Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([NH2:9])[CH:3]=1.[C:10]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:15]=[CH:14][C:13]([CH:16]2[CH2:22][C:21](=O)[O:20][C:18](=[O:19])[CH2:17]2)=[CH:12][CH:11]=1.Cl>ClCCl.O1CCOCC1>[ClH:1].[C:10]1([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:15]=[CH:14][C:13]([CH:16]([CH2:22][C:21]2[NH:9][C:4]3[CH:3]=[C:2]([Cl:1])[CH:7]=[CH:6][C:5]=3[N:8]=2)[CH2:17][C:18]([OH:20])=[O:19])=[CH:12][CH:11]=1
Reactant: O=C1CC(c2ccc(-c3ccccc3)cc2)CC(=O)O1
Reactant: Nc1ccc(Cl)cc1N
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: O=C(O)CC(Cc1nc2ccc(Cl)cc2[nH]1)c1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.2 %

Procedure:
Commercial 4-chloro-1,2-phenylenediamine (214 mg) and 3-(biphenyl-4-yl)glutaric anhydride (399 mg) were dissolved in dichloromethane (5 ml) with heating. The dark solution was stirred at rt for 1 h. The precipitate formed was collected by suction filtration, washed with dichloromethane, and dried in vacuo to give a mixture of regioisomeric amides (0.48 g) as light brown solid. This solid was dissolved in 1,4-dioxane (1 ml) with heating. 4M HCl in 1,4-dioxane (3 ml) was added and the solution was heated to reflux for 1.5 h. The precipitate formed is isolated by suction filtration and washed with 1,4-dioxane and diethyl ether. The crude (0.4 g) is crystallised from acetic acid to provide 3-(biphenyl-4-yl)-4-(5-chloro-2-benzimidazolyl)butanoic acid HCl (0.27 g) as light brown crystals.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4](Cl)[CH:3]=1.[NH2:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17](=[O:26])[O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:12][CH:11]=1.Cl.C(OCC)(=O)C.CCCCCC>C(OCCO)C>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17](=[O:26])[O:18][CH2:19][C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)=[CH:12][CH:11]=2)[CH:3]=1
Reactant: Nc1cc(Cl)ncn1
Reactant: Nc1ccc(NC(=O)OCc2ccccc2)cc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCOCCO
Solvent: CCCCCC
Product: Nc1cc(Nc2ccc(NC(=O)OCc3ccccc3)cc2)ncn1
Temperature: 120 °C
Reaction time: 8 h
Yield: 46.7 %

Procedure:
6-Amino-4-chloropyrimidine (259 mg) was dissolved in 2-ethoxyethanol (10 ml), and then benzyl N-(4-aminophenyl)carbamate (533 mg) and 2 N HCl (2 ml) were added thereto, followed by stirring at 120° C. overnight. The reaction mixture was cooled down to room temperature, and partitioned between ethyl acetate and a saturated aqueous solution of sodium hydrogencarbonate. The organic layer was washed with brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under a reduced pressure to give a residue, which was then purified by silica gel column chromatography (eluent; ethyl acetate:methanol=95:5). Fractions containing the target compound were concentrated to give a residue, to which ethyl acetate-hexane was then added to precipitate crystals. The solid was filtered, and dried under aeration to provide the titled compound (313.1 mg, 47%) as opaline crystals.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:12][CH2:11][CH:10]([CH2:13][NH2:14])[CH2:9][CH2:8]2)=[CH:3][CH:2]=1.[N+:15]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[CH2:24][C:25](O)=[O:26])([O-])=O.CCOC(C)=O.O>CN(C=O)C>[NH2:15][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[CH2:24][C:25]([NH:14][CH2:13][CH:10]1[CH2:9][CH2:8][N:7]([C:4]2[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=2)[CH2:12][CH2:11]1)=[O:26]
Reactant: NCC1CCN(c2ccncc2)CC1
Reactant: O=C(O)Cc1ccccc1[N+](=O)[O-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: Nc1ccccc1CC(=O)NCC1CCN(c2ccncc2)CC1
Reaction time: 2.5 h
Yield: 59.8 %

