2CC2)cc1
Agent: O=C([O-])O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Product: IC1(Sc2ccccc2)CC1
Temperature: 25 °C

Procedure:
Cyclopropylphenyl thioether (5.0 g, 33.3 mmol) was dissolved in tetrahydrofuran (50 mL), and n-butyllithium (25.1 mL, 39.9 mmol) was dropwisely added at 0° C. for 5 minutes under an argon atmosphere. Then, a solution of N-iodosuccinimide (8.99 g, 39.9 mmol) in tetrahydrofuran (100 mL) was dropwisely added at −78° C. The resultant mixture was stirred overnight, and gradually warmed to room temperature. The reaction solution was added with a saturated aqueous solution of sodium hydrogen carbonate, and extracted with hexane. The organic layer was washed with brine, dried over anhydrous sodium sulfate, concentrated in vacuo, and purified using silica-gel column chromatography (hexane), to obtain a crude product ((1-iodocyclopropyl)(phenyl)sulfane:cyclopropylphenylthioether (=2.4:1) (5.64 g). Next, 5-hydroxy-2-methylpyridine (1.82 g, 16.7 mmol) was dissolved in toluene (150 mL). The resultant mixture was added with silver carbonate (9.19 g, 33.3 mmol) and 1-iodocyclopropyl)(phenypsulfane:cyclopropylphenylthioether (=2.4:1) mixture (5.64 g, 16.7 mmol (*converted in terms of 1-iodocyclopropyl)(phenyl)sulfane), and stirred overnight at room temperature. Then, acetic acid (200 mL) was added thereto, and stirred for 10 minutes. The reaction solution was filtered using celite and concentrated in vacuo. The obtained residue was purified using silica-gel column chromatography (hexane/ethyl acetate), and 2-methyl-5-(1-(phenylthio)cyclopropoxy)pyridine (1.88 g, yield 44%) was obtained as a yellow oil.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([S:7][CH2:8][C:9]2[CH:17]=[CH:16][C:12](C(O)=O)=[C:11]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[CH3:24])[CH:10]=2)[CH:2]=1.N[C@H](C(O)=O)CCSC.Cl.C[O:36][C:37](=[O:59])[C@H:38]([CH2:55][CH2:56][S:57][CH3:58])[NH:39][C:40](=[O:54])C1C=CC(N)=CC=1C1C=CC=CC=1.N>>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([S:7][CH2:8][C:9]2[CH:17]=[CH:16][C:12]([C:40]([NH:39][C@H:38]([C:37]([OH:59])=[O:36])[CH2:55][CH2:56][S:57][CH3:58])=[O:54])=[C:11]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[CH3:24])[CH:10]=2)[CH:2]=1
Reactant: COC(=O)[C@H](CCSC)NC(=O)c1ccc(N)cc1-c1ccccc1
Reactant: Cc1ccccc1-c1cc(CSc2cccnc2)ccc1C(=O)O
Agent: CSCC[C@H](N)C(=O)O
Agent: Cl
Agent: N
Product: CSCC[C@H](NC(=O)c1ccc(CSc2cccnc2)cc1-c1ccccc1C)C(=O)O

Procedure:
The desired compound was prepared by coupling of 4-(3-pyridylthiomethyl)-2-(2-methylphenyl)benzoic acid with methionine phenylsulfonimide hydrochloride using the procedure used in step C of the preparation of compound 8. 1H NMR (300 MHz, CDCl3) δ 8.50 (m, 2H), 8.02 (m, 2H), 7.93 (t, 1H), 7.62 (m, 2H), 7.51 (m, 2H), 7.17-7.42 (m, 5H), 7.09 (m, 2H), 5.71 (d, 1H), 4.40 (m, 1H), 4.13 (s, 2H), 1.86-2.13 (m, 8H), 1.71 (m, 1H), 1.25 (m, 1H). MS (CI, NH3) m/e 606, 225. Anal calcd for C31H31N3O4S3 1.53 TFA: C, 52.43; H, 4.20; N, 5.39. Found: C, 52.42; H, 4.14; N, 5.43.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:40])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17](B3OC(C)(C)C(C)(C)O3)=[CH:16][C:15]=2[CH2:29][N:30]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:31][CH3:32])[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)[CH3:2].Cl[C:42]1[N:47]=[CH:46][C:45]([F:48])=[CH:44][N:43]=1>>[CH2:1]([O:3][C:4](=[O:40])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17]([C:42]3[N:47]=[CH:46][C:45]([F:48])=[CH:44][N:43]=3)=[CH:16][C:15]=2[CH2:29][N:30]([C:33]([O:35][C:36]([CH3:38])([CH3:37])[CH3:39])=[O:34])[CH2:31][CH3:32])[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)[CH3:2]
Reactant: CCOC(=O)Cc1ccc(OC)c(-c2ccc(B3OC(C)(C)C(C)(C)O3)cc2CN(CC)C(=O)OC(C)(C)C)c1
Reactant: Fc1cnc(Cl)nc1
Product: CCOC(=O)Cc1ccc(OC)c(-c2ccc(-c3ncc(F)cn3)cc2CN(CC)C(=O)OC(C)(C)C)c1

