Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS(O[CH2:6][CH:7]1[CH2:22][N:11]2[CH2:12][CH2:13][N:14]([C:16]3[N:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[CH2:15][CH:10]2[CH2:9][CH2:8]1)(=O)=O.[C-:23]#[N:24].[Na+].C(=O)(O)[O-].[Na+]>CN(C=O)C>[N:17]1[CH:18]=[CH:19][CH:20]=[N:21][C:16]=1[N:14]1[CH2:13][CH2:12][N:11]2[CH2:22][CH:7]([CH2:6][C:23]#[N:24])[CH2:8][CH2:9][CH:10]2[CH2:15]1
Reactant: CS(=O)(=O)OCC1CCC2CN(c3ncccn3)CCN2C1
Reactant: [C-]#N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#CCC1CCC2CN(c3ncccn3)CCN2C1
Temperature: 25 °C
Yield: 48.2 %

Procedure:
A solution of 38.1 g (117 mmol) of (7SR,9aSR)-7-(methanesulfonyloxy)methyl-2-(pyrimidin-2-yl)-2,3,4,6,7,8,9,9a-octahydro-1H-pyrido[1,2-a]pyrazine (prepared according to U.S. Pat. No. 5,122,525) and 6.01 g (122 mmol) of sodium cyanide in 500 mL of dry DMF was heated at 110° C. for 16 h. The mixture was cooled to room temperature, 10 mL of saturatic sodium bicarbonate was added and the mixture concentrated in vacuo. Water (1000 mL) and ethyl acetate (1000 mL) were added to the solid residue, the pH was adjusted to 11, and the layers were separated. The organic phase was washed with water (2×), dried (sodium sulfate), filtered and evaporated. Recrystalization from ethyl acetate-hexane gave 14.5 g of [(7SR,9aSR)-2-(pyrimidin-2-yl)-2,3,4,6,7,8,9,9a-octahydro-1H-pyrido[1,2-a]pyrazin-7-yl]acetonitrile. 13C NMR (CDCl3): d 19.5, 24.1, 26.9, 31.3, 33.1, 43.6, 48.9, 54.5, 109.8, 119.8, 157.7, 161.4.
Reaction SMILES: CI.[Br:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([F:11])[CH:5]=1.[C:12]([O-])([O-])=O.[K+].[K+]>CC(C)=O>[Br:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:12])=[C:6]([F:11])[CH:5]=1
Reactant: O=C([O-])[O-]
Reactant: Oc1ccc(Br)cc1F
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: COc1ccc(Br)cc1F
Reaction time: 48 h

Procedure:
Methyl iodide (182.1 mL, 1.319 mol) was added at 0° C. to a well stirred suspension of 4-bromo-2-fluorophenol (210 g, 1.099 mol; see step (i) above) and K2CO3 (303.92 g, 2.19 mol) in dry acetone (1.7 L). Stirring was continued at 60° C. for two days under a nitrogen atmosphere before the reaction mixture was filtered and the solvent was concentrated under reduced pressure. This provided 4-bromo-2-fluoro-1-methoxybenzene (225 g) as a liquid, which was employed directly in the next step without further purification.
Reaction SMILES: Br[CH:2]([CH3:12])[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[CH:6]=1)=[O:4].[C:13]([NH2:17])([CH3:16])([CH3:15])[CH3:14].CCCCCC.C(OCC)(=O)C>C(#N)C>[C:13]([NH:17][CH:2]([CH3:12])[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[CH:6]=1)=[O:4])([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(Br)C(=O)c1cccc(Cl)c1
Reactant: CC(C)(C)N
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: CC#N
Product: CC(NC(C)(C)C)C(=O)c1cccc(Cl)c1
Temperature: 25 °C
Yield: 94.3 %