Procedure:
A solution of 1-(4-pyridyl)piperidine-4-methylamine (156 mg, 0.817 mmol), 2-nitrophenylacetic acid (159 mg, 0.875 mmol) and 1-[3-(dimethylaminopropyl]-3-ethylcarbodiimide hydrochloride (168 mg, 0.875 mmol) in DMF was stirred 16 h; and the mixture was poured into EtOAc and H2O. The aqueous layer was washed with EtOAc (2×) and the combined extracts were dried (K2CO3) and concentrated. The residue and 10% Pd/C (164 mg) in 25 mL of EtOH were placed under an atmosphere of hydrogen gas. After 2.5 h, the mixture was filtered and the filtrate concentrated. The residue was dissolved in 5% HOAc in MeOH and loaded onto a SCX Column (Varian). The column was eluted with MeOH followed by 2 M NH3 in MeOH. The latter fractions were concentrated yielding 158.6 mg (60%) of the title compound.
Reaction SMILES: [Cl:1][C:2](OC(C)C)=O.F[C:9]1[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=1C([Cl:13])=O>>[CH3:16][CH2:17][CH2:9][CH2:10][CH2:14][CH3:15].[Cl:13][CH2:2][Cl:1]
Reactant: O=C(Cl)c1ccccc1F
Reactant: CC(C)OC(=O)Cl
Product: CCCCCC
Product: ClCCl
Yield: 81 %

Procedure:
This compound was prepared according to the method described in Example 7, except that isopropyl chloroformate was replaced by an equivalent portion of o-fluorobenzoyl chloride and the reaction product was purified by recrystallization from a mixture of hexane/dichloromethane as colourless crystals mp 113.5°-114° C., yield 81%.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([CH3:10])[CH3:9])=[CH:6][CH:7]=1.[C:11](Cl)(C)(C)C.[CH2:16]=[CH:17][C:18](C)([CH3:20])[CH3:19].[Cl-].[Al+3].[Cl-].[Cl-].C([Al](CC)CC)C>>[CH3:9][C:8]1([CH3:11])[C:5]2[C:6](=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=2)[C:18]([CH3:20])([CH3:19])[CH:17]([CH3:16])[CH2:10]1
Reactant: C=CC(C)(C)C
Reactant: CC(C)(C)Cl
Reactant: Cc1ccc(C(C)C)cc1
Agent: CC[Al](CC)CC
Agent: [Al+3]
Agent: [Cl-]
Product: Cc1ccc2c(c1)C(C)(C)C(C)CC2(C)C

Procedure:
p-cymene is reacted with t-butylchloride, neohexene and a mixture of aluminium chloride and triethylaluminium to form 1,1,3,4,4,6-hexamethyl tetralin by the general process described in U.S. Pat. No. 3,856,875 or Japanese 79125647 but modified by cooling the reaction mixture by including dichloromethane in it and refluxing this from the mixture at about 20 mm Hg, thereby maintaining a reaction temperature of about -15° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14](=[O:21])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:10][C:9]=1[NH2:22])([CH3:4])([CH3:3])[CH3:2].C([O:26][C:27](=O)[CH2:28][C:29]([C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([C:37]#[N:38])[CH:32]=1)=[O:30])C>>[C:1]([O:5][C:6](=[O:23])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14](=[O:21])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:10][C:9]=1[NH:22][C:27](=[O:26])[CH2:28][C:29]([C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([C:37]#[N:38])[CH:32]=1)=[O:30])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccc(C(=O)c2ccccc2)cc1N
Reactant: CCOC(=O)CC(=O)c1cccc(C#N)c1
Product: CC(C)(C)OC(=O)Nc1ccc(C(=O)c2ccccc2)cc1NC(=O)CC(=O)c1cccc(C#N)c1
Yield: 29.3 %