Procedure:
Prepared according to the procedure described in Example 1, Step 4, using the following starting materials: [2′-[(tert-butoxycarbonyl-ethyl-amino)-methyl]-6-methoxy-4′-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-biphenyl-3-yl]-acetic acid ethyl ester and 2-chloro-5-fluoropyrimidine.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]([NH:9][C:10]([C:13]2[N:19]([CH3:20])[C:17](=[O:18])[C:16]([OH:21])=[C:15]([C:22]([NH:24][CH2:25][C:26]3[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=3)=[O:23])[N:14]=2)([CH3:12])[CH3:11])=[O:8])=[N:4][N:3]=1.CO.[OH-].[Ba+2:36].[OH-]>C(#N)C>[CH3:1][C:2]1[O:6][C:5]([C:7]([NH:9][C:10]([C:13]2[N:19]([CH3:20])[C:17](=[O:18])[C:16]([OH:21])=[C:15]([C:22]([NH:24][CH2:25][C:26]3[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=3)=[O:23])[N:14]=2)([CH3:12])[CH3:11])=[O:8])=[N:4][N:3]=1.[Ba:36]
Reactant: [Ba+2]
Agent: Cc1nnc(C(=O)NC(C)(C)c2nc(C(=O)NCc3ccc(F)cc3)c(O)c(=O)n2C)o1
Agent: [OH-]
Solvent: CO
Solvent: CC#N
Product: [Ba]
Temperature: 62.5 °C
Reaction time: 20 h

Procedure:
Raltegravir (10 gm), methanol (60 ml), acetonitrile (40 ml) and barium hydroxide (4.2 gm) were added at 25 to 30° C. The contents were heated to 60 to 65° C. to obtain a solution. The solution was cooled to 25 to 30° C. and stirred for 20 hours at 25 to 30° C. The solid obtained was collected by filtration and dried to obtain 10 gm of raltegravir barium.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([CH:7]=[O:8])=[CH:4][CH:3]=1.Cl.[NH2:10]O.C([O-])(=O)C.[Na+]>C(O)(=O)C>[CH3:1][C:2]1[S:6][C:5]([C:7]([NH2:10])=[O:8])=[CH:4][CH:3]=1
Reactant: Cc1ccc(C=O)s1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Product: Cc1ccc(C(N)=O)s1
Reaction time: 4 h
Yield: 82 %

Procedure:
5-Methyl-2-thiophenecarbaldehyde (2.6 g, 0.1 M), hydroxylamine hydrochloride (8.3 g, 0.12 M), and sodium acetate (9.8 g, 0.12 M) were added to. acetic acid (50 ml) and the mixture was refluxed for 13 to 15 hours. After disappearance of the starting material was confirmed by high performance liquid chromatography (HPLC retention time ca 13 min.), the reaction mixture was concentrated under reduced pressure to about one-half of its volume. To this concentrate was added concentrated hydrochloric acid (100 ml) and the reaction was allowed to proceed at 60° C. for 4 hours. The reaction mixture was then diluted with 100 ml of water and stirred under ice-cooling for 30 minutes. The resulting crystals were recovered by filtration and rinsed with 100 ml of iced water to provide 5-methyl-2-thiophenecarboxamide (HPLC retention time ca 4 min.)
Reaction SMILES: Cl.[CH3:2][NH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH2:10].[C:11](=[S:13])=S.[OH-].[Na+].Cl>C(O)C.O>[SH:13][C:11]1[N:3]([CH3:2])[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[N:10]=1
Reactant: CNc1ccccc1N
Reactant: S=C=S
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cn1c(S)nc2ccccc21
Yield: 49.5 %

