Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:11]2[N:10]3[CH2:12][CH2:13][CH2:14][CH:9]3[CH2:8][O:7][C:6]=2[CH:5]=[C:4]([NH2:15])[CH:3]=1.C[Al](C)C.N#N.[NH:22](/[C:26](/[CH3:32])=[CH:27]\[C:28](OC)=[O:29])[C:23]([CH3:25])=O>C(Cl)Cl>[F:1][C:2]1[C:11]2[N:10]3[CH2:12][CH2:13][CH2:14][CH:9]3[CH2:8][O:7][C:6]=2[CH:5]=[C:4]([N:15]2[C:28](=[O:29])[CH:27]=[C:26]([CH3:32])[N:22]=[C:23]2[CH3:25])[CH:3]=1
Reactant: Nc1cc(F)c2c(c1)OCC1CCCN21
Reactant: COC(=O)/C=C(/C)NC(C)=O
Agent: C[Al](C)C
Agent: N#N
Solvent: ClCCl
Product: Cc1cc(=O)n(-c2cc(F)c3c(c2)OCC2CCCN32)c(C)n1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 33 %

Procedure:
To a solution of 9-fluoro-2,3,3a,4-tetrahydro-1H-benzo[b]pyrrolo[1,2-d][1,4]oxazin-7-amine (2.00 g, 9.61 mmol) in anhydrous CH2Cl2 (50 mL) was added trimethylaluminum (48 mL, 48 mmol, 1 M in heptane) slowly under N2. Upon the end of addition the mixture was stirred at rt for 40 min, followed by addition of a solution of methyl 3-acetaminocrotonate (2.66 g, 16.92 mmol) in anhydrous CH2Cl2 (30 mL) dropwise. The reaction mixture was stirred at rt for another 5 h, then quenched with an appropriate amount of water. The organic phase was washed with brine, dried over anhydrous Na2SO4 and concentrated in vacuo to give the title compound as a white solid (1.00 g, 33.0%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[C:8]([C:10]([N:12]2[CH2:18][CH2:17][CH2:16][CH2:15][C:14]3[CH:19]=[CH:20][CH:21]=[CH:22][C:13]2=3)=[O:11])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[BH4-].[Na+]>CO.[Co](Cl)Cl>[NH2:5][CH2:4][C:3]1[CH:6]=[CH:7][C:8]([C:10]([N:12]2[CH2:18][CH2:17][CH2:16][CH2:15][C:14]3[CH:19]=[CH:20][CH:21]=[CH:22][C:13]2=3)=[O:11])=[CH:9][C:2]=1[CH3:1]
Reactant: Cc1cc(C(=O)N2CCCCc3ccccc32)ccc1C#N
Agent: Cl[Co]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Cc1cc(C(=O)N2CCCCc3ccccc32)ccc1CN
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2-methyl-4-(2,3,4,5-tetrahydrobenzo[b]azepine-1-carbonyl)benzonitrile from Example F1 (430 mg, 1.48 mmol) in methanol (25 ml) was added cobalt (II) chloride (710 mg, 3.0 mmol) and cooled in an ice/water bath. Sodium borohydride (570 mg, 15 mmol) was added portionwise and the mixture was stirred at room temperature for 1 h. The mixture was evaporated, 1N HCl(aq) (20 ml) was added and stirred for 15 mins. The mixture was filtered through Celite® and the Celite® was washed with 2-propanol:chloroform, 20:80 (100 ml). The mixture was separated and the aqueous layer washed with diethyl ether. The aqueous layer was basified with 2N NaOH(aq), chloroform was added and the mixture filtered through Celite®. The Celite® was washed with chloroform. The mixture was separated and the organic layer dried and evaporated, yield 340 mg, 78%.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][NH:8]2)=[CH:4][C:3]=1[O:11]C.B(Br)(Br)Br>C(Cl)Cl>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][NH:8]2)=[CH:4][C:3]=1[OH:11]
Reactant: COc1cc2cn[nH]c2cc1Br
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Oc1cc2cn[nH]c2cc1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.3 %