Procedure:
Crude 2-bromo-1-(3-chlorophenyl)propan-1-one (2) (152 g, 0.65 mol) was dissolved in 600 ml of acetonitrile (HPLC grade) in a 3-necked 2 L round bottomed flask fitted with a condenser and a dropping funnel. Tert-butylamine (172.5 ml, 1.63 mol) was added drop wise to the resulting mixture, at room temperature and under nitrogen. The reaction mixture was then heated to reflux for approximately 5 hours. During this time the reaction progress was monitored by TLC analysis (silica, hexane: ethyl acetate, 90:10). On consumption of the starting material, the reaction mixture was cooled to room temperature, filtered through celite and the celite washed with approximately 250 ml of ethyl acetate. The filtrate was washed with a 2M solution of KOH (350 ml). The layers were separated and the organic phase was dried over sodium sulphate anhydrous, filtered and concentrated to dryness to give a pale orange oil (147 g, quantitative yield), which did not need any further purification.
Reaction SMILES: [CH2:1]([C:3]1[C:8]([CH2:9][CH:10]=O)=[CH:7][CH:6]=[CH:5][C:4]=1[C:12]1[S:16][C:15]([C:17]2[CH:18]=[CH:19][C:20]([O:25][CH:26]([CH3:28])[CH3:27])=[C:21]([CH:24]=2)[C:22]#[N:23])=[N:14][CH:13]=1)[CH3:2].C(O)(=O)C.C([O-])(=O)C.[Na+].[NH:38]1[CH2:43][CH2:42][CH:41]([C:44]([O:46][CH2:47][CH3:48])=[O:45])[CH2:40][CH2:39]1>C(O)C>[C:22]([C:21]1[CH:24]=[C:17]([C:15]2[S:16][C:12]([C:4]3[C:3]([CH2:1][CH3:2])=[C:8]([CH2:9][CH2:10][N:38]4[CH2:43][CH2:42][CH:41]([C:44]([O:46][CH2:47][CH3:48])=[O:45])[CH2:40][CH2:39]4)[CH:7]=[CH:6][CH:5]=3)=[CH:13][N:14]=2)[CH:18]=[CH:19][C:20]=1[O:25][CH:26]([CH3:28])[CH3:27])#[N:23]
Reactant: CCOC(=O)C1CCNCC1
Reactant: CCc1c(CC=O)cccc1-c1cnc(-c2ccc(OC(C)C)c(C#N)c2)s1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Product: CCOC(=O)C1CCN(CCc2cccc(-c3cnc(-c4ccc(OC(C)C)c(C#N)c4)s3)c2CC)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99.9 %

Procedure:
To a solution of 5-{5-[2-ethyl-3-(2-oxoethyl)phenyl]-1,3-thiazol-2-yl}-2-[(1-methylethyl)oxy]benzonitrile (D76) (150 mg), acetic acid (0.044 mL) and sodium acetate (63.0 mg) in ethanol (20.00 mL) stirred under nitrogen at room temperature was added ethyl 4-piperidinecarboxylate (181 mg) in one charge. The reaction mixture was stirred at room temperature for 30 min, then the solvent was evaporated in vacuo. The residue was dissolved in dichloromethane (DCM) (20 mL), sodium triacetoxyborohydride (204 mg) was added to the mixture. The reaction mixture was stirred at room temperature overnight. The reaction mixture was partitioned between ethyl acetate (100 mL) and saturated brine (30 mL). The organic phase was dried over sodium sulphate and evaporated in vacuo to give the crude product ethyl 1-{2-[3-(2-{3-cyano-4-[(1-methylethyl)oxy]phenyl}-1,3-thiazol-5-yl)-2-ethylphenyl]ethyl}-4-piperidinecarboxylate (D86) (204 mg) as a brown oil. The crude product was used for next step without further purification. MS (ES): C31H37N3O3S requires 531. found 532.3 (M+H+).
Reaction SMILES: F[C:2]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].[O-]P([O-])([O-])=O.[K+].[K+].[K+].[OH:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[NH:28][CH:27]=[CH:26]2.CCOCC>COCCOCCOC>[NH:28]1[C:29]2[C:25](=[CH:24][C:23]([O:22][C:2]3[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:3]=3[C:4]([O:6][CH2:7][CH3:8])=[O:5])=[CH:31][CH:30]=2)[CH:26]=[CH:27]1
Reactant: Oc1ccc2[nH]ccc2c1
Reactant: CCOC(=O)c1ccc(F)cc1F
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: COCCOCCOC
Product: CCOC(=O)c1ccc(F)cc1Oc1ccc2[nH]ccc2c1

