Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[C:5]([O:9][C:10]([N:12]1[CH2:17][CH2:16][C:15]2([C:25]3[C:20](=[CH:21][CH:22]=[C:23]([Cl:26])[CH:24]=3)[NH:19][CH2:18]2)[CH2:14][CH2:13]1)=[O:11])([CH3:8])([CH3:7])[CH3:6].C(N(CC)CC)C>ClCCl>[C:5]([O:9][C:10]([N:12]1[CH2:13][CH2:14][C:15]2([C:25]3[C:20](=[CH:21][CH:22]=[C:23]([Cl:26])[CH:24]=3)[N:19]([C:1](=[O:3])[CH3:2])[CH2:18]2)[CH2:16][CH2:17]1)=[O:11])([CH3:8])([CH3:6])[CH3:7]
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CNc1ccc(Cl)cc12
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N1CC2(CCN(C(=O)OC(C)(C)C)CC2)c2cc(Cl)ccc21
Reaction time: 1 h
Yield: 87 %

Procedure:
Acetyl chloride (2.8 ml) was added dropwise to a stirred solution of 5-chlorospiro[indoline-3,4′-piperidine]-1′-carboxylic acid tert-butyl ester (9.8 g) and triethylamine (15 ml) in anhydrous dichloromethane (400 ml) under an atmosphere of nitrogen. The reaction was stirred for 1 h and was then quenched with saturated sodium bicarbonate solution (200 ml). The organic layer was dried over anhydrous sodium sulphate and concentrated in vacuo to yield 9.8 g (87%) of the desired amide as an off-white solid. M.p. 64-66° C. 1H NMR (400 MHz, CDCl3) δ 6:1 mixture of rotamers. Major rotamer 1.5 (9H, s), 1.70 (m, 2H), 1.85 (m, 2H), 2.25 (s, 3H), 2.85 (m, 2H), 3.90 (s, 2H), 4.2 (m, 2H), 6.97 (d, J=1 Hz, 1H), 7.20 (dd, J=7 & 1 Hz, 1H), 8.15 (d, J=7 Hz, 1H). Minor rotamer 1.5 (9H, s), 1.70 (m, 2H), 1.85 (m, 2H), 2.45 (s, 3H), 2.85 (m, 2H), 4.05 (s, 2H), 4.2 (m, 2H), 7.2 (d, J=1 Hz, 1H), 7.25 (dd, J=7 & 1 Hz, 1H), 7.48 (d, J=7 Hz, 1H).
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[C:7]([Cl:9])[CH:6]=[CH:5][C:4]=1[CH:10]([CH3:12])[CH3:11].CN(C)[CH:15]=[O:16].Cl>O1CCCC1>[Cl:9][C:7]1[CH:6]=[CH:5][C:4]([CH:10]([CH3:12])[CH3:11])=[C:3]([CH:8]=1)[CH:15]=[O:16]
Reactant: CC(C)c1ccc(Cl)cc1Br
Reactant: CN(C)C=O
Agent: Cl
Agent: [Mg]
Solvent: C1CCOC1
Product: CC(C)c1ccc(Cl)cc1C=O
Temperature: 40 °C
Yield: 78.2 %

