Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O.Cl.C(N1CC(C2C=CC([Cl:37])=C(Cl)C=2)(CCN2CCC(O)(C3C=CC=CC=3)CC2)[O:13]CC1=O)C1C=CC=CC=1.[CH2:40]([N:47]1[CH2:52][C:51]([CH2:61][CH2:62][N:63]2[CH2:68][CH2:67][C:66]([C:70]3[CH:75]=[CH:74][CH:73]=[CH:72][CH:71]=3)(O)[CH2:65][CH2:64]2)([C:53]2[CH:58]=[CH:57][C:56]([Cl:59])=[C:55]([Cl:60])[CH:54]=2)[O:50][CH2:49][C:48]1=[O:76])[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1.Cl.FC(F)(F)C(O)=O.[CH2:85]([O:87][C:88]([NH:90]C1(C2C=CC=CC=2)CCNCC1)=[O:89])[CH3:86].C([O-])([O-])=O.[K+].[K+].Cl>CN(C=O)C.C(Cl)Cl.CCOCC.O>[OH2:13].[ClH:37].[CH2:40]([N:47]1[CH2:52][C:51]([CH2:61][CH2:62][N:63]2[CH2:64][CH2:65][C:66]([NH:90][C:88]([O:87][CH2:85][CH3:86])=[O:89])([C:70]3[CH:71]=[CH:72][CH:73]=[CH:74][CH:75]=3)[CH2:67][CH2:68]2)([C:53]2[CH:58]=[CH:57][C:56]([Cl:59])=[C:55]([Cl:60])[CH:54]=2)[O:50][CH2:49][C:48]1=[O:76])[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1
Reactant: CCOC(=O)NC1(c2ccccc2)CCNCC1
Reactant: O=C1COC(CCN2CCC(O)(c3ccccc3)CC2)(c2ccc(Cl)c(Cl)c2)CN1Cc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)NC1(c2ccccc2)CCN(CCC2(c3ccc(Cl)c(Cl)c3)CN(Cc3ccccc3)C(=O)CO2)CC1
Temperature: 90 °C
Reaction time: 0.5 h
Yield: 83.2 %

Procedure:
A mixture of 1.1 g of the compound obtained in step B of EXAMPLE 14, 1 g of 4-(ethoxycarbonylamino)-4-phenylpiperidine trifluoroacetate and 0.7 g of K2CO3 in 3 ml of DMF is heated at 80-100° C. for 2 hours. After cooling to RT, the reaction mixture is poured into water and stirred for 30 minutes and the precipitate formed is wrung, washed with water and dried under vacuum at 60° C. The precipitate is chromatographed on silica H using a DCM/MeOH mixture (from 100/1; v/v to 100/4.5; v/v) as the eluent. The product obtained is dissolved in DCM, a saturated solution of hydrochloric acid in ether is added until the pH is 1, and the precipitate formed is wrung to give 0.52 g of the expected product. M.p.=148-150° C.
Reaction SMILES: [CH:1]1([CH2:7][O:8][C:9]2[CH:10]=[CH:11][C:12]3[CH2:18][CH2:17][CH2:16][C:15]([C:19]([O:21]C)=[O:20])=[CH:14][C:13]=3[CH:23]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+].Cl>CO.C1COCC1>[CH:1]1([CH2:7][O:8][C:9]2[CH:10]=[CH:11][C:12]3[CH2:18][CH2:17][CH2:16][C:15]([C:19]([OH:21])=[O:20])=[CH:14][C:13]=3[CH:23]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)C1=Cc2cc(OCC3CCCCC3)ccc2CCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)C1=Cc2cc(OCC3CCCCC3)ccc2CCC1
Temperature: 50 °C
Reaction time: 6 h
Yield: 95.6 %