Procedure:
Prepared from (2-amino-4-benzoyl-phenyl)-carbamic acid tert.-butyl ester (Example G24) (375 mg, 1.20 mmol) and 3-(3-cyano-phenyl)-3-oxo-propionic acid ethyl ester (Pol. J. Chem. 1978, 25) (313 mg, 1.44 mmol) according to the general procedure K. Obtained as a light yellow solid (170 mg).
Reaction SMILES: O.O.O.O.O.[OH-].C[N+](C)(C)C.CN(C=O)C.[C:17]([OH:20])(=[O:19])[CH3:18].[CH2:21]([O:23][C:24]([C:26]1[CH:31]=[CH:30][C:29]([C:32]2[CH:37]=[CH:36][C:35]([O:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48]Br)=[CH:34][CH:33]=2)=[CH:28][CH:27]=1)=[O:25])[CH3:22]>CCOCC>[CH2:21]([O:23][C:24]([C:26]1[CH:31]=[CH:30][C:29]([C:32]2[CH:37]=[CH:36][C:35]([O:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][O:20][C:17](=[O:19])[CH3:18])=[CH:34][CH:33]=2)=[CH:28][CH:27]=1)=[O:25])[CH3:22]
Reactant: CC(=O)O
Reactant: CCOC(=O)c1ccc(-c2ccc(OCCCCCCCCCCBr)cc2)cc1
Agent: C[N+](C)(C)C
Agent: [OH-]
Solvent: CCOCC
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1ccc(-c2ccc(OCCCCCCCCCCOC(C)=O)cc2)cc1
Reaction time: 1 h
Yield: 69.8 %

Procedure:
60 m moles(10.9 g) of tetramethylammonium hydroxide pentahydrate was added to a DMF solution of 60 m moles(3.6 g) of acetic acid, and stirred for one hour, then 50 m moles(23.1 g) of the above 4'-(10-bromodecyloxy)biphenyl-4-carboxylic acid ethyl ester was added thereto, and stirred for 12 hours. The reaction solution was ether extracted and concentrated, and then purified by column chromoatography, to obtain 15.4 g of 4'-(10-acetyloxydecyloxy)biphenyl-4-carboxylic acid ethyl ester. (yield: 70%)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]3[CH:13]=[C:14]4[C@:19]([C:21]([C:23]5[S:24][CH:25]=[CH:26][N:27]=5)=[O:22])([CH2:20][C:11]=3[CH:10]=[N:9]2)[CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16][CH2:15]4)=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.[F:44][C:45]1[CH:50]=[CH:49][C:48]([S:51](Cl)(=[O:53])=[O:52])=[CH:47][CH:46]=1>ClCCl.FC(F)(F)C(O)=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12]3[CH:13]=[C:14]4[C@:19]([C:21]([C:23]5[S:24][CH:25]=[CH:26][N:27]=5)=[O:22])([CH2:20][C:11]=3[CH:10]=[N:9]2)[CH2:18][N:17]([S:51]([C:48]2[CH:49]=[CH:50][C:45]([F:44])=[CH:46][CH:47]=2)(=[O:53])=[O:52])[CH2:16][CH2:15]4)=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC2=Cc3c(cnn3-c3ccc(F)cc3)C[C@]2(C(=O)c2nccs2)C1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: O=C(c1nccs1)[C@]12Cc3cnn(-c4ccc(F)cc4)c3C=C1CCN(S(=O)(=O)c1ccc(F)cc1)C2
Temperature: 25 °C
Reaction time: 48 h
Yield: 72.8 %