Procedure:
Ethyl 2,4-difluorobenzoate (12.75 g), K3PO4 (14.54 g) and 5-hydroxyindole (9.12 g) were stirred at 110° C. in diglyme (125 mL) for 24 hours. The reaction was cooled and poured into ether. The solution was washed three times with 1M NaOH solution, and brine, and dried. The solution was then concentrated, and the crude product was poured into hexanes, stirred, and filtered to give the product.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:12]3[N:13]([N:21]=[C:22]([NH2:24])[N:23]=3)[CH:14]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:16]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].Br[C:26]1[CH:31]=[CH:30][C:29]([N:32]2[CH2:37][CH2:36][N:35]([CH3:38])[CH2:34][CH2:33]2)=[CH:28][CH:27]=1>>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:12]3[N:13]([N:21]=[C:22]([NH:24][C:26]4[CH:27]=[CH:28][C:29]([N:32]5[CH2:37][CH2:36][N:35]([CH3:38])[CH2:34][CH2:33]5)=[CH:30][CH:31]=4)[N:23]=3)[CH:14]=[C:15]([C:17]([F:19])([F:20])[F:18])[CH:16]=2)=[CH:7][CH:6]=1)(=[O:3])=[O:4]
Reactant: CS(=O)(=O)c1ccc(-c2cc(C(F)(F)F)cn3nc(N)nc23)cc1
Reactant: CN1CCN(c2ccc(Br)cc2)CC1
Product: CN1CCN(c2ccc(Nc3nc4c(-c5ccc(S(C)(=O)=O)cc5)cc(C(F)(F)F)cn4n3)cc2)CC1

Procedure:
[8-(4-Methanesulfonyl-phenyl)-6-trifluoromethyl-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[4-(4-methyl-piperazin-1-yl)-phenyl]-amine was prepared from 8-(4-methanesulfonyl-phenyl)-6-trifluoromethyl-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine and 1-(4-bromo-phenyl)-4-methyl-piperazine in a manner analogous to Step 2d and was isolated as a yellow solid (21% yield). MP 126-134° C. 1H NMR (400 MHz, (CDCl3, δ, ppm): 8.82 (s, 1H), 8.25 (d, J=7.8 Hz, 2H), 8.13 (d, J=7.3 Hz, 2H), 7.79 (s, 1H), 7.49 (d, J=8.2 Hz, 2H), 6.99 (d, J=8.2 Hz, 2H), 6.88 (s, 1H), 3.21 (bm, 4H), 3.13 (s, 3H), 2.66 (bm, 4H), 2.40 (s, 3H). MS=531.0 (MH)+.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:12](=[O:13])[C:11]2[C:6](=[CH:7][C:8]([Cl:14])=[CH:9][CH:10]=2)[N:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:4]=1.Cl[C:22]([O:24][C:25]1[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[CH:27][CH:26]=1)=[O:23].C(N(CC)C(C)C)(C)C>C(Cl)Cl>[N+:31]([C:28]1[CH:27]=[CH:26][C:25]([O:24][C:22](=[O:23])[NH:1][CH2:2][C:3]2[C:12](=[O:13])[C:11]3[C:6](=[CH:7][C:8]([Cl:14])=[CH:9][CH:10]=3)[N:5]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:4]=2)=[CH:30][CH:29]=1)([O-:33])=[O:32]
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: NCc1cn(-c2ccccc2)c2cc(Cl)ccc2c1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(NCc1cn(-c2ccccc2)c2cc(Cl)ccc2c1=O)Oc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 101.3 %