Procedure:
Magnesium (4.6 g, 0.189 mol) together with tetrahydrofuran (65 ml) were placed in a reaction vessel and heated while stirring to 40° C. About 5% of a solution of 2-bromo-4-chloro-1-isopropylbenzene (IV) (43 g, 0.180 mol) in tetrahydrofuran (95 ml) is then added dropwise. After the reaction has commenced, the remainder of the 2-bromo-4-chloro-1-isopropylbenzene in tetrahydrofuran was added under gentle reflux over a period of 1 hour. The mixture was then cooled to 0° C. and dimethylformamide (13.8 g. 0.189 mol) was added dropwise over a period of 1 hour. The reaction mixture obtained was stirred for another 1 hour and hydrochloric acid (86.7 g, 0.369 mol) was added in such a way that the temperature was kept below 30° C. The phases were then separated and extracted with toluene (2×50 ml). The combined organic phases were distilled under reduced pressure and the crude product obtained was recrystallized from isopropanol/water 4:1. 5-Chloro-2-isopropylbenzaldehyde (25.7 g, 99 GC-% by area, 77% of theory) was obtained as a colourless solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[CH:9]=[C:10]([C:11]([F:14])([F:13])[F:12])[C:3]=12.[F:23][C:24]1[CH:30]=[C:29]([N+:31]([O-:33])=[O:32])[CH:28]=[CH:27][C:25]=1[NH2:26].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.C(=O)([O-])[O-].[K+].[K+]>C(O)(C)(C)C.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]>[F:23][C:24]1[CH:30]=[C:29]([N+:31]([O-:33])=[O:32])[CH:28]=[CH:27][C:25]=1[NH:26][C:2]1[C:3]2[C:10]([C:11]([F:14])([F:13])[F:12])=[CH:9][N:8]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[C:4]=2[N:5]=[CH:6][CH:7]=1
Reactant: C[Si](C)(C)CCOCn1cc(C(F)(F)F)c2c(Cl)ccnc21
Reactant: Nc1ccc([N+](=O)[O-])cc1F
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CC(C)(C)O
Product: C[Si](C)(C)CCOCn1cc(C(F)(F)F)c2c(Nc3ccc([N+](=O)[O-])cc3F)ccnc21
Temperature: 25 °C

Procedure:
A solution of 170 mg (0.485 mmol) of 4-chloro-3-(trifluoromethyl)-1-{[2-(trimethylsilyl)ethoxy]-methyl}-1H-pyrrolo[2,3-b]pyridine, 91 mg (0.58 mmol) of 2-fluoro-4-nitroaniline, 31 mg (0.035 mmol) of tris(dibenzylideneacetone)dipalladium, 33 mg (0.07 mmol) of dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine and 100 mg (0.72 mmol) of potassium carbonate in 3.00 ml of degassed tert-butanol is stirred in a sealed pressure vessel at 100° C. for 3 h. After cooling to RT, the reaction mixture is filtered through kieselguhr, the kieselguhr is washed with ethyl acetate and the filtrate is freed from the solvent. The residue is purified by preparative HPLC.
Reaction SMILES: Cl.[N:2]1([C:8]2[CH:20]=[CH:19][C:11]([C:12]([O:14][CH2:15][CH2:16][CH2:17][CH3:18])=[O:13])=[CH:10][CH:9]=2)[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[CH3:21][S:22](Cl)(=[O:24])=[O:23]>N1C=CC=CC=1>[CH3:21][S:22]([N:5]1[CH2:4][CH2:3][N:2]([C:8]2[CH:9]=[CH:10][C:11]([C:12]([O:14][CH2:15][CH2:16][CH2:17][CH3:18])=[O:13])=[CH:19][CH:20]=2)[CH2:7][CH2:6]1)(=[O:24])=[O:23]
Reactant: CS(=O)(=O)Cl
Reactant: CCCCOC(=O)c1ccc(N2CCNCC2)cc1
Agent: Cl
Solvent: c1ccncc1
Product: CCCCOC(=O)c1ccc(N2CCN(S(C)(=O)=O)CC2)cc1
Reaction time: 8 h

Procedure:
To a mixture of 27 g. (0.1 mole) n-butyl 4-(piperazin-1-yl)-benzoate hydrochloride and 270 ml. anhydrous pyridine are added at 5°-10° C. 11.4 g. (0.1 mole) methanesulphonyl chloride. The reaction mixture is left to stand overnight at 20° C. and then poured into 250 ml. ice water and extracted twice with methylene chloride. The extracts are dried with anhydrous sodium sulphate and evaporated in a vacuum. After trituration of the residue with ligroin, 17.1 g. (55% of theory) of the desired product are obtained as yellow crystals; m.p. 145°-150° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH:16]3[CH2:17][CH2:18][CH2:19][CH:12]2[C:13](=[CH:21]O)[C:14](=O)[CH2:15]3)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH2:23][C:24]1[N:28]=[CH:27][NH:26][N:25]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH:16]3[CH2:17][CH2:18][CH2:19][CH:12]2[C:13]2[CH:21]=[N:23][C:24]4[N:25]([C:14]=2[CH2:15]3)[N:26]=[CH:27][N:28]=4)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=C1CC2CCCC(C1=CO)N2S(=O)(=O)c1ccc(Cl)cc1
Reactant: Nc1nc[nH]n1
Product: O=S(=O)(c1ccc(Cl)cc1)N1C2CCCC1c1cnc3ncnn3c1C2