Procedure:
A solution of (R)-tert-butyl 1-(4-fluorophenyl)-4a-(thiazole-2-carbonyl)-4a,5,7,8-tetrahydro-1H-pyrazolo[3,4-g]isoquinoline-6(4H)-carboxylate (0.25 g, 0.520 mmol) in dichloromethane (8 mL) and trifluoroacetic acid (2 mL) was stirred at room temperature for 90 minutes, then evaporated, azeotroping twice with toluene to give a brown oil. This material was re-dissolved in dichloromethane (8 mL), and diisopropylethylamine (0.454 mL, 2.60 mmol) was added, followed by 4-fluorobenzene-1-sulfonyl chloride (0.121 g, 0.624 mmol), and the reaction mixture stirred at room temperature for 48 hours. The reaction mixture was then evaporated in vacuo and the residue purified by column chromatography on silica gel (gradient: 0 to 40% ethyl acetate in isohexane) to give a white solid (204 mg). 80 mg of this sample was purified by preparative HPLC (Varian, Acidic (0.1% Formic acid), Waters X-Select Prep-C18, 5 μm, 19×50 mm column, 25-80% acetonitrile in water) to afford (R)-(1-(4-fluorophenyl)-6-(4-fluorophenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(thiazol-2-yl)methanone as a pale yellow solid (45 mg). LCMS (Method F, ES-API): RT 2.58 min, m+H=538.9; 1H NMR (400 MHz, CDCl3): δ 8.02 (d, 1H, J=3.1 Hz), 7.75-7.70 (m, 2H), 7.68 (d, 1H, J=3.1 Hz), 7.45-7.40 (m, 2H), 7.29 (s, 1H), 7.20-7.11 (m, 4H), 6.53 (d, 1H, J=2.2 Hz), 5.49 (dd, 1H, J=12.3, 2.0 Hz), 4.20 (d, 1H, J=16.8 Hz), 3.93-3.86 (m, 1H), 2.94-2.83 (m, 2H), 2.74 (d, 1H, J=12.4 Hz), 2.57-2.47 (m, 2H).
Reaction SMILES: C(S([N:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:17]=[CH:16][C:15]([NH:18][C:19]([C:21]3[O:22][C:23]4[C:28]([C:29](=[O:31])[CH:30]=3)=[CH:27][C:26]([F:32])=[CH:25][C:24]=4[N:33]3[CH2:38][CH2:37][N:36]([CH3:39])[CH2:35][CH2:34]3)=[O:20])=[CH:14][CH:13]=2)[CH2:8][CH2:7]1)(=O)=O)C.C(N(CC)CC)C.[CH2:47]([N:49]=[C:50]=[O:51])[CH3:48]>C(Cl)Cl>[CH2:47]([NH:49][C:50]([N:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:17]=[CH:16][C:15]([NH:18][C:19]([C:21]3[O:22][C:23]4[C:28]([C:29](=[O:31])[CH:30]=3)=[CH:27][C:26]([F:32])=[CH:25][C:24]=4[N:33]3[CH2:34][CH2:35][N:36]([CH3:39])[CH2:37][CH2:38]3)=[O:20])=[CH:14][CH:13]=2)[CH2:8][CH2:7]1)=[O:51])[CH3:48]
Reactant: CCN=C=O
Reactant: CCS(=O)(=O)N1CCN(c2ccc(NC(=O)c3cc(=O)c4cc(F)cc(N5CCN(C)CC5)c4o3)cc2)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCNC(=O)N1CCN(c2ccc(NC(=O)c3cc(=O)c4cc(F)cc(N5CCN(C)CC5)c4o3)cc2)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
6-Fluoro-8-(4-methyl-piperazin-1-yl)-4-oxo-4H-chromene-2-carboxylic acid (4-piperazin-1-yl-phenyl)-amide (Example 71) (150 mg, 0.216 mmol) was placed in a 50 mL flask with 10 of CH2Cl2. This suspension was treated with triethylamine (0.1 mL, 0.67 mmol) and ethylisocyanate (0.21 mL, 18.7 mg, 0.26 mmol) and the reaction stirred at room temperature for 18 hours. The reaction was concentrated (1 mm Hg pressure) and the concentrate purified by chromatography on silica eluting with 1% methanol in chloroform, then concentrated (1 mm Hg pressure). Then triturated with either to yield a yellow powder with was dried under high vacuum for 48 h at 50° C. (79 mg) LCMS-AP+ 537.4, mp=236-238° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:11])[CH3:10])=[C:4]([F:12])[CH:3]=1.[S:13](=O)(=[O:16])([OH:15])[OH:14]>>[C:9]([NH:8][C:5]1[C:4]([F:12])=[CH:3][C:2]([Br:1])=[C:7]([S:13]([OH:16])(=[O:15])=[O:14])[CH:6]=1)(=[O:11])[CH3:10]
Reactant: O=S(=O)(O)O
Reactant: CC(=O)Nc1ccc(Br)cc1F
Product: CC(=O)Nc1cc(S(=O)(=O)O)c(Br)cc1F
Temperature: 20 °C
Reaction time: 2 h