Procedure:
To a solution of 6-bromo-5-methoxy-1H-indazole (60 g, 0.265 mol) in DCM (1300 mL) is added a solution of BBr3 (105 g, 0.42 mol) in DCM (200 mL) at 0° C. The reaction mixture is warmed to RT and stirred overnight. Then the reaction solution is quenched with MeOH at 0° C. The solvent is removed in vacuo and the residue is neutralized with NaHCO3 solid. The mixture is partitioned by water (1500 mL) and EtOAc (1500 mL). The aqueous layer is extracted with EtOAc (1500 mL) two times. The combined organic layers are dried and concentrated to give crude product, which is purified by silica gel column chromatography (PE:THF=2:1) to give the desired product (42.5 g, 75% yield). MS (m/z): 215.0 (M+H).
Reaction SMILES: [C:1](O)(=[O:7])[CH2:2][CH2:3][CH2:4][C:5]#[CH:6].C(N(CC)CC)C.CC(C)(C)C(Cl)=O.[Cl-].[Li+].[C:25]1([C@H:31]2[CH2:35][O:34][C:33](=[O:36])[NH:32]2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>O1CCCC1>[C:1]([N:32]1[C@@H:31]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH2:35][O:34][C:33]1=[O:36])(=[O:7])[CH2:2][CH2:3][CH2:4][C:5]#[CH:6]
Reactant: O=C1N[C@@H](c2ccccc2)CO1
Reactant: C#CCCCC(=O)O
Agent: CC(C)(C)C(=O)Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C#CCCCC(=O)N1C(=O)OC[C@@H]1c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.3 %

Procedure:
To a solution of 69.0 g (615 mmol) of 5-hexynoic acid and 214 mL (1540 mmol) of triethylamine in 1.0 L of anhydrous tetrahydrofuran at −25° C. under an atmosphere of nitrogen was added 83.0 mL (677 mmol) of trimethylacetyl chloride over 20 min. Upon addition a white precipitate formed and the resulting suspension was stirred for 2 h. Next, 28.7 g (677 mmol) of anhydrous lithium chloride and 100.0 g (615.0 mmol) of (4S)-4-phenyl-1,3-oxazolidin-2-one were added sequentially and the mixture was allowed to gradually warm to ambient temperature over 12 h. All volatiles were removed in vacuo and the residue was diluted with water (1 L) and extracted with ethyl acetate (3×300 mL). The combined organic layers were washed with brine (250 mL), dried over magnesium sulfate, filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography eluting with a 5-50% ethyl acetate in hexanes gradient to afford the title compound as a colorless solid (135 g, 85.4%). 1H NMR (500 MHz, CDCl3): δ 7.40-7.37 (m, 2H), 7.36-7.32 (m, 1H), 7.31-7.28 (m, 2H), 5.42 (dd, J=8.9, 3.7 Hz, 1H), 4.69 (t, J=8.9 Hz, 1H), 4.28 (dd, J=9.2, 3.7 Hz, 1H), 3.13-3.02 (m, 2H), 2.24-2.21 (m, 2H), 1.94 (t, J=2.6 Hz, 1H), 1.84 (quintet, J=7.1 Hz, 2H). LC-MS: m/z (ES) 258.2 (MH)+.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5](Cl)=[O:6].[NH2:12][C:13]1[CH:14]=[C:15]([C:20]([F:23])([F:22])[F:21])[CH:16]=[CH:17][C:18]=1[F:19].C(N(C(C)C)CC)(C)C>ClCCl>[F:19][C:18]1[CH:17]=[CH:16][C:15]([C:20]([F:22])([F:23])[F:21])=[CH:14][C:13]=1[NH:12][C:5](=[O:6])[C:4]1[CH:8]=[CH:9][C:10]([CH3:11])=[C:2]([I:1])[CH:3]=1
Reactant: Cc1ccc(C(=O)Cl)cc1I
Reactant: Nc1cc(C(F)(F)F)ccc1F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(C(=O)Nc2cc(C(F)(F)F)ccc2F)cc1I
Temperature: 0 °C