Procedure:
In a 250 mL round-bottomed flask, 3-(aminomethyl)-7-chloro-1-phenylquinolin-4(1H)-one (intermediate D) (1 g, 3.51 mmol), 4-nitrophenyl chloroformate (708 mg, 3.51 mmol) and N,N-diisopropylethylamine (1.36 g, 1.84 mL, 10.5 mmol) were combined with CH2Cl2 (30 mL). The reaction mixture was stirred overnight at room temperature. After this time, the reaction mixture was concentrated to dryness to afford (7-chloro-4-oxo-1-phenyl-1,4-dihydro-quinolin-3-ylmethyl)-carbamic acid 4-nitro-phenyl ester (1.6 g, 100%)
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].[F:6][C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=1[NH:14][C:15]([C:17]1[CH:18]=[C:19]([C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=2[F:31])[CH:20]=[CH:21]C=1O)=[O:16].Cl>O1CCCC1.N1C=CC=CC=1>[F:6][C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=1[N:14]1[C:15](=[O:16])[C:17]2[CH:18]=[C:19]([C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=3[F:31])[CH:20]=[CH:21][C:5]=2[O:4][C:2]1=[O:3]
Reactant: COC(=O)Cl
Reactant: O=C(Nc1ccc(F)cc1F)c1cc(-c2ccc(F)cc2F)ccc1O
Agent: Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: O=c1oc2ccc(-c3ccc(F)cc3F)cc2c(=O)n1-c1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 10 h
Yield: 61 %

Procedure:
A solution of methyl chloroformate (1.2 mL, 12 mmol) was added drop wised to a stirred solution of compound 2 (1.44 g, 4 mmol) in dry anhydrous tetrahydrofuran/pyridine (30 mL) at 0° C. The mixture was refluxed for 3 h. After 10 h stirring at room temperature, the pH value of the mixture was adjusted to pH=6 by 5% HCl(aq). The mixture was cooled to obtain crystalline compound on an ice bath for 2-3 h. After cooling, precipitated crystals were filtered off and washed with diluted HCl and water. The crude product was purified by crystallization from hot ethanol to afford compound 14.
Reaction SMILES: [F:1][C:2]1([F:30])[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:19](=[O:29])[N:20]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([OH:28])[CH:23]=4)[CH2:21][C:16]3=[C:15]3[C:10]=2[CH:11]=[CH:12][CH:13]=[N:14]3)[CH2:4][CH2:3]1.[H-].[Na+].[CH3:33][N:34]([CH3:38])[C:35](Cl)=[O:36]>CS(C)=O.C(OCC)(=O)C>[CH3:33][N:34]([CH3:38])[C:35](=[O:36])[O:28][C:24]1[CH:25]=[CH:26][CH:27]=[C:22]([N:20]2[CH2:21][C:16]3[C:17](=[CH:18][C:9]([CH2:8][N:5]4[CH2:6][CH2:7][C:2]([F:1])([F:30])[CH2:3][CH2:4]4)=[C:10]4[C:15]=3[N:14]=[CH:13][CH:12]=[CH:11]4)[C:19]2=[O:29])[CH:23]=1
Reactant: O=C1c2cc(CN3CCC(F)(F)CC3)c3cccnc3c2CN1c1cccc(O)c1
Reactant: CN(C)C(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CN(C)C(=O)Oc1cccc(N2Cc3c(cc(CN4CCC(F)(F)CC4)c4cccnc34)C2=O)c1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of 5-[(4,4-difluoropiperidin-1-yl)methyl]-8-(3-hydroxyphenyl)-8,9-dihydro-7H-pyrrolo[3,4-h]quinolin-7-one (0.070 g, 0.17 mmol) in 3 mL of dimethylsulfoxide was added sodium hydride (0.034 g, 0.86 mmol). After 5 min, dimethyl carbamyl chloride (0.047 mL, 0.51 mmol) was added. The mixture was stirred at ambient temperature for 15 hr, diluted with ethyl acetate, washed 3× with brine, dried with sodium sulfate, filtered, and concentrated in vacuo. The residue was purified via preparative reverse phase HPLC to provide the title compound that gave a proton NMR spectra consistent with theory and a mass ion (ES+) of 481.2066 for [M+H]+ [Calc'd for C26H27F2N4O3, [M+H]+=481.2046].
Reaction SMILES: C1(C(=[N:14][C:15]([CH3:22])([CH2:18][CH:19]([F:21])[F:20])[C:16]#[N:17])C2C=CC=CC=2)C=CC=CC=1.[ClH:23]>O1CCCC1.O>[ClH:23].[NH2:14][C:15]([CH3:22])([CH2:18][CH:19]([F:21])[F:20])[C:16]#[N:17]
Reactant: CC(C#N)(CC(F)F)N=C(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: CC(N)(C#N)CC(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
10.84 g (33.43 mmol; 92% purity) of rac-2-[(diphenylmethylene)amino]-4,4-difluoro-2-methylbutanonitrile from Example 70A were dissolved in 156 ml of tetrahydrofuran and 6 ml of water, 73.5 ml (36.77 mmol) of hydrogen chloride solution (0.5 N in diethyl ether) were added and the mixture was stirred at room temperature overnight. The reaction solution was admixed with 16.71 ml (33.43 mmol) of hydrogen chloride solution (2 N in diethyl ether) and concentrated by rotary evaporation. The isolated crude product was reacted further directly without further purification.
Reaction SMILES: [C:1](#[N:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].C([Sn](=O)CCCC)CCC.C[Si]([N:22]=[N+:23]=[N-:24])(C)C>C1(C)C=CC=CC=1>[CH2:2]([C:1]1[NH:24][N:23]=[N:22][N:7]=1)[CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: CCCCCC#N
Agent: CCCC[Sn](=O)CCCC
Solvent: Cc1ccccc1
Product: CCCCCc1nnn[nH]1
Temperature: 25 °C
Yield: 70.2 %