Procedure:
N-(4-Bromo-2-fluorophenyl)acetamide (173.2 g) was suspended in conc. sulfuric acid (80 ml), and 60% fuming sulfuric acid (340 ml) was dropwise added thereto at 10° to 20° C., followed by stirring at 20° C., for 2 hours. The reaction mixture was dropwise added to ice water (500 g) at 10° to 20° C., and the precipitated crystals were collected by filtration, washed with cold water (400 ml) and dried under reduced pressure to give 175.8 g of 5-(N-acetylamino)-2-bromo-4-fluorobenzenesulfonic acid. M.P., more than 300° C.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=O)=[CH:6][CH:5]=1)[CH3:2].[CH2:12]([NH2:18])[C:13]1[O:17][CH:16]=[CH:15][CH:14]=1.COC(OC)OC.[BH4-].[Na+]>CO.CC(O)=O>[CH2:1]([O:3][C:4]1[CH:11]=[CH:10][C:7]([CH2:8][NH:18][CH2:12][C:13]2[O:17][CH:16]=[CH:15][CH:14]=2)=[CH:6][CH:5]=1)[CH3:2]
Reactant: CCOc1ccc(C=O)cc1
Reactant: NCc1ccco1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: COC(OC)OC
Solvent: CC(=O)O
Product: CCOc1ccc(CNCc2ccco2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 79.9 %

Procedure:
4-Ethoxy benzaldehyde (5 g, 33 mmol) and furfuryl amine (4.2 g, 43 mmoL) in a mixture of methanol (50 mL), trimethylorthoformate (10 mL) and AcOH (1 mL) were stirred at room temperature, under an atmosphere of nitrogen for 16 hours. Sodium borohydride (1.4 g, 35 mmol) was added, in 4 portions, over a period of 30 minutes (exothermic reaction). The reaction was stirred for an additional 2 hours at room temperature. The solvent was removed under vacuum and the residue taken up in ethyl acetate (150 mL). The organic phase was washed with H2O (200 mL) and aqueous phase was back extracted with ethyl acetate (2×, 100 mL). The combined organic layers were concentrated and the residue was purified on silica gel (70% ethyl acetate in hexanes with ˜0.5% triethylamine) to afford N-(4-ethoxybenzyl)-1-(furan-2-yl)methanamine (6.1 g, 80%) as a clear oil. NMR (CDCl3, 400 MHz): δ 1.40 (t, J=7.2 Hz, 3H), 3.71 (s, 2H), 3.76 (s, 2H), 4.02 (q, J=7.2 Hz, 2H), 6.17 (d, J=4 Hz, 1H), 6.31 (m, 1H), 6.84 (d, J=8.8 Hz, 2H), 7.23 (d, J=8.8 Hz, 2H), 7.36 (m, 1H).
Reaction SMILES: [F:1][C:2]1[C:7]2[N:8]=[N:9][S:10][C:6]=2[CH:5]=[C:4]([C:11]([O:13]C)=[O:12])[C:3]=1[NH:15][C:16]1[CH:21]=[CH:20][C:19]([I:22])=[CH:18][C:17]=1[F:23].[Li+].[OH-].Cl>C1COCC1.CO>[F:1][C:2]1[C:7]2[N:8]=[N:9][S:10][C:6]=2[CH:5]=[C:4]([C:11]([OH:13])=[O:12])[C:3]=1[NH:15][C:16]1[CH:21]=[CH:20][C:19]([I:22])=[CH:18][C:17]=1[F:23]
Reactant: COC(=O)c1cc2snnc2c(F)c1Nc1ccc(I)cc1F
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1cc2snnc2c(F)c1Nc1ccc(I)cc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.3 %