Procedure:
Prepared as described in Example 5 using 9-(4-chlorophenylsulfonyl)-2-(hydroxymethylene)-9-azabicyclo[3.3.1]nonan-3-one which was prepared as described in Example 34 and 3-amino-1,2,4-triazole
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:15][CH2:16][NH:17][CH:18]=[O:19])[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][C:11]#[C:12][CH2:13][CH3:14].C(N(CC)CC)C.C(=O)(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl.[Cl:39][C:40]1[CH:41]=[C:42]([CH:45]=[CH:46][C:47]=1[Cl:48])[CH:43]=[O:44].Cl>C(Cl)Cl.Cl[Ti](Cl)(Cl)Cl>[Cl:39][C:40]1[CH:41]=[C:42]([CH:43]([OH:44])[C:18]([NH:17][CH2:16][CH2:15][C:5]2[CH:6]=[CH:7][C:8]([O:9][CH2:10][C:11]#[C:12][CH2:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=2)=[O:19])[CH:45]=[CH:46][C:47]=1[Cl:48]
Reactant: CCC#CCOc1ccc(CCNC=O)cc1OC
Reactant: O=Cc1ccc(Cl)c(Cl)c1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: Cl
Agent: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC#CCOc1ccc(CCNC(=O)C(O)c2ccc(Cl)c(Cl)c2)cc1OC
Temperature: -78 °C
Reaction time: 4 h

Procedure:
34 g (13.0 mmol) N-[2-(3-methoxy-4-pent-2-ynyloxy-phenyl)-ethyl]-formamide and 4.3 ml (32 mmol) triethylamine are dissolved in 13 ml CH2Cl2. 1.4 g (4.7 mmol) bis(trichloromethyl) carbonate (triphosgene) in 9 ml CH2Cl2 is added at +5° C. The mixture is stirred for 4 hours at +5° C. and then cooled to −78° C. A solution of 1.43 ml (13.0 mmol) TiCl4 in 20 ml CH2Cl2 is added and the mixture is stirred for 2 hours at −40° C. 2.5 g (12.9 mmol) 3,4-dichlorobenzal-dehyde in 7 ml CH2Cl2 is added dropwise and the mixture is stirred for 17 h at room temperature. The mixture is hydrolysed with 7 ml HCl 5N, stirred 30 minutes at room temperature and washed with water. After evaporation the residue is submitted to flash-chromatography (ethyl acetate 6,hexanes 4) to give the 2-(3,4-dichloro-phenyl)-2-hydroxy-N-[2-(3-methoxy-4-pent-2-ynyloxy-phenyl)-ethyl]-acetamide.
Reaction SMILES: C1([C:7]2[C:12]([N+:13]([O-])=O)=[CH:11][CH:10]=[CH:9][C:8]=2[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([N+]([O-])=O)[C:19]=2C2CCCCC2)=O)CCCCC1.Cl.[F:34][C:35]1[CH:36]=[C:37]([CH:42]([NH2:44])[CH3:43])[CH:38]=[CH:39][C:40]=1[F:41].[BH4-].[Na+]>[Ti](Cl)(Cl)(Cl)Cl.O.O.O.O.O.O.[Ni](Cl)Cl>[CH:18]1([CH:16]([NH:44][CH:42]([C:37]2[CH:38]=[CH:39][C:40]([F:41])=[C:35]([F:34])[CH:36]=2)[CH3:43])[C:8]2[CH:7]=[C:12]([NH2:13])[CH:11]=[CH:10][CH:9]=2)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]1
Reactant: O=C(c1cccc([N+](=O)[O-])c1C1CCCCC1)c1cccc([N+](=O)[O-])c1C1CCCCC1
Reactant: CC(N)c1ccc(F)c(F)c1
Agent: Cl[Ni]Cl
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: Cl
Solvent: O
Product: CC(NC(c1cccc(N)c1)C1CCCCC1)c1ccc(F)c(F)c1
Yield: 67.2 %