Procedure:
A mixture of hexanenitrile (938 mg, 9.65 mmol), dibutyltin oxide (293 mg, 0.98 mmol) and 97% trimethylsilylazide (2.60 mL, 19.1 mmol) in toluene (20 mL) were heated at ~110° C. for 25 hours and ambient temperature for one hour. The reaction mixture was extracted with 1M sodium hydroxide solution (4×10 mL) and the combined aqueous extracts were acidified with 6M hydrochloric acid to pH 3-4 and extracted with 10% isopropanol in chloroform (3×10 mL). The combined organic extracts were washed with brine, dried over magnesium sulfate and concentrated in vacuo to afford 950 mg (70%) of the title compound. 1H NMR (CDCl3, 300 MHz) δ0.87 (t, J=7 Hz, 3H), 1.30-1.45 (m, 4H), 1.90 (pentet, J=7 Hz, 2H), 3.12 (t, J=7 Hz, 2H). 13C NMR (CDCl3, 75 MHz) 13.70, 22.06, 23.35, 27.31, 31.05, 156.97. IR (CDCl3) 2900, 1555 cm-1. MS (DCl/NH3) m/e 141 (M+H)+, 158 (M+H+NH3)+. Anal calcd for C6H12N4 : C, 51.41; H, 8.63; N, 39.97. Found: C, 51.25; H, 8.59; N, 39.93.
Reaction SMILES: [CH:1]([C:4]1[S:5][CH:6]=[C:7]([C:9]([OH:11])=O)[N:8]=1)([CH3:3])[CH3:2].[ClH:12].[O:13]1[C:18]2([CH2:23][CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20][CH2:19]2)[CH2:17][NH:16][CH2:15][CH2:14]1.C(N(CC)CC)C.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC>CC1CCCO1.O>[ClH:12].[CH:1]([C:4]1[S:5][CH:6]=[C:7]([C:9]([N:16]2[CH2:17][C:18]3([CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)[O:13][CH2:14][CH2:15]2)=[O:11])[N:8]=1)([CH3:2])[CH3:3]
Reactant: CC(C)c1nc(C(=O)O)cs1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CNCCO2
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: Cl
Solvent: O
Solvent: CC1CCCO1
Solvent: CCN(CC)CC
Product: CC(C)c1nc(C(=O)N2CCOC3(CCNCC3)C2)cs1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 2-isopropylthiazole-4-carboxylic acid (12 g) and tert-butyl 1-oxa-4,9-diazaspiro[5.5]undecane-9-carboxylate hydrochloride [WuXi PharmaTech] (20 g) in 2-methyltetrahydrofuran (140 mL) was cooled in ice-water and treated with triethylamine (47 mL), followed by T3P (1.6M in THF, 54 mL). The mixture was allowed to warm to RT and was stirred for 1 h. Water (140 mL) was added with stirring, then the phases were separated. The organic phase was washed with water (80 mL), and then concentrated to a volume of (˜100 mL) under reduced pressure using a temperature of <30° C. IPA (75 mL) was added, and the mixture was concentrated to a volume of (˜100 mL). More IPA (75 mL) was added, and the mixture was again concentrated to a volume of (˜100 mL). A solution of hydrogen chloride in IPA (˜6M, 81 mL) was added with cooling in ice-water, then the mixture was warmed to 40° C. and stirred for 3.5 h. The mixture was cooled to RT, diluted with MTBE (34 mL) and stirred for 30 min. The resulting precipitated solid was removed by filtration and dried in a vacuum oven at 55° C. overnight. Yield 20.5 g.
Reaction SMILES: [H-].[Na+].[C:3]([N:10]1[CH2:15][CH2:14][CH:13]([OH:16])[CH2:12][CH2:11]1)([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].[CH2:17](Br)[CH:18]=[CH2:19]>CN(C=O)C>[C:3]([N:10]1[CH2:15][CH2:14][CH:13]([O:16][CH2:19][CH:18]=[CH2:17])[CH2:12][CH2:11]1)([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4]
Reactant: C=CCBr
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCOC1CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 0.17 h