Procedure:
To a solution of methyl 4-fluoro-5-((2-fluoro-4-iodophenyl)amino)benzo[d][1,2,3]thiadiazole-6-carboxylate (1.90 g, 4.25 mmol) in THF and MeOH (20 mL, 4:1, v/v) was added 1.0 M LiOH (aq., 10 mL, 10 mmol). After stirring at ambient temperature for 2 h, the reaction was treated with 1.0 M HCl (aq.) till the solution was acidic. The aqueous layer was extracted with ethyl acetate (30 mL×3). The combined organic phase was washed with water (30 mL×3) and brine (30 mL) sequentially, dried over Na2SO4, filtered and concentrated to give the desired product (brown solid, 1.70 g, 94.0% yield). 1H NMR (400 MHz, CDCl3): δ 8.63 (s, 1H), 8.49 (s, 1H), 7.38 (d, J=10.3 Hz, 1H), 7.29 (d, J=8.6 Hz, 1H), 6.64 (dd, J=14.3, 8.3 Hz, 1H).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[OH:11][CH2:12][CH:13]1[CH2:17][CH2:16][C:15](=[O:18])[N:14]1[CH2:19][CH2:20][CH2:21][C:22]1[S:26][C:25]([C:27]([O:29][CH3:30])=[O:28])=[CH:24][CH:23]=1.CCN(CC)CC>C(Cl)Cl>[CH:12]([CH:13]1[CH2:17][CH2:16][C:15](=[O:18])[N:14]1[CH2:19][CH2:20][CH2:21][C:22]1[S:26][C:25]([C:27]([O:29][CH3:30])=[O:28])=[CH:24][CH:23]=1)=[O:11]
Reactant: COC(=O)c1ccc(CCCN2C(=O)CCC2CO)s1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CS(C)=O
Product: COC(=O)c1ccc(CCCN2C(=O)CCC2C=O)s1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 98.1 %

Procedure:
A DCM solution of oxalyl chloride (4.38 mL, 2.0 M 8.76 mmol) was diluted with dry DCM (50 mL) and cooled to −78° C. then a solution of DMSO (0.76 mL, 10.77 mmol) in DCM (5 mL) was added dropwise. After 15 min., a solution of methyl 5-[3-(2-(hydroxymethyl)-5-oxopyrrolidin-1-yl)propyl]thiophene-2-carboxylate (2.0 g, 6.73 mmol) in DCM (10 mL) was added dropwise to this solution. The resulting solution was stirred at −78° C. for 2 hours. Et3N (4.7 mL, 33.65 mmol) was added and the solution warmed to RT. After 15 min. the solution was diluted with DCM (100 mL) and washed with a saturated solution of NH4Cl (2×100 mL), brine (100 mL), dried over sodium sulfate and concentrated in vacuo to afford the aldehyde intermediate (1.95 g, 98%) used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[C:7]([CH3:12])[CH:8]=[CH:9][CH:10]=2)[C:5]([C:13]([OH:15])=O)=[CH:4][N:3]=1.[C:16]([NH2:20])([CH3:19])([CH3:18])[CH3:17]>>[C:16]([NH:20][C:13]([C:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][C:7]=2[CH3:12])[C:2]([Cl:1])=[N:3][CH:4]=1)=[O:15])([CH3:19])([CH3:18])[CH3:17]
Reactant: Cc1cccc2c(Cl)ncc(C(=O)O)c12
Reactant: CC(C)(C)N
Product: Cc1cccc2c(Cl)ncc(C(=O)NC(C)(C)C)c12

Procedure:
This compound was prepared by using 1-chloro-5-methylisoquinolin-4-carboxylic acid (Intermediate-10) and tert-butylamine by following the similar procedure as described for Intermediate-11a.
Reaction SMILES: [CH3:1][CH2:2][O:3]/[C:4](/[O-:8])=[CH:5]/[N+]#N.[O:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1>>[O:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH:10]1[CH2:5][C:4]([O:3][CH2:2][CH3:1])=[O:8]
Reactant: CCO/C([O-])=C/[N+]#N
Reactant: C1CCOCC1
Product: CCOC(=O)CC1CCCCO1