Procedure:
In a similar manner to that described in Example (25a), cyclohexyl-3-nitrophenylketone (3.0 g), 1-(3,4-difluorophenyl)ethylamine hydrochloride (4.98 g) triethylamine (10.8 ml), titanium tetrachloride (1.70 ml), nickel chloride hexahydrate (6.11 g), and sodium borohydride (2.05 g) were reacted, to afford the title compound (1.59 g) as a yellow oil.
Reaction SMILES: O=[C:2]([CH2:18][CH3:19])[CH2:3][NH:4][C:5]([C:7]1[O:11][C:10]2[CH:12]=[CH:13][CH:14]=[C:15]([O:16][CH3:17])[C:9]=2[CH:8]=1)=[O:6].CC[N+](S(N=C(OC)[O-])(=O)=O)(CC)CC.O>C1COCC1>[CH2:18]([C:2]1[O:6][C:5]([C:7]2[O:11][C:10]3[CH:12]=[CH:13][CH:14]=[C:15]([O:16][CH3:17])[C:9]=3[CH:8]=2)=[N:4][CH:3]=1)[CH3:19]
Reactant: CCC(=O)CNC(=O)c1cc2c(OC)cccc2o1
Agent: CC[N+](CC)(CC)S(=O)(=O)N=C([O-])OC
Solvent: C1CCOC1
Solvent: O
Product: CCc1cnc(-c2cc3c(OC)cccc3o2)o1
Yield: 83.8 %

Procedure:
To a solution of N-(2-oxobutyl)-4-methoxybenzo(b)furan-2-carboxamide (2.00 g) in THF (60 ml) was added Burgess reagent (7.30 g), and the mixture was stirred with refluxing. Water (200 ml) was added to the reaction mixture and the mixture was extracted with ether. The organic layer was washed with water and saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound (1.56 g) as colorless crystals, melting point 88-87° C.
Reaction SMILES: Cl.[N+:2]([C:5]1[CH:12]=[CH:11][CH:10]=[C:9](/[CH:13]=[CH:14]\[CH3:15])[C:6]=1[C:7]#[N:8])([O-])=O.[OH-].[Na+]>CO.O1CCOCC1.[Fe]>[NH2:2][C:5]1[CH:12]=[CH:11][CH:10]=[C:9](/[CH:13]=[CH:14]\[CH3:15])[C:6]=1[C:7]#[N:8]
Reactant: C/C=C\c1cccc([N+](=O)[O-])c1C#N
Agent: [Fe]
Agent: Cl
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CO
Product: C/C=C\c1cccc(N)c1C#N
Temperature: 0 °C
Yield: 81.6 %

Procedure:
Concentrated HCl (1.54 mL) was added to a suspension of (Z)-2-nitro-6-(prop-1-enyl)benzonitrile (Example 3c) (0.35 g, 1.86 mmol) in MeOH (30 mL) and 1,4-dioxane (15 mL) at room temperature, followed by portion wise addition of iron powder (0.73 g, 13.0 mmol). The obtained mixture was heated at refluxed for 2.5 h, cooled to 0° C. and the pH was adjusted to pH˜10 with aqueous 50% solution of NaOH. The mixture was extracted with EtOAc (3×50 mL), the combined extract was dried with MgSO4, filtered and concentrated. The residue was purified by chromatography on silica gel eluting with gradient 0% to 100% DCM in hexanes, to give 0.24 g (80%) of (Z)-2-amino-6-(prop-1-enyl)benzonitrile as a yellow oil. 1H NMR (400 MHz, DMSO-d6) δ 7.24-7.30 (m, 1H), 6.68 (d, J=8.4 Hz, 1H), 6.55 (d, J=7.2 Hz, 1H), 6.42-6.48 (m, 1H), 5.98 (broad s, 2H), 5.89-5.97 (m, 1H), 1.74-1.78 (m, 3H). MS 159 (MH+).
Reaction SMILES: [I-].[CH3:2][O:3][C:4]1[CH:20]=[CH:19][CH:18]=[C:17]2[C:5]=1[C:6]1[N+:7]([CH3:24])=[C:8]3[C:13](=[CH:14][C:15]=1[N:16]2C(=O)C)[CH:12]=[CH:11][CH:10]=[CH:9]3.C([O-])([O-])=O.[Na+].[Na+]>C(O)C>[CH3:2][O:3][C:4]1[C:5]2[C:17]([CH:18]=[CH:19][CH:20]=1)=[N:16][C:15]1[C:6]=2[N:7]([CH3:24])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=2[CH:14]=1
Reactant: COc1cccc2c1c1c(cc3ccccc3[n+]1C)n2C(C)=O
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CCO
Product: COc1cccc2nc3cc4ccccc4n(C)c-3c12