Procedure:
A solution of 3-iodo-4-methylbenzoic acid (10.0 g, 38.2 mmol) in thionyl chloride (30.0 mL) was heated at reflux for 3 hours. The resulting yellow solution was cooled to room temperature and concentrated under reduced pressure to afford 3-iodo-4-methylbenzoyl chloride. A solution of 3-iodo-4-methylbenzoyl chloride (1 g, 4 mmol) in dichloromethane (10 mL) was added slowly to a 0° C. solution of 3-amino-4-fluorobenzotrifluoride (0.7 ml, 4 mmol) and diisopropylethylamine (0.9 ml, 5 mmol) in dichloromethane (10 mL). The reaction stirred at 0° C. and warmed to room temperature over 20 hours. The reaction mixture was purified via column chromatography on silica gel (gradient elution with 0 to 100% ethyl acetate-hexane) to afford N-(2-fluoro-5-(trifluoromethyl)phenyl)-3-iodo-4-methylbenzamide 34 MS m/z found 423.9 [MH+]; calc. for C15H10F4INO=423.14.
Reaction SMILES: [C:1](Cl)([Cl:3])=[O:2].[CH2:5]1[O:13][C:12]2[C:7](=[CH:8][C:9]([N+:17]([O-:19])=[O:18])=[C:10]([CH:14]([OH:16])[CH3:15])[CH:11]=2)[O:6]1.CCOCC.CCCCCC>C1COCC1>[Cl:3][C:1]([O:16][CH:14]([C:10]1[CH:11]=[C:12]2[O:13][CH2:5][O:6][C:7]2=[CH:8][C:9]=1[N+:17]([O-:19])=[O:18])[CH3:15])=[O:2]
Reactant: O=C(Cl)Cl
Reactant: CC(O)c1cc2c(cc1[N+](=O)[O-])OCO2
Solvent: CCOCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(OC(=O)Cl)c1cc2c(cc1[N+](=O)[O-])OCO2
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.8 %

Procedure:
Phosgene (500 mL of 20% w/v in toluene from Fluka: 965 mmole; 4 eq.) was added slowly to a cold, stirring solution of 50 g (237 mmole; 1 eq.) of 1-(4,5-methylenedioxy-2-nitrophenyl)ethanol in 400 mL dry THF. The solution was stirred overnight at ambient temperature at which point TLC.(20% Et2O/hexane) indicated >95% conversion. The mixture was evaporated (an oil-less pump with downstream aqueous NaOH trap is recommended to remove the excess phosgene) to afford a viscous brown oil. Purification was effected by flash chromatography on a short (9×13 cm) column of silica gel eluted with 20% Et2O/hexane. Typically 55 g (85%) of the solid yellow MeNPOC-Cl is obtained by this procedure. The crude material has also been recrystallized in 2-3 crops from 1:1′ether/hexane. On this scale, ˜100 ml is used for the first crop, with a few percent THF added to aid dissolution, and then cooling overnight at −20° C. (this procedure has not been optimized). The product should be stored desiccated at −20° C.
Reaction SMILES: [O:1]=[C:2]1[NH:10][C:9]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[C:3]1=[CH:11][NH:12][C:13]1[CH:18]=[CH:17][C:16]([S:19]([NH2:22])(=[O:21])=[O:20])=[CH:15][CH:14]=1>O>[O:1]=[C:2]1[NH:10][C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]1=[CH:11][NH:12][C:13]1[CH:18]=[CH:17][C:16]([S:19]([NH2:22])(=[O:21])=[O:20])=[CH:15][CH:14]=1
Reactant: NS(=O)(=O)c1ccc(NC=C2C(=O)Nc3ccncc32)cc1
Solvent: O
Product: NS(=O)(=O)c1ccc(NC=C2C(=O)Nc3ncccc32)cc1
Reaction time: 8 h

Procedure:
Inorganics were removed by filtration through a short silica gel column, eluting with DMF. The resulting solution was diluted with an equal volume of ice water, and the suspension was refrigerated overnight. The solid was isolated by filtration and dried to give 36 mg (21%) of the title compound as a yellow solid: 1H NMR (400 MHz, DMSO-d6) (4:1 ratio of Z:E isomers): δ (Z) 11.07 (s, 1H), 10.76 (d, J=12.4 Hz, 1H), 8.67 (d, J=12.5 Hz, 1H), 7.92 (d, J=5.1 Hz, 1H), 7.84 (d, J=7.3 Hz, 1H), 7.77 (d, J=8.7 Hz, 2H), 7.55 (d, J=8.6 Hz, 2H), 7.25 (s, 2H), 6.93 (dd, J=7.3, 5.1 Hz, 1H); (E) 10.79 (s, 1H), 9.70 (d, J=13.4 Hz, 1H), 8.23 (d, J=7.3 Hz, 1H). ESI−MS m/z 315 (M−H). Anal. Calcd. for C14H12N4O3S. 0.5 H2O: C, 51.68; H, 4.03; N, 17.03. Found: C, 51.75; H, 3.95; N, 17.26.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[C:10](=[O:27])[N:11]([CH2:24][CH2:25]O)[N:12]=[C:13]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[F:23])[C:14]=2[CH3:15])[CH:6]=[CH:7][CH:8]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:47]NC(=O)CCC(N)=O>ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[C:10](=[O:27])[N:11]([CH2:24][CH2:25][Br:47])[N:12]=[C:13]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[F:23])[C:14]=2[CH3:15])[CH:6]=[CH:7][CH:8]=1
Reactant: NC(=O)CCC(=O)NBr
Reactant: COc1cccc(-c2c(C)c(Cc3ccccc3F)nn(CCO)c2=O)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1cccc(-c2c(C)c(Cc3ccccc3F)nn(CCBr)c2=O)c1