Procedure:
Following the procedure of Preparative Example 14, 2.0 g (17.5 mmol) of ethyl diazo acetate was reacted with tetrahydropyran to give 1.75 g of the product as a colorless oil, bp 95°-106° C. at 20 mm Hg.
Reaction SMILES: [CH2:1]([C:8]1[C:13](I)=[CH:12][CH:11]=[C:10]([N:15]2[CH2:19][C@@H:18]([O:20][CH3:21])[C@H:17]([OH:22])[CH2:16]2)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:23]([C:25]1([NH:31][CH2:32][CH2:33][OH:34])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1)#[CH:24]>>[CH2:1]([C:8]1[C:13]([C:24]#[C:23][C:25]2([NH:31][CH2:32][CH2:33][OH:34])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)=[CH:12][CH:11]=[C:10]([N:15]2[CH2:19][C@@H:18]([O:20][CH3:21])[C@H:17]([OH:22])[CH2:16]2)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C#CC1(NCCO)CCCCC1
Reactant: CO[C@@H]1CN(c2ccc(I)c(Cc3ccccc3)n2)C[C@H]1O
Product: CO[C@@H]1CN(c2ccc(C#CC3(NCCO)CCCCC3)c(Cc3ccccc3)n2)C[C@H]1O

Procedure:
This was synthesized in the same manner as in Example 6 except that 2-benzyl-3-iodo-6-[(3R,4R)-3-hydroxy-4-methoxypyrrolidin-1-yl]pyridine (Production Example 1) and 2-[(1-ethynylcyclohexyl)amino]ethanol (Production Example 20) were used.
Reaction SMILES: [OH-:1].[Na+].[NH2:3][C:4]1[CH:17]=[CH:16][CH:15]=[CH:14][C:5]=1[C:6]([NH:8][C:9]1[NH:13][N:12]=[N:11][N:10]=1)=[O:7].C([OH:20])C>[Pd]>[N+:3]([C:4]1[CH:17]=[CH:16][CH:15]=[CH:14][C:5]=1[C:6]([NH:8][C:9]1[NH:13][N:12]=[N:11][N:10]=1)=[O:7])([O-:20])=[O:1]
Reactant: CCO
Reactant: Nc1ccccc1C(=O)Nc1nnn[nH]1
Reactant: [OH-]
Agent: [Pd]
Agent: [Na+]
Product: O=C(Nc1nnn[nH]1)c1ccccc1[N+](=O)[O-]

Procedure:
Hydrogenation of 19 g of 2-nitro-N-(1H-tetrazol-5-yl)benzamide in 100 ml of aqueous 1N sodium hydroxide solution and 100 ml of ethanol using 0.5 g of 5% Pd/C catalyst and 2 atmospheres pressure gave 2-amino-N-(1H-tetrazol-5-yl)benzamide melting at about 253°-254° C.
Reaction SMILES: [CH3:1][N+:2]#[C-:3].[CH3:4][C:5]1[CH:13]=[CH:12][CH:11]=[CH:10][C:6]=1[C:7](Cl)=[O:8].Cl.CC(C)=[O:17]>O>[CH3:3][NH:2][C:1](=[O:17])[C:7]([C:6]1[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=1[CH3:4])=[O:8]
Reactant: CC(C)=O
Reactant: Cc1ccccc1C(=O)Cl
Reactant: [C-]#[N+]C
Agent: Cl
Solvent: O
Product: CNC(=O)C(=O)c1ccccc1C
Temperature: 60 °C
Reaction time: 16 h