Procedure:
To a suspension of NaH (0.48 g, 11.9 mmol; 60% dispersion) in dry DMF (50 mL) at 0° C. was added a solution of 21-2 (2.0 g, 9.9 mmol) in DMF (15 mL). After 10 min, the cooling bath was removed, but then returned after another 10 min, followed by addition of allyl bromide (4.3 mL, 50 mmol). After 1.5 h, the reaction was quenched with 10% KHSO4 and then diluted with H2O (90 mL). The reaction mixture was extracted with EtOAc, the layers separated, and the EtOAc portion washed with H2O, 5% KHSO4, sat. NaHCO3 and brine, dried (MgSO4) and concentrated. Flash chromatography (silica, 20% EtOAc/hexanes) gave 21-3 as a yellowish oil. Rf 0.47 (silica, 20% EtOAc/hexanes).
Reaction SMILES: CN.N.[CH3:4][C:5]1[C:6]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[N:7][N:8]([CH:10]([CH2:14][CH2:15][CH3:16])[C:11](O)=[O:12])[CH:9]=1.C[CH:24]([N:28]1C=C(C)C(C2C=CC=CC=2)=N1)C(O)=O>>[CH3:24][NH:28][C:11](=[O:12])[CH:10]([CH2:14][CH2:15][CH3:16])[N:8]1[CH:9]=[C:5]([CH3:4])[C:6]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[N:7]1
Reactant: Cc1cn(C(C)C(=O)O)nc1-c1ccccc1
Reactant: CCCC(C(=O)O)n1cc(C)c(-c2ccccc2)n1
Agent: CN
Agent: N
Product: CCCC(C(=O)NC)n1cc(C)c(-c2ccccc2)n1