Procedure:
11.7 g of N-methyl-o-phenylenediamine hydrochloride, 9.1 g of carbon disulfide and an aqueous solution containing 7.2 g of sodium hydroxide and 20 ml of water were added to 150 ml of ethanol and the mixture was heated and refluxed for 4 hours. After cooling, a 3 N hydrochloric acid aqueous solution was added to the reaction mixture to make the reaction solution slightly acidic and, thereby, crystals were precipitated. After filtration, the crystals were recrystallized from a mixture of water and ethanol (70:30 by volume) to obtain 6 g of 2-mercapto-1-methylbenzimidazole (Compound (III-11)) having a melting point of 194° to 195° C. (yield: 67%).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[N:8]=[C:7]([OH:9])[CH:6]=[C:5]([OH:10])[CH:4]=1.[N+:13]([O-])([OH:15])=[O:14]>S(=O)(=O)(O)O>[N+:13]([C:6]1[C:7]([OH:9])=[N:8][C:3]([C:2]([F:1])([F:11])[F:12])=[CH:4][C:5]=1[OH:10])([O-:15])=[O:14]
Reactant: Oc1cc(O)nc(C(F)(F)F)c1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: O=[N+]([O-])c1c(O)cc(C(F)(F)F)nc1O
Temperature: -50 °C
Reaction time: 1.5 h
Yield: 71 %

Procedure:
6-Trifluoromethyl-pyridine-2,4-diol (56 g, 310 mmol) was added in 3-5 gm portions to concentrated sulphuric acid (140 mL) with stirring to give a pale brown solution. The temperature increased to −50° C. during the addition. Nitric acid (21.1 mL 328 mmol, 70% HNO3 d=1.4 gm/ml) was added drop wise at such a rate as to maintain a reaction temperature of between 45° and 50° C. which took approximately 90 minutes. Once all the nitric acid had been added the reaction was allowed to cool to ambient temperature over 3 hours. Poured into ice/water (˜1.3 kg) with stirring, after a few minutes a pale yellow precipitate formed which was filtered off, dissolved in ethyl acetate and dried over sodium sulphate, filtered and evaporated. A second crop of material was obtained by extraction of the aqueous filtrate with ethyl acetate. Combined batches and purified by crystallization from ethyl acetate/n-heptane gave 3-nitro-6-trifluoromethyl-pyridine-2,4-diol as a white ‘fluffy’ solid (49.5 gm 71% yield).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:12][CH2:11][C:10](=O)[CH2:9][CH2:8]2)=[CH:3][CH:2]=1.O.[NH2:15][NH2:16]>C(O)C>[N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:12][CH2:11][C:10](=[N:15][NH2:16])[CH2:9][CH2:8]2)=[CH:3][CH:2]=1
Reactant: O=C1CCN(c2ccncc2)CC1
Reactant: NN
Solvent: O
Solvent: CCO
Product: NN=C1CCN(c2ccncc2)CC1

Procedure:
A solution of 1-(4-pyridyl)-4-piperidone (3.52 g) and hydrazine hydrate (1.25 q) in ethanol (50 ml) was stirred at room temperature for 15 hours. The reaction mixture was concentrated and the residue obtained was crystallized from ether to obtain [1-(4-pyridyl)-4-piperidinylidene]hydrazine (3.51 g) as colorless crystals.
Reaction SMILES: [NH2:1][C:2]1[N:3]([CH3:24])[C:4](=[O:23])[C:5]2([C:15]3[C:10](=[CH:11][CH:12]=[C:13](Br)[CH:14]=3)[O:9][CH:8]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:7]2)[N:6]=1.[F:25][C:26]([F:37])([F:36])[C:27]1[CH:28]=[C:29](B(O)O)[CH:30]=[CH:31][CH:32]=1>O1CCOCC1.C([O-])([O-])=O.[Cs+].[Cs+].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>[NH2:1][C:2]1[N:3]([CH3:24])[C:4](=[O:23])[C:5]2([C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:31]4[CH:30]=[CH:29][CH:28]=[C:27]([C:26]([F:37])([F:36])[F:25])[CH:32]=4)[CH:14]=3)[O:9][CH:8]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:7]2)[N:6]=1
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Reactant: CN1C(=O)C2(CC(c3ccccc3)Oc3ccc(Br)cc32)N=C1N
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: CN1C(=O)C2(CC(c3ccccc3)Oc3ccc(-c4cccc(C(F)(F)F)c4)cc32)N=C1N
Temperature: 120 °C
Yield: 18.4 %