Procedure:
To methyl 2-cyclohexylmethyloxy-6,7-dihydro-5H-benzocycloheptene-8-carboxylate (425 mg, 1.35 mmol) dissolved in a mixed solvent of methanol (5 ml) and THF (5 ml) was added a 1N aqueous solution of sodium hydroxide (4 ml), and the resulting mixture was stirred at 50° C. for 6 hours. The reaction mixture was mixed with 1 N hydrochloric acid (4 ml) at 0° C., was concentrated under reduced pressure and was mixed with water, and an insoluble material was collected by filtration. The insoluble material was washed with water and was dried under reduced pressure to obtain 2-cyclohexylmethyloxy-6,7-dihydro-5H-benzocycloheptene-8-carboxylic acid (389 mg, 1.29 mmol, 96%).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([N:10]([CH3:12])[CH3:11])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[H-].[H-].[H-].[H-].[Li+].[Al+3].II>C1COCC1>[NH2:5][CH2:4][C:3]1[CH:6]=[CH:7][C:8]([N:10]([CH3:11])[CH3:12])=[CH:9][C:2]=1[Cl:1]
Reactant: CN(C)c1ccc(C#N)c(Cl)c1
Agent: II
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: CN(C)c1ccc(CN)c(Cl)c1
Reaction time: 0.17 h

Procedure:
To a solution of 2-chloro-4-(dimethylamino)benzonitrile (0.76 g, 4.21 mmol) in THF (5 mL) was added 1M LiAlH4/I2 in THF (8.41 ml, 8.41 mmol, as prepared in Step 2 of Intermediate 3). The mixture was stirred for 10 min, at which time LCMS indicated the formation of the desired product. Water (15 mL) was added to the mixture, which was acidified to pH=2 with 6N HCl. The aqueous layer was separated and washed with Et2O (2×25 mL). The aqueous layer was then basified with 6N NaOH, and extracted with Et2O (3×30 mL). The organics were dried over Na2SO4. The ether layer was evacuated to ⅓ volume at which time 8 mL of 1M HCl in ether solution was added. After stirring for 10 minutes, solids precipitated from solution. The solids were filtered, washed with ether and dried to afford the title compound (1.0 g, 92%) as a light yellow solid. MS (ES+): m/e 185.0 [M+H]+.
Reaction SMILES: OO.C([OH:5])C.[C:6]([C:8]1[C:9]([NH:14][C:15](=O)[CH2:16][O:17][CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)=[N:10][CH:11]=[CH:12][CH:13]=1)#[N:7].Cl>[OH-].[Na+].O>[F:26][C:23]1[CH:24]=[CH:25][C:20]([CH2:19][CH2:18][O:17][CH2:16][C:15]2[NH:7][C:6](=[O:5])[C:8]3[CH:13]=[CH:12][CH:11]=[N:10][C:9]=3[N:14]=2)=[CH:21][CH:22]=1
Reactant: CCO
Reactant: N#Cc1cccnc1NC(=O)COCCc1ccc(F)cc1
Agent: Cl
Agent: OO
Agent: [Na+]
Solvent: O
Product: O=c1[nH]c(COCCc2ccc(F)cc2)nc2ncccc12

Procedure:
Hydrogen peroxide (3% in H2O, 2.8 ml) and ethanol (0.6 ml) were added to a suspension of N-(3-cyano-pyridin-2-yl)-2-[2-(4-fluoro-phenyl)-ethoxy]-acetamide (900 mg, 3 mmol) in 5N NaOH (11 ml), and the mixture was heated to reflux (4 h). Upon cooling, the solution was diluted with water and acidified (HCl, pH ˜3). The precipitated title compound was filtered off, triturated with tert-butyl methyl ether, and dried. MS: m/e=300.3 [M+H+], 1H NMR (d6-DMSO): 2.89 (t, 2H), 3.77 (t, 2H), 4.45 (s, 2H), 7.04-7.12 (m, 2H), 7.28-7.33 (m, 2H), 7.54 (dd, 1H), 8.50 (d, 1H), 8.95 (d, 1H), 12.45 (bs, 1H).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]([NH:11][C:12](=[O:19])OCC(Cl)(Cl)Cl)[CH:8]=[CH:9][CH:10]=1)(=[O:3])[CH3:2].[C:20]1([C:26]2[N:27]=[C:28]([N:31]3[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]3)[S:29][CH:30]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(N(C(C)C)CC)(C)C.CS(C)=O>O>[C:1]([NH:4][C:5]1[CH:6]=[C:7]([NH:11][C:12]([N:34]2[CH2:35][CH2:36][N:31]([C:28]3[S:29][CH:30]=[C:26]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[N:27]=3)[CH2:32][CH2:33]2)=[O:19])[CH:8]=[CH:9][CH:10]=1)(=[O:3])[CH3:2]
Reactant: c1ccc(-c2csc(N3CCNCC3)n2)cc1
Reactant: CC(=O)Nc1cccc(NC(=O)OCC(Cl)(Cl)Cl)c1
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CC(=O)Nc1cccc(NC(=O)N2CCN(c3nc(-c4ccccc4)cs3)CC2)c1
Yield: 33.6 %