Procedure:
A solution of 6-methoxy-5-methyl-10-acetylquindolinium iodide obtained in Example 37 dissolved in approximately 50 mL of ethanol-free chloroform was adsorbed onto anhydrous Na2CO3 (1 g/100 mg iodide salt) and applied to a column filled with basic alumina. The mixture was eluted with CHCl3 until the UV active impurities eluted. Elution with CHCl3 -MeOH (97:3) provided the title compound as a purple solid; 1H NMR (CDCl3) δ 8.74 (s, 1H), 8.22 (d, J=8.4, 1H), 7.85 (d, J=8.4, 1H), 7.73 (d, J=8.4, 1H), 7.57 (m, 1H), 7.48 (m, 1H), 7.18 (d, J=7.6, 1H), 7.08 (m, 1H), 5.07 (s, 3H) , 4.12 (s, 3H); 13C NMR (CDCl3) δ 159.8, 150.5 (2 carbons), 144.1, 141.5, 131.2, 127.2, 126.3, 124.4, 124.1, 122.2, 119.5, 117.6, 114.1, 109.4, 56.5, 45.3; MS (LSIMS, m/z) 263 (M+).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[C:8](=[O:9])/[C:7](=[CH:10]/[C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH3:19])=[CH:13][CH:12]=2)/[S:6][C:5]1=[O:20].Cl[C:22]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23].CCN(C(C)C)C(C)C.C(OC1C=CC(/C=C2/C(=O)N(CCNC(=O)C)C(=O)S/2)=CC=1)C>>[CH2:18]([O:17][C:14]1[CH:15]=[CH:16][C:11](/[CH:10]=[C:7]2/[C:8](=[O:9])[N:4]([CH2:3][CH2:2][NH:1][C:22](=[O:23])[O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:5](=[O:20])[S:6]/2)=[CH:12][CH:13]=1)[CH3:19]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CCOc1ccc(/C=C2\SC(=O)N(CCN)C2=O)cc1
Agent: CCOc1ccc(/C=C2\SC(=O)N(CCNC(C)=O)C2=O)cc1
Solvent: CCN(C(C)C)C(C)C
Product: CCOc1ccc(/C=C2\SC(=O)N(CCNC(=O)OCc3ccccc3)C2=O)cc1

Procedure:
The title compound 26d was prepared from compound 76 (70 mg, 0.17 mmol), benzyl chloroformate (27 μL, 0.19 mmol) and DIPEA (75 μL, 0.43 mmol) in a manner similar to that described for 25a in 95.5% (70 mg) yield as a light-yellow solid.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].F[B-](F)(F)F.[O:17]=[N+:18]=[O:19]>C(#N)C.O>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([CH3:11])=[C:9]([N+:18]([O-:19])=[O:17])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=[N+]=O
Reactant: Cc1ccc(C(C)(C)C)cc1
Agent: F[B-](F)(F)F
Solvent: CC#N
Solvent: O
Product: Cc1ccc(C(C)(C)C)cc1[N+](=O)[O-]
Reaction time: 0.5 h
Yield: 58.4 %