Procedure:
Pd(PPh3)2Cl2 (10 mg) in a 10 mL CEM test tube under Ar was treated sequentially with 2′-amino-6-bromo-1′-methyl-2-phenylspiro[chroman-4,4′-imidazol]-5′(1′H)-one (20 mg, 0.052 mmol) in 1,4-dioxane (1 mL), Cs2CO3 (2 N, 0.3 mL) and 3-(trifluoromethyl)phenylboronic acid (19.7 mg, 0.1 mmol). The mixture was heated under microwave at 120° C. for 30 minutes. The reaction mixture was concentrated in vacuo to give the residue, which was purified by preparative TLC and preparative HPLC to give pure 2′-amino-1′-methyl-2-phenyl-6-(3-(trifluoromethyl)phenyl)spiro[chroman-4,4′-imidazol]-5′(1′H)-one (4.31 mg, 18%). 1H-NMR (CDCl3): 1.95 (d, 1H), 2.66 (t, 1H), 3.16 (d, 3H), 5.97 (d, 1H), 6.96 (s, 1H), 7.06 (m, 2H), 7.20 (s, 1H), 7.38 (m, 3H), 7.44 (m, 3H), 7.53 (m, 1H), 7.62 (m, 1H), 7.70 (s, 1H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:17])[CH3:16])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[Si](OS(C(F)(F)F)(=O)=O)(C)(C)C.C1C(=O)N([Br:46])C(=O)C1>C(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15](=[O:17])[CH2:16][Br:46])=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)c1ccc(OCc2ccccc2)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(CBr)c1ccc(OCc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 1-(4-(benzyloxy)-phenyl)-ethanone (49.12 g; 217.1 mmol) in CH2Cl2 (750 mL) was added drop wise DIPEA (45.37 mL; 260.5 mmol) and TMSOTf (45.18 mL; 249.6 mmol), both at 0° C. The resulting solution was maintained at 0° C. for 1 h, and then NBS (42.50 g; 238.8 mmol) was added in four portions. The resulting mixture was allowed to warm to RT and stirred 1 hour. Subsequently, the mixture was concentrated in vacuo and the residue was treated with EtOAc and washed twice with water, and brine. The organic layer was dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO2, Et2O) and crystallization from iPr2O to afford 1-(4-benzyloxy-phenyl)-2-bromo-ethanone.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[CH2:6][NH2:7].[Cl:13][CH2:14][CH2:15][N:16]=[C:17]=[O:18]>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:6][NH:7][C:17]([NH:16][CH2:15][CH2:14][Cl:13])=[O:18])[CH:8]=[CH:9][C:10]=1[O:11][CH3:12]
Reactant: COc1ccc(CN)cc1OC
Reactant: O=C=NCCCl
Solvent: C1CCOC1
Product: COc1ccc(CNC(=O)NCCCl)cc1OC
Yield: 89 %