Procedure:
Following the procedure of Example 68, but substituting aqueous methylamine for aqueous ammonia, and 4-methyl-3-phenyl-α-propylpyrazole-1-acetic acid for α,4-dimethyl-3-phenylpyrazole-1-acetic acid, there was obtained N,4-dimethyl-3-phenyl-α-propylpyrazole-1-acetamide having a melting point of 84°-86° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:16]2[CH2:18][CH2:17]2)[C:5]2[O:12][C:9]3([CH2:11][CH2:10]3)[CH2:8][C:7]([CH3:14])([CH3:13])[C:6]=2[CH:15]=1.[CH3:19][Si:20]([C:23]#[CH:24])([CH3:22])[CH3:21].C(N(CC)CC)C.O1CCCC1>CCCCCC.[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.C(OCC)(=O)C>[CH:16]1([C:4]2[C:5]3[O:12][C:9]4([CH2:11][CH2:10]4)[CH2:8][C:7]([CH3:13])([CH3:14])[C:6]=3[CH:15]=[C:2]([C:24]#[C:23][Si:20]([CH3:22])([CH3:21])[CH3:19])[CH:3]=2)[CH2:17][CH2:18]1
Reactant: C#C[Si](C)(C)C
Reactant: CC1(C)CC2(CC2)Oc2c(C3CC3)cc(Br)cc21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CC1(C)CC2(CC2)Oc2c(C3CC3)cc(C#C[Si](C)(C)C)cc21

Procedure:
Following general procedure D and 6-bromo-8-cyclopropyl-3,4-dihydro-4,4-dimethylspiro[2H-1-benzopyran-2,1′-cyclopropane] (Intermediate 42, 0.74 g, 2.4 mmol), (trimethylsilyl)acetylene (4 mL, 28 mmol), triethyl amine (8 mL), anhydrous tetrahydrofuran, copper(I)iodide (0.050 g, 0.26 mmol) and dichlorobis(triphenylphosphine)palladium(II) (0.15 g, 0.22 mmol), followed by flash column chromatography over silica gel (230-400 mesh) using 1-2% ethyl acetate in hexane as the eluent, the title compound was obtained as an oil (0.62 g, 80%).
Reaction SMILES: C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.[F:15][C:16]1[CH:53]=[CH:52][C:19]([O:20][C:21]2[CH:26]=[CH:25][C:24]([S:27]([N:30]3[CH2:39][CH2:38][C:37]4[C:32](=[CH:33][CH:34]=[C:35]([O:40][CH2:41][CH2:42][N:43]5[CH2:48][CH2:47][O:46][CH2:45][CH2:44]5)[CH:36]=4)[CH:31]3[C:49](O)=[O:50])(=[O:29])=[O:28])=[CH:23][CH:22]=2)=[CH:18][CH:17]=1.[O:54]1[CH2:59][CH2:58][CH2:57][CH2:56][CH:55]1[O:60][NH2:61]>CN(C=O)C>[O:54]1[CH2:59][CH2:58][CH2:57][CH2:56][CH:55]1[O:60][NH:61][C:49]([CH:31]1[C:32]2[C:37](=[CH:36][C:35]([O:40][CH2:41][CH2:42][N:43]3[CH2:44][CH2:45][O:46][CH2:47][CH2:48]3)=[CH:34][CH:33]=2)[CH2:38][CH2:39][N:30]1[S:27]([C:24]1[CH:25]=[CH:26][C:21]([O:20][C:19]2[CH:18]=[CH:17][C:16]([F:15])=[CH:53][CH:52]=2)=[CH:22][CH:23]=1)(=[O:28])=[O:29])=[O:50]
Reactant: NOC1CCCCO1
Reactant: O=C(O)C1c2ccc(OCCN3CCOCC3)cc2CCN1S(=O)(=O)c1ccc(Oc2ccc(F)cc2)cc1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: O=C(NOC1CCCCO1)C1c2ccc(OCCN3CCOCC3)cc2CCN1S(=O)(=O)c1ccc(Oc2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80 %