Procedure:
A solution of 2,2,2-trichloroethyl [3-(acetylamino)phenyl]carbamate (200 mg, 0.614 mmol), 1-(4-phenyl-1,3-thiazol-2-yl)piperazine (150 mg, 0.614 mmol), diisopropylethylamine (0.107 ml, 0.614 mmol) and dimethylsulfoxide (4 ml) was stirred at 70° C. for 12 hours, the reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was recrystallized from chloroform to obtain the desired product (87.0 mg, 33.6%) as a solid.
Reaction SMILES: [NH2:1][CH:2]([C:5]1[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][C:6]=1[CH2:7][N:8]([CH2:15][C:16]1[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[C:18]([C:26]([F:29])([F:28])[F:27])[CH:17]=1)[C:9]1[N:10]=[N:11][N:12]([CH3:14])[N:13]=1)[CH2:3][CH3:4].[N:38]1[CH:43]=[CH:42][CH:41]=[C:40]([CH:44]=O)[CH:39]=1.[BH4-].[Na+]>C(O)C>[F:28][C:26]([F:29])([F:27])[C:18]1[CH:17]=[C:16]([CH:21]=[C:20]([C:22]([F:24])([F:23])[F:25])[CH:19]=1)[CH2:15][N:8]([CH2:7][C:6]1[CH:30]=[C:31]([C:34]([F:37])([F:36])[F:35])[CH:32]=[CH:33][C:5]=1[CH:2]([NH:1][CH2:44][C:40]1[CH:39]=[N:38][CH:43]=[CH:42][CH:41]=1)[CH2:3][CH3:4])[C:9]1[N:10]=[N:11][N:12]([CH3:14])[N:13]=1
Reactant: CCC(N)c1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1nnn(C)n1
Reactant: O=Cc1cccnc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CCC(NCc1cccnc1)c1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1nnn(C)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 864.6 %