Procedure:
To a solution of 4-tert-butyl toluene (5 g, 33.7 mmol) in acetonitrile (150 mL) at 0° C. was added nitronium tetrafluoroborate (5.83 g, 40.5 mmol). After 30 min at room temperature, the reaction was diluted with water (50 mL) and extracted with ethyl acetate (3×30 mL). The combined organic extracts were washed with brine and dried (MgSO4). Removal of the volatiles in vacuo left a residue which was purified by flash chromatography using 10% methylene chloride in petroleum ether as eluent. Concentration in vacuo of the product rich fractions provided 3.8 g of 4-tert-butyl-2-nitrotoluene.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[C:14]([F:15])=[C:13]2[NH:16][C:17](=[O:39])[C:18]3([CH:22]([C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[C:24]=4[F:30])[CH:21]([C:31](O)=[O:32])[NH:20][CH:19]3[CH2:34][C:35]([CH3:38])([CH3:37])[CH3:36])[C:12]2=[CH:11][CH:10]=1.C(N(C(C)C)CC)(C)C.C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[NH2:64][C:65]1[CH:72]=[CH:71][C:68]([C:69]#[N:70])=[CH:67][CH:66]=1>>[C:69]([C:68]1[CH:71]=[CH:72][C:65]([NH:64][C:31]([CH:21]2[NH:20][CH:19]([CH2:34][C:35]([CH3:36])([CH3:38])[CH3:37])[C:18]3([C:12]4[C:13](=[C:14]([F:15])[C:9]([Cl:8])=[CH:10][CH:11]=4)[NH:16][C:17]3=[O:39])[CH:22]2[C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[C:24]=2[F:30])=[O:32])=[CH:66][CH:67]=1)#[N:70]
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C12C(=O)Nc1c2ccc(Cl)c1F
Reactant: N#Cc1ccc(N)cc1
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)CC1NC(C(=O)Nc2ccc(C#N)cc2)C(c2cccc(Cl)c2F)C12C(=O)Nc1c2ccc(Cl)c1F
Yield: 33.3 %

Procedure:
In a manner similar to the method described in Example 5, rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-7-fluoro-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid trifluoroacetic acid prepared in Example 174 (0.4 g, 0.67 mmol), was reacted with diisopropylethylamine (0.43 g, 3.4 mmol), diphenylphosphinic chloride (0.32 g, 1.3 mmol) at room temperature, then reacted with 4-aminobenzonitrile (Aldrich) (0.12 g, 1 mmol) to give rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-7-fluoro-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid (4-cyano-phenyl)-amide as a yellow solid (Yield 0.13 g, 33%).
Reaction SMILES: [CH:1]1([C:4]23[O:11][CH2:10][C:7]([CH2:12][OH:13])([CH2:8][O:9]2)[CH2:6][O:5]3)[CH2:3][CH2:2]1.[CH:14]1(C#N)CCC1>>[CH:1]1([C:4]23[O:5][CH2:6][C:7]([CH2:12][OH:13])([CH2:8][O:9]2)[CH2:10][O:11]3)[CH2:3][CH2:2][CH2:14]1
Reactant: N#CC1CCC1
Reactant: OCC12COC(C3CC3)(OC1)OC2
Product: OCC12COC(C3CCC3)(OC1)OC2
Yield: 51 %

Procedure:
The same procedure as in the steps (37a) to (37c) of Example 37 was repeated using cyclobutanecarbonitrile to obtain the title compound (15 g, total yield: 51%) as a light yellow oil.
Reaction SMILES: [C:1]([C:3]1([OH:10])[CH2:8][CH2:7][CH2:6][CH:5]([CH3:9])[CH2:4]1)#[CH:2].[CH3:11][CH2:12][NH:13][C:14]([C@H:16]1[O:20][C@@H:19]([N:21]2[C:25]3[N:26]=[C:27](I)[N:28]=[C:29]([NH2:30])[C:24]=3[N:23]=[CH:22]2)[CH:18]([OH:32])[C@H:17]1[OH:33])=[O:15]>>[CH2:12]([NH:13][C:14]([CH:16]1[CH:17]([OH:33])[CH:18]([OH:32])[CH:19]([N:21]2[CH:22]=[N:23][C:24]3[C:25]2=[N:26][C:27]([C:2]#[C:1][C:3]2([OH:10])[CH2:8][CH2:7][CH2:6][CH:5]([CH3:9])[CH2:4]2)=[N:28][C:29]=3[NH2:30])[O:20]1)=[O:15])[CH3:11]
Reactant: C#CC1(O)CCCC(C)C1
Reactant: CCNC(=O)[C@H]1O[C@@H](n2cnc3c(N)nc(I)nc32)C(O)[C@H]1O
Product: CCNC(=O)C1OC(n2cnc3c(N)nc(C#CC4(O)CCCC(C)C4)nc32)C(O)C1O