Procedure:
A solution of 4-(3-methoxyphenyl)-5-methyl-6-(2-fluorobenzyl)-2-(2-hydroxyethyl)-pyridazin-3-one (from above) and triphenylphospine (570 mg, 22 mmol) in dichloromethane (8 mL) was treated with N-bromosuccinamide (400 mg, 22 mmol) at room temperature for 2 hours. The crude product was used for next step. MS: 431 (MH+).
Reaction SMILES: O[C@H:2]1[C@H:7]([N:8]2[CH2:12][CH2:11][CH2:10][S:9]2(=[O:14])=[O:13])[C:6]2[CH:15]=[C:16]([S:19]([CH3:22])(=[O:21])=[O:20])[CH:17]=[CH:18][C:5]=2[O:4][C:3]1([CH3:24])[CH3:23].C(OC(=O)C)(=O)C.O>N1C=CC=CC=1>[O:14]=[S:9]1(=[O:13])[CH2:10][CH2:11][CH2:12][N:8]1[C:7]1[C:6]2[CH:15]=[C:16]([S:19]([CH3:22])(=[O:20])=[O:21])[CH:17]=[CH:18][C:5]=2[O:4][C:3]([CH3:23])([CH3:24])[CH:2]=1
Reactant: CC1(C)Oc2ccc(S(C)(=O)=O)cc2[C@@H](N2CCCS2(=O)=O)[C@@H]1O
Solvent: c1ccncc1
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: CC1(C)C=C(N2CCCS2(=O)=O)c2cc(S(C)(=O)=O)ccc2O1
Reaction time: 8 h
Yield: 46 %

Procedure:
A solution of trans-3,4-dihydro-3-hydroxy-4-(1,1-dioxoisothiazolidin-2-yl)-6-mesyl-2,2-dimethyl-2H-1-benzopyran (0.32 g) in pyridine (10 ml) was treated with acetic anhydride (5 ml), and the mixture was stood at room temperature overnight. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed successively with 1N hydrochloric acid, a saturated aqueous solution of sodium bicarbonate and brine, and then dried over anhydrous magnesium sulfate. Removal of the solvent under reduced pressure gave the crude product, which was purified by recrystallization from ethyl acetate to give 4-(1,1-dioxoisothiazolidin-2-yl)-6-mesyl-2,2-dimethyl-2H-1-benzopyran (0.14 g).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]1.Cl[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][CH2:15][CH2:16][CH2:17][CH3:18]>>[CH2:15]([O:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][N:1]1[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]1)[CH2:16][CH2:17][CH3:18]
Reactant: O=C1CCNCC1
Reactant: CCCCOCCCCCCl
Product: CCCCOCCCCCN1CCC(=O)CC1

Procedure:
1-(5-Butoxypentyl)-4-piperidone is prepared from 4-piperidone and 1-chloro-5-butoxypentane essentially as described above in Example 38, Scheme C, step a.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([O:10]CC)=O)=[CH:6][N:5]=[CH:4][C:3]=1[CH2:13][CH2:14][CH3:15].Cl.[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([NH:24][NH2:25])=[CH:20][CH:19]=1>C(O)CCC>[ClH:1].[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]2[C:8](=[O:10])[C:7]3=[CH:6][NH:5][CH:4]=[C:3]([CH2:13][CH2:14][CH3:15])[C:2]3=[N:25]2)=[CH:20][CH:19]=1
Reactant: CCCc1cncc(C(=O)OCC)c1Cl
Reactant: NNc1ccc(Cl)cc1
Agent: Cl
Solvent: CCCCO
Product: CCCc1c[nH]cc2c(=O)n(-c3ccc(Cl)cc3)nc1-2
Yield: 54.1 %