Procedure:
Methyl isocyanide (0.84 ml) was added to 2-methylbenzoyl chloride (1.55 g). The mixture was stirred at 60° C. for 16 hours. Then, 5N hydrochloric acid (1.5 ml) and acetone (2 ml) were added, and the mixture was stirred at room temperature for 1.5 hours for hydrolysis. Then, water was added. The mixture was extracted with methylene chloride, washed with water and dried. The solvent was evaporated under reduced pressure to obtain the title compound as an oil (1.68 g).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:8]2[CH:12]=[C:11]([C@:13]3([CH3:22])[C:18]([F:20])([F:19])[CH2:17][O:16][C:15]([NH2:21])=[N:14]3)[CH:10]=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[C:23]([Si:25]([CH3:28])([CH3:27])[CH3:26])#[CH:24].C(N(CC)CC)C>O1CCCC1.[Cu]I.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.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[F:19][C:18]1([F:20])[CH2:17][O:16][C:15]([NH2:21])=[N:14][C@:13]1([CH3:22])[C:11]1[CH:10]=[N:9][N:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([C:24]#[C:23][Si:25]([CH3:28])([CH3:27])[CH3:26])[CH:3]=2)[CH:12]=1
Reactant: C[C@]1(c2cnn(-c3cccc(Br)c3)c2)N=C(N)OCC1(F)F
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C[C@]1(c2cnn(-c3cccc(C#C[Si](C)(C)C)c3)c2)N=C(N)OCC1(F)F
Temperature: 70 °C
Reaction time: 20 h
Yield: 44.2 %

Procedure:
A solution of (R)-4-(1-(3-bromophenyl)-1H-pyrazol-4-yl)-5,5-difluoro-4-methyl-5,6-dihydro-4H-1,3-oxazin-2-amine (227 mg, 612 μmol) (intermediate K7.1) in tetrahydrofuran (5 ml) was treated consecutively with ethynyltrimethylsilane (120 mg, 169 μl, 1.22 mmol), triphenylphosphine (4.81 mg, 18.3 μmol) and triethylamine (186 mg, 256 μl, 1.83 mmol). The mixture was degassed by bubbling argon through the solution, then copper(I) iodide (1.16 mg, 6.12 μmol) and bis(triphenylphosphine)palladium(II) chloride (21.5 mg, 30.6 μmol) were added. The reaction mixture was stirred at 70° C. in a sealed tube. In order to complete the reaction, ethynyltrimethylsilane (120 mg, 169 μl, 1.22 mmol) and bis(triphenylphosphine)palladium(II) chloride (21.5 mg, 30.6 μmol) were added again and stirring continued at 70° C. for 20 hours. Thereafter, the reaction mixture was evaporated and the residue purified by chromatography on silica gel using a gradient of heptane/ethyl acetate=100:0 to 0:100 as the eluent. The (R)-5,5-difluoro-4-methyl-4-[1-(3-trimethylsilanylethynyl-phenyl)-1H-pyrazol-4-yl]-5,6-dihydro-4H-[1,3]oxazin-2-ylamine (105 mg, 44% yield) was obtained as a brown, amorphous material. MS (ISP): m/z=389.3 [M+H]+.
Reaction SMILES: [Cl-:1].[Cl-].[Cl-].[Al+3].[C:5](Cl)(=[O:11])/[CH:6]=[CH:7]/[C:8](Cl)=[O:9].[Cl:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([C:5](/[CH:6]=[CH:7]/[C:8](=[O:9])[C:14]2[CH:19]=[CH:18][C:17]([Cl:1])=[CH:16][CH:15]=2)=[O:11])=[CH:16][CH:15]=1
Reactant: O=C(Cl)/C=C/C(=O)Cl
Reactant: Clc1ccccc1
Reactant: [Cl-]
Agent: [Al+3]
Product: O=C(/C=C/C(=O)c1ccc(Cl)cc1)c1ccc(Cl)cc1
Temperature: 45 °C
Reaction time: 1.3 h

Procedure:
To a stirred suspension of 31 gm (0.23 mol) of aluminum trichloride in 230 ml chlorobenzene, 18 gm (0.12 mol) of fumaryl chloride were added slowly in drops at room temperature. The mixture was stirred for 1.3 hours at room temperature and for another 1.3 hours at 45° C. After introduction into ice-water and acidification with concentrated HCl, the mixture was extracted with 1.5 liters of methylene chloride. After evaporation of the methylene chloride, the residue was washed with about 200 ml of ethanol and recrystallized from acetone. 27 gm (75% of the theory) of trans-1,2-bis-(p-chlorobenzoyl)-ethene were obtained with a melting point of 174°-176° C.