Procedure:
A solution of 40 mg (0.264 mmol) of HOBt and 51 mg (0.264 mmol) of EDC in 2 ml of DMF was added dropwise to a solution of 98 mg (0.176 mmol) of 2-[4-(4-fluoro-phenoxy)benzenesulfonyl]-6-(2-morpholin-4-ylethoxy)-1,2,3,4-tetrahydroisoquinoline-1-carboxylic acid and 46 mg (0.325 mmol) of O-(tetrahydropyran-2-yl)hydroxylamine in 3 ml of DMF at 0° C., and the mixture was stirred at room temperature. After standing overnight, it was poured onto H2O and extracted with ethyl acetate. The organic phase was dried with MgSO4 and concentrated. The residue was chromatographed on silica gel (dichloromethane→dichloromethane/methanol 99:1), the title compound being isolated as a colorless solid. Yield: 80%.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[S:10][CH2:9][CH:8]=[CH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[C:12](OC(=O)C)(=[O:14])[CH3:13]>ClCCCC>[C:12]([NH:1][C:2]1[C:11]2[S:10][CH2:9][CH:8]=[CH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1)(=[O:14])[CH3:13]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1cccc2c1SCC=C2
Solvent: CCCCCl
Product: CC(=O)Nc1cccc2c1SCC=C2

Procedure:
To a solution of 21.1 g of 8-amino-2H-1-benzothiopyran in 200 ml of 1-chlorobutane was added a solution of 13.3 ml of acetic anhydride in 50 ml of 1-chlorobutane. The temperature of the mixture rose during the addition and the mixture was refluxed for an additional 30 minutes. The solution was cooled in ice and filtered to give 18.0 g of the desired acetamide as colorless needles, m.p. 133°-135° C. The mother liquor was concentrated to ~1/5 volume to give a second crop of 4.1 g, m.p. 133°-135° C.
Reaction SMILES: [N+]([C:4]1[CH:11]=[CH:10][CH:9]=[C:6]([C:7]#[N:8])[C:5]=1[C:12]#[N:13])([O-])=O.N([O-])=O.[Na+].C(=O)([O-])[O-].[K+].[K+].ClC[Si](C)(C)C.Cl>CN(C)C(=O)C.CN1CCCC1=O>[C:12](#[N:13])[C:5]1[C:6](=[CH:9][CH:10]=[CH:11][CH:4]=1)[C:7]#[N:8]
Reactant: N#Cc1cccc([N+](=O)[O-])c1C#N
Agent: C[Si](C)(C)CCl
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CN1CCCC1=O
Solvent: CC(=O)N(C)C
Product: N#Cc1ccccc1C#N
Temperature: 165 °C
Reaction time: 0.67 h
Yield: 134.2 %

Procedure:
In 180 ml of an N,N-dimethylacetamide/1-methyl-2-pyrrolidone (=1/1 volume ratio) mixed solvent were dissolved 30 g of 3-nitrophthalonitrile, to which 11.97 g of sodium nitrite were added. The mixture was stirred at 165° C. for 40 minutes. After being cooled to room temperature, the mixture was added with 16.8 g of potassium carbonate, which was further stirred at 150° C. for 40 minutes and thereafter cooled to 40° C. Then, 25 g of chloromethyltrimethylsilane were added dropwise. After the addition, the mixture was stirred for 28 hours while maintaining the reaction temperature at 80°-90° C. The reaction vessel was then cooled to room temperature and 350 ml of dilute hydrochloric acid was added. The mixture was extracted with 1.5 liters of toluene. The organic layer was washed well with water and water was removed with magnesium sulfate. Thereafter, toluene was removed by distillation and the residue was purified with a toluene/silica gel column to obtain 29.8 g (yield: 74.7%) of a compound having the above-described formula (XV).