Procedure:
A mixture of ethyl 4-chloro-3-propyl-5-pyridinecarboxylate (0.3199 g, 1.40 mmol) and 4-chlorophenylhydrazine hydrochloride (0.3019 g, 1.69 mmol) in anhydrous 1-butanol (12 ml) was degassed by evaporating the flask under vacuum and refilling with nitrogen several times and then stirred at reflux under nitrogen for 4 h. After leaving to cool overnight, the mixture was filtered, and the solid was washed with ethyl acetate and dried at 60° C. under vacuum to afford 0.2454 g (54%) of the title compound as a yellow solid; mp 213-218° C. (CH2Cl2-MeOH-EtOAc); 1H NMR (360 MHz, DMSO-d6) δ0.94 (3H, t, J 7.4 Hz), 1.76 (2H, m), 2.64 (2H, t, J 7.3 Hz), 7.41 (1H, s), 7.48 (2H, d, J 9.0 Hz), 8.24 (2H, d, J 8.9 Hz), 8.52 (1H, s), 12.36 (1H, br s); MS (ES+) m/z 288/290 [MH]+. Anal. found: C, 56.13; H, 4.64; N, 13.02. C15H14CIN3O.0.9HCl requires: C, 56.20; H, 4.69; N, 13.11%.
Reaction SMILES: [N+:1]([C:4]1[CH:22]=[CH:21][C:7]([O:8][C:9]2([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[N+]([NH:26][C:27](N)=[O:28])([O-])=O.O>C(O)C>[NH2:26][C:27]([N:12]1[CH2:11][CH2:10][C:9]([O:8][C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:22][CH:21]=2)([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:14][CH2:13]1)=[O:28]
Reactant: O=[N+]([O-])c1ccc(OC2(c3ccccc3)CCNCC2)cc1
Reactant: NC(=O)N[N+](=O)[O-]
Solvent: O
Solvent: CCO
Product: NC(=O)N1CCC(Oc2ccc([N+](=O)[O-])cc2)(c2ccccc2)CC1
Yield: 88.3 %

Procedure:
To a stirred solution of 4.0 g of 4-(4-nitrophenoxy)-4-phenylpiperidine in 50 ml of 95% ethanol was added 1.68 g of nitrourea in 50 ml of 95% ethanol. The reaction mixture was refluxed for two hours and then poured into 200 ml of water. The aqueous suspension was extracted with dichloromethane. The organic layer was washed with water, dried over anhydrous magnesium sulfate, filtered and concentrated. The resulting solid was purified by high pressure liquid chromatography (silica gel; elution with 5% methanol/dichloromethane) to yield 4.04 g (91.20%) of 1-aminocarbonyl-4-(4-nitrophenoxy)-4-phenylpiperidine, m.p. 203°-206° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([S:12][C:13]2[C:21]3[C:16](=[C:17]([F:23])[C:18]([Cl:22])=[CH:19][CH:20]=3)[NH:15][C:14]=2[CH3:24])[N:7]=1)=[O:5])[CH3:2].Br[C:26]1[CH:27]=[N:28][N:29]([CH:31]([CH3:33])[CH3:32])[CH:30]=1>>[CH2:1]([O:3][C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([S:12][C:13]2[C:21]3[C:16](=[C:17]([F:23])[C:18]([Cl:22])=[CH:19][CH:20]=3)[N:15]([C:26]3[CH:27]=[N:28][N:29]([CH:31]([CH3:33])[CH3:32])[CH:30]=3)[C:14]=2[CH3:24])[N:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cccc(Sc2c(C)[nH]c3c(F)c(Cl)ccc23)n1
Reactant: CC(C)n1cc(Br)cn1
Product: CCOC(=O)c1cccc(Sc2c(C)n(-c3cnn(C(C)C)c3)c3c(F)c(Cl)ccc23)n1