Procedure:
To a solution of 3,4-dimethoxybenzylamine (2 g, 12 mmol) in anh. THF (25 mL), at r.t., under N2, was added 2-chloroethyl isocyanate (1.02 mL, 1 eq). The reaction was complete after the addition. It was concentrated and the residue was purified by flash chromatography (silica gel, cHex/EtOAc 1:1→7:3 EtOAc/NH3 (0.5 in MeOH)) to give the title compound as a white solid (2.9 g, 89%).
Reaction SMILES: [CH:1]1([NH:4][C:5]([NH:7][C:8]2[CH:13]=[CH:12][C:11]([B:14]3[O:18][C:17]([CH3:20])([CH3:19])[C:16]([CH3:22])([CH3:21])[O:15]3)=[CH:10][CH:9]=2)=[O:6])[CH2:3][CH2:2]1.[CH3:23][N:24]1[CH2:29][CH2:28][N:27]([C:30]2C=CC(N)=[CH:32][CH:31]=2)[CH2:26][CH2:25]1>>[CH3:23][N:24]1[CH2:29][CH2:28][N:27]([C:30]2[CH:3]=[CH:2][C:1]([NH:4][C:5]([NH:7][C:8]3[CH:13]=[CH:12][C:11]([B:14]4[O:18][C:17]([CH3:19])([CH3:20])[C:16]([CH3:21])([CH3:22])[O:15]4)=[CH:10][CH:9]=3)=[O:6])=[CH:32][CH:31]=2)[CH2:26][CH2:25]1
Reactant: CN1CCN(c2ccc(N)cc2)CC1
Reactant: CC1(C)OB(c2ccc(NC(=O)NC3CC3)cc2)OC1(C)C
Product: CN1CCN(c2ccc(NC(=O)Nc3ccc(B4OC(C)(C)C(C)(C)O4)cc3)cc2)CC1

Procedure:
A procedure analogous to that used for the preparation of 1-cyclopropyl-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)urea was used, using 4-(4-methylpiperazin-1-yl)aniline as the amine component.
Reaction SMILES: [N:1]1([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH:14]([C:16]([CH3:18])=[O:17])=[CH2:15]>C1COCC1>[O:17]=[C:16]([CH3:18])[CH2:14][CH2:15][N:4]1[CH2:5][CH2:6][N:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:2][CH2:3]1
Reactant: C=CC(C)=O
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: C1CCOC1
Product: CC(=O)CCN1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 87 %

Procedure:
A solution of tert-butyl piperazine-1-carboxylate (6 g, 32.3 mmol) in THF (50 ml) was gradually added dropwise to a solution of methyl vinyl ketone (2.3 g, 32.9 mmol) in THF (25 ml) while cooling in an ice-bath, and the mixture was stirred at room temperature for 3 days. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (methylene chloride/methanol=20/1) to afford tert-butyl 4-(3-oxobutyl)piperazine-1-carboxylate (7.2 g, yield 87%)as a pale yellow oil.
Reaction SMILES: [O:1]([C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([CH:18]=[CH:19][CH2:20][OH:21])[CH:16]=2)[N:11]=[CH:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.[C:28](Cl)(=[O:30])[CH3:29]>C(Cl)Cl.Cl>[O:1]([C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([CH:18]=[CH:19][CH2:20][O:21][C:28](=[O:30])[CH3:29])[CH:16]=2)[N:11]=[CH:10][N:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)Cl
Reactant: OCC=Cc1ccc2ncnc(Oc3ccccc3)c2c1
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)OCC=Cc1ccc2ncnc(Oc3ccccc3)c2c1
Reaction time: 2 h

Procedure:
To alcohol 25 (900 mg, 3.23 mmol) and pyridine (0.8 mL, 10 mmol) in dry CH2Cl2 (15 mL) at 0° C. was added acetyl chloride (0.3 mL, 4.2 mmol). The resulting mixture was stirred for 2 hours, the diluted with CH2Cl2 (10 mL) and 5% HCl (10 mL). The mixture was transferred to a separatory funnel and the organic layer washed with H2O and brine. The organic layer was dried (Na2SO4), solids filtered and the solvent removed in vacuo to provide the desired acetate 26 as a yellow waxy solid (1.04 g, 100%).1H NMR (CDCl3; 400 MHz): δ: 8.72 (s, 1H), 8.30 (d, 1H, J=1.7 Hz), 7.98 (m, 2H), 7.49 (m, 2H), 7.30 (m, 1H), 7.25 (m, 2H), 6.84 (d, 1H, J=16.0 Hz), 6.46 (m, 1H), 4.79 (dd, 2H, J=6.2 Hz, 1.2 Hz), 2.11 (s, 3H).