Procedure:
The reaction of 1-Ethynyl-3-methyl-cyclohexanol (JR3149B) (100 mg, 0.72 mmol) with 2-iodo-NECA (25 mg, 0.06 mmol) under the general coupling conditions gave JR3179 (15.0 mg, 59%) as a white solid after purification by a silica plug and RP-HPLC. 1H NMR (CD3OD-d4) δ 8.49 (s, 1H), 6.06 (d, J=6.9 Hz, 1H), 4.75 (dd, J=6.4 Hz, J=4.9 Hz, 1H), 4.46 (d, J=1.9 Hz, 1H), 4.34 (dd, J=4.9 Hz, J=2.1 Hz, 1H), 3.42 (m, 2H), 2.09 (d, J=12.3 Hz, 2H), 1.73 (m, 4H), 1.46 (m, 1H), 1.23 (m, 1H), 1.16 9 (t, J=7.1 Hz, 3H), 0.95 (d, J=6.2 Hz, 3H), 0.89 (m, 1H). 13C NMR (CD3OD-d4) δ. APCI m/z (rel intensity) 445.3 (MH+, 100), 427.4 (40), 254.4 (4).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[C:17](=[O:18])[C:16]3[C:15]4[C:10](=[CH:11][C:12]([C:19]#[N:20])=[CH:13][CH:14]=4)[NH:9][C:8]=3[C:7]([CH3:22])([CH3:21])[C:6]=2[CH:23]=1.[Br:24][CH2:25][CH2:26]O>>[Br:24][CH2:25][CH2:26][O:1][C:2]1[CH:3]=[CH:4][C:5]2[C:17](=[O:18])[C:16]3[C:15]4[C:10](=[CH:11][C:12]([C:19]#[N:20])=[CH:13][CH:14]=4)[NH:9][C:8]=3[C:7]([CH3:21])([CH3:22])[C:6]=2[CH:23]=1
Reactant: OCCBr
Reactant: CC1(C)c2cc(O)ccc2C(=O)c2c1[nH]c1cc(C#N)ccc21
Product: CC1(C)c2cc(OCCBr)ccc2C(=O)c2c1[nH]c1cc(C#N)ccc21

Procedure:
Under the same conditions as the method for synthesizing Compound A7-1, the title compound was prepared from Compound A6 and 2-bromoethanol.
Reaction SMILES: C[Al](C)C.COC(=O)[C@@H](OC)C1C=CC=CC=1.[F:18][C:19]([F:24])([F:23])[C:20]([OH:22])=[O:21].[CH3:25][O:26][CH:27]([C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)[C:28]1[NH:29][CH:30]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH:31]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[N:32]=1>>[F:18][C:19]([F:24])([F:23])[C:20]([OH:22])=[O:21].[CH3:25][O:26][CH:27]([C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)[C:28]1[NH:32][C@H:31]([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[C@H:30]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[N:29]=1
Reactant: COC(C1=NC(c2ccccc2)C(c2ccccc2)N1)c1ccccc1
Agent: COC(=O)[C@@H](OC)c1ccccc1
Agent: C[Al](C)C
Solvent: O=C(O)C(F)(F)F
Product: COC(C1=N[C@@H](c2ccccc2)[C@@H](c2ccccc2)N1)c1ccccc1