Procedure:
Prepared according to the procedure described in Example 9, Step 4, using the following starting materials: 6-(6-chloro-7-fluoro-2-methyl-1H-indol-3-ylsulfanyl)-pyridine-2-carboxylic acid ethyl ester and 4-bromo-1-isopropyl-1H-pyrazole.
Reaction SMILES: [CH2:1]([N:4]([CH2:17][CH:18]=[CH2:19])[C:5]([CH:7]1[CH2:12][C:11]([CH3:14])([CH3:13])[NH:10][C:9]([CH3:16])([CH3:15])[CH2:8]1)=[O:6])[CH:2]=[CH2:3].[CH:20](O)=O.[OH-].[Na+]>C=O>[CH2:17]([N:4]([CH2:1][CH:2]=[CH2:3])[C:5]([CH:7]1[CH2:8][C:9]([CH3:16])([CH3:15])[N:10]([CH3:20])[C:11]([CH3:13])([CH3:14])[CH2:12]1)=[O:6])[CH:18]=[CH2:19]
Reactant: C=CCN(CC=C)C(=O)C1CC(C)(C)NC(C)(C)C1
Reactant: O=CO
Agent: C=O
Agent: [Na+]
Agent: [OH-]
Product: C=CCN(CC=C)C(=O)C1CC(C)(C)N(C)C(C)(C)C1

Procedure:
4-[(Diallylamino)carbonyl]-2,2,6,6-tetramethylpiperidine (58.0 grams; 0.219 mole) is slurried in 37% formaldehyde (98.6 mls) at room temperature and 95% formic acid (17.4 mls) is added thereto. The mixture is heated at reflux for 18 hours and the resulting two-phase reaction mixture is adjusted to pH 11-12 by adding 50% sodium hydroxide. The mixture is extracted with dichloromethane and the organic extracts are combined and evaporated to obtain a clear liquid which on distillation affords 58.3 grams of the desired product which boils at 118°-125° C. at 0.10-0.15 mm of mercury.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:31])[CH2:5][N:6]1[C:14]2[CH2:13][CH2:12][CH2:11][C@@H:10]([N:15]([S:17]([C:20]3[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[C:22](Br)[CH:21]=3)(=[O:19])=[O:18])[CH3:16])[C:9]=2[CH:8]=[N:7]1)[CH3:2].C1([As](C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:51]([O:53]C([Sn](CCCC)(CCCC)CCCC)=C)[CH3:52].Cl>CN(C)C=O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O>[CH2:1]([O:3][C:4](=[O:31])[CH2:5][N:6]1[C:14]2[CH2:13][CH2:12][CH2:11][C@@H:10]([N:15]([S:17]([C:20]3[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[C:22]([C:51](=[O:53])[CH3:52])[CH:21]=3)(=[O:19])=[O:18])[CH3:16])[C:9]=2[CH:8]=[N:7]1)[CH3:2]
Reactant: CCOC(=O)Cn1ncc2c1CCC[C@H]2N(C)S(=O)(=O)c1cc(Br)cc(C(F)(F)F)c1
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Agent: [Pd]
Agent: Cl
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)Cn1ncc2c1CCC[C@H]2N(C)S(=O)(=O)c1cc(C(C)=O)cc(C(F)(F)F)c1
Temperature: 80 °C
Reaction time: 2 h
Yield: 86.4 %

Procedure:
To a solution of {(R)-4-[(3-bromo-5-trifluoromethyl-benzenesulfonyl)-methyl-amino]-4,5,6,7-tetrahydro-indazol-1-yl}-acetic acid ethyl ester (example 2-5) (prepared by the method analogous to the one described for example 2-1) (1.0 g, 1.9 mmol) in N,N-dimethylformamide (8 mL) was added tris(dibenzylideneacetone)dipalladium(0) (Pd2(dba)3) (175 mg, 0.19 mmol), triphenylarsine (Ph3As) (175 mg, 5.72 mmol) and 1-ethoxy-vinyltributyltin (1 mL, 2.86 mmol). After being stirred at 80° C. for 2 hours under an argon atmosphere, the reaction mixture was cooled to room temperature, 4N hydrochloric acid (1 mL) was added, and the mixture was stirred at room temperature for 20 minutes. The resulting mixture was poured into water (40 mL) and extracted with ethyl acetate (3×20 mL). The combined organic layers were washed with water (20 mL) and brine (20 mL), and then concentrated in vacuo. The residue was purified by flash column (gradient elution: 15-30% ethyl acetate in petroleum ether) to afford {(R)-4-[(3-acetyl-5-trifluoromethyl-benzenesulfonyl)-methyl-amino]-4,5,6,7-tetrahydro-indazol-1-yl}-acetic acid ethyl ester as a yellow oil (800 mg, 86.4%). MS cald. for C21H24F3N3O5S 487, obsd. (ESI+) [(M+H)+] 488.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=1[C:16]1[CH2:20][N:19](C(OC(C)(C)C)=O)[CH:18]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:17]=1>ClCCl>[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=1[C:16]1[CH2:20][NH:19][CH:18]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:17]=1.[C:3]([OH:5])([C:2]([F:7])([F:6])[F:1])=[O:4]
Reactant: CC(C)(C)OC(=O)N1CC(c2cc(F)ccc2Cl)=CC1c1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Fc1ccc(Cl)c(C2=CC(c3ccccc3)NC2)c1
Reaction time: 0.5 h

Procedure:
Trifluoroacetic acid (10 mL) was added to a solution of tert-butyl 4-(2-chloro-5-fluorophenyl)-2-phenyl-2,5-dihydro-1H-pyrrole-1-carboxylate (14, 320 mg, 0.856 mmol, 1 equiv) in dichloromethane (40 mL) at 23° C., and the resulting mixture was stirred for 30 min, then concentrated to give 4-(2-chloro-5-fluorophenyl)-2-phenyl-2,5-dihydro-1H-pyrrole (1-5) as a TFA salt (brown oil). LRMS m/z (M+H) 274.1 found, 274.1 required.
Reaction SMILES: CCOCC.Br[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15].[CH2:17]([OH:20])[C:18]#[CH:19].Cl>[OH-].[Na+]>[C:14]([CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][O:20][CH2:17][C:18]#[CH:19])([OH:16])=[O:15]
Reactant: C#CCO
Reactant: O=C(O)CCCCCCCBr
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Product: C#CCOCCCCCCCC(=O)O
Temperature: 60 °C
Yield: 124.2 %

Procedure:
An ether solution of 8-bromooctanoic acid (15.1 g, 65 mmol) was reacted with 325 mmol propargyl alcohol dissolved in aqueous NaOH solution containing 975 mmol NaOH. After heating at 60° C. for 24 hours, the reaction was stopped by neutralizing the base with hydrochloric acid. Ether extraction provided 16 g of opaque white liquid, which was further purified by distillation under reduced pressure (160°-163° C./0.075 mm Hg). The sample was analyzed with 1H-NMR in CDCl3, and the observed chemical shift peaks were at δ=1.34 (br singlet, 6H, --(CH2)--), 1.61 (pentate center, 4H, --(CH2)--), 2.35 (t, 2H, CH2 --COO), 2.42, (d, J=2.6 Hz, 1H, C≡CH), 3.51 (t, J=6.6 Hz, 2H, --CH2 --O), and 4.14 (d, J=2.6 Hz, 2H, O--CH2 --C≡C). Observed IR (KBr) peaks were at 1709 (COOH), 2120 (--C≡C--) and 3298 (--C≡CH) cm-1.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]2[NH:8][C:9](=[O:13])[C:10]([CH3:12])([CH3:11])[C:5]2=[CH:4][CH:3]=1.[CH:14]1(B(O)O)[CH2:16][CH2:15]1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>CN(C1C=CN=CC=1)C.C1(C)C=CC=CC=1.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[Cl:1][C:2]1[N:7]=[C:6]2[N:8]([CH:14]3[CH2:16][CH2:15]3)[C:9](=[O:13])[C:10]([CH3:11])([CH3:12])[C:5]2=[CH:4][CH:3]=1
Reactant: OB(O)C1CC1
Reactant: CC1(C)C(=O)Nc2nc(Cl)ccc21
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: CN(C)c1ccncc1
Solvent: Cc1ccccc1
Product: CC1(C)C(=O)N(C2CC2)c2nc(Cl)ccc21
Temperature: 95 °C
Reaction time: 16 h

Procedure:
To a suspension of 6-chloro-3,3-dimethyl-1H-pyrrolo[2,3-b]pyridin-2(3H)-one (150 mg, 763 mol), cyclopropylboronic acid (131 mg, 1.53 mmol), copper (II) acetate (145 mg, 801 μmol) and DMAP (280 mg, 2.29 mmol) in toluene (15 ml) was added sodium bis(trimethylsilyl)amide (2 M in THF, 400 μl, 801 μmol). While bubbling dry air through the reaction mixture, it was heated to 95° C. and stirred for 16 hours. The reaction mixture was poured into 1 M aqueous HCl solution (20 ml) and extracted with tBuOMe. The organic layers were washed with 1 M aqueous HCl solution and brine, dried over Na2SO4 and concentrated in vacuo. The crude material was purified by silica gel chromatography using heptane/ethyl acetate as eluent. The title compound was obtained as yellow viscous oil (178 mg).