Procedure:
Employing the general trimethylaluminum coupling procedure and using methoxy-(S)-phenyl-acetic acid methyl ester prepared in accordance with Step 1 as described above and meso-1,2-diphenylethylene-diamine there was made, 2-(Methoxy-phenyl-methyl)-4,5-diphenyl-4,5-dihydro-1H-imidazole trifluoroacetate. 1H NMR (DMSO) δ 11.11 (bs, 1 H), 7.7-7.5 (m, 5 H), 7.1-7.0 (m, 6 H), 6.90-6.85 (m, 2 H), 6.8-6.7 (m, 2 H), 5.81 (s, 2 H), 5.65 (s, 1 H), 3.49 (s, 3 H); LC/MS: 3.69 min, m/z 343 (M++1)
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[S:7][C:8]2[N:9]=[C:10]([N:15]([CH3:36])[C:16]3[CH:17]=[C:18]([NH:22][C:23](=[O:35])[C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([C:33]#[N:34])([CH3:32])[CH3:31])[CH:25]=4)[CH:19]=[CH:20][CH:21]=3)[N:11]=[CH:12][C:13]=2[N:14]=1)=[O:4].C(N(CC)CC)C.[NH:44]1[CH2:49][CH2:48][S:47](=[O:51])(=[O:50])[CH2:46][CH2:45]1.C(=O)([O-])O.[Na+]>O1CCCC1>[C:33]([C:30]([C:26]1[CH:25]=[C:24]([CH:29]=[CH:28][CH:27]=1)[C:23]([NH:22][C:18]1[CH:19]=[CH:20][CH:21]=[C:16]([N:15]([C:10]2[N:11]=[CH:12][C:13]3[N:14]=[C:6]([NH:5][C:3](=[O:4])[CH2:2][N:44]4[CH2:49][CH2:48][S:47](=[O:51])(=[O:50])[CH2:46][CH2:45]4)[S:7][C:8]=3[N:9]=2)[CH3:36])[CH:17]=1)=[O:35])([CH3:32])[CH3:31])#[N:34]
Reactant: O=S1(=O)CCNCC1
Reactant: CN(c1cccc(NC(=O)c2cccc(C(C)(C)C#N)c2)c1)c1ncc2nc(NC(=O)CCl)sc2n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CN(c1cccc(NC(=O)c2cccc(C(C)(C)C#N)c2)c1)c1ncc2nc(NC(=O)CN3CCS(=O)(=O)CC3)sc2n1
Temperature: 60 °C
Reaction time: 16 h
Yield: 56.5 %

Procedure:
To a solution of N-{3-[{2-[(chloroacetyl)amino][1,3]thiazolo[5,4-d]pyrimidin-5-yl}(methyl)amino]phenyl}-3-(1-cyano-1-methylethyl)benzamide (140 mg, 269 μmol) produced in Example D10 in tetrahydrofuran (4 mL) were added triethylamine (112 μL, 807 μmol) and thiomorpholine 1,1-dioxide (109 mg, 807 μmol), and the mixture was stirred at 60° C. for 16 hr. To the reaction mixture was added saturated aqueous sodium hydrogen carbonate solution (10 mL), and the mixture was extracted with ethyl acetate (15 mL, 5 mL). The combined organic layer was washed with saturated brine (5 mL), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (hexane/ethyl acetate=40/60→20/80), and the fractions containing the object product were concentrated under reduced pressure. The obtained residue was recrystallized from ethanol to give the title compound (94 mg, 56%) as a colorless solid.
Reaction SMILES: O/[CH:2]=[C:3](/[CH2:9][C:10]1[CH:11]=[N:12][CH:13]=[N:14][CH:15]=1)\[C:4]([O:6]CC)=O.[NH2:16][C:17]([NH2:19])=[S:18].CC(C)([O-])C.[K+]>C(O)(C)C>[N:14]1[CH:15]=[C:10]([CH2:9][C:3]2[C:4](=[O:6])[NH:16][C:17](=[S:18])[NH:19][CH:2]=2)[CH:11]=[N:12][CH:13]=1
Reactant: NC(N)=S
Reactant: CCOC(=O)/C(=C\O)Cc1cncnc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)O
Product: O=c1[nH]c(=S)[nH]cc1Cc1cncnc1
Temperature: 80 °C

Procedure:
To a solution of ethyl (2Z)-3-hydroxy-2-(5-pyrimidinylmethyl)-2-propenoate (3 g, 7.20 mmol) in isopropanol (30 ml) was added thiourea (1.1 g, 14.45 mmol) and potassium tert-butoxide (1 g, 8.91 mmol). The mixture was heated at 80° C. for 4 h. The solvent was evaporated and residue was dissolved in water, extracted with ether twice to remove impurity. The aqueous phase was acidified to PH 4 with AcOH, and white participate formed. The mixture was filtered to afford the title compound as a white solid.