Procedure:
To a solution of N-[2-(1-aminopropyl)-5-(trifluoromethyl)benzyl]-N-[3,5-bis(trifluoromethyl)benzyl]-2-methyl-2H-tetrazol-5-amine (60.0 mg, 0.01 mmoles) in ethanol (0.85 mL) was added 3-pyridinecarboxaldehyde (26.0 mg, 0.122 mmoles) and the reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was cooled to 0° C. and sodium borohydride (10.0 mg, 0.133 mmoles) was added in one portion. The reaction mixture was stirred in ice bath for 2 hours and then at room temperature for overnight. The reaction mixture was concentrated to remove ethanol and the residue was taken up in ethyl acetate and water. The aqueous layer was extracted with ethyl acetate (2×) and the combined organic layer was washed with brine, dried over sodium sulfate and concentrated. The crude product was purified using silica gel chromatography on the ISCO Combiflash system with a 1-9% methanol in dichloromethane gradient to yield the title compound (54.6 mg, 78% yield) as colorless gum.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6](=[O:12])[O:7]2.Br[CH2:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[CH2:21]([O:20][C:18](=[O:19])[CH2:17][CH2:16][CH2:15][CH2:14][O:1][C:2]1[C:3]2[CH:4]=[CH:5][C:6](=[O:12])[O:7][C:8]=2[CH:9]=[CH:10][CH:11]=1)[CH3:22]
Reactant: O=c1ccc2c(O)cccc2o1
Reactant: CCOC(=O)CCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CCOC(=O)CCCCOc1cccc2oc(=O)ccc12
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of 2.25 g (18.6 mmol) of 5-hydroxycoumarin, 4.2 g (20 mmol) of ethyl 5-bromovalerate, 7.0 g (50 mmol) of anhydrous, granular potassium carbonate, and 10 mL of dimethyl sulfoxide was stirred at room temperature for 24 hr. The resulting slurry was filtered with suction and the solids washed well with ethyl acetate. The filtrate and washes were combined and poured into water and the mixture was worked-up with ethyl acetate in the usual manner. The semi-solid residue was triturated and washed with hexane giving 2.36 g (44%) of 5-[(2-oxo-2H-1-benzopyran-5-yl)oxy]pentanoic acid ethyl ester as a tan solid.
Reaction SMILES: [C:1]([OH:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.C([O-])(=O)C.[Zn+2:14].C([O-])(=O)C.O.N>O>[C:1]([O-:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.[Zn+2:14].[C:1]([O-:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1
Reactant: O=C(O)c1cccnc1
Agent: CC(=O)[O-]
Agent: N
Agent: [Zn+2]
Solvent: O
Product: O=C([O-])c1cccnc1
Temperature: 80 °C
Yield: 47.7 %

Procedure:
5.0 g of nicotinic acid was dissolved in 100 ml of deionized water with stirring in a hot bath. Similarly, 4.5 g of zinc acetate.2H2O was dissolved in 100 ml of deionized water in a hot bath, and both were mixed with vigorous stirring. Subsequently, ammonia water (1:1 mixture of 25% ammonia water and distilled water) was added to adjust the pH to 8.5. The mixture was heated in a hot bath of about 80° C. for 10 minutes to complete the reaction, was continuously applied to concentrate the mixture, then being evaporated to about 20 ml. After cooling in a refrigerator, the precipitate was filtrated with a No. 5B filter paper, and washed with deionized water. The obtained material was dissolved with heating in 200 ml of deionized water, followed by concentration to 20 ml. The concentrate was cooled at room temperature, and washed three times with deionized water. The obtained material was dried sufficiently at 65° C. in an electric oven to obtain 3.0 g of zinc nicotinate (hereinafter abbreviated as Compound A).
Reaction SMILES: [O:1]=[C:2]1[C:10]2[NH:9][CH:8]=[C:7]([C:11]([O:13][CH3:14])=[O:12])[C:6]=2[CH2:5][CH2:4][CH2:3]1.[CH3:15]N(C=O)C.CI>O>[CH3:15][N:9]1[C:10]2[C:2](=[O:1])[CH2:3][CH2:4][CH2:5][C:6]=2[C:7]([C:11]([O:13][CH3:14])=[O:12])=[CH:8]1
Reactant: COC(=O)c1c[nH]c2c1CCCC2=O
Reactant: CN(C)C=O
Solvent: CI
Solvent: O
Product: COC(=O)c1cn(C)c2c1CCCC2=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 95 %

Procedure:
To a solution of methyl 7-oxo-4,5,6,7-tetrahydro-1H-indole-3-carboxylate (300 mg, 1.55 mmol) in dry DMF (5 mL) K2CO3 (429 mg, 3.10 mmol) and methyl iodide (0.193 mL, 3.10 mmol) were added. The reaction was stirred at room temperature for 3 h, then H2O was added (100 mL) and the product extracted with DCM (3×30 mL). The organic fractions were dried over Na2SO4, filtered, and concentrated in vacuo to give 305 mg (yield: 95%) as light yellow solid.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7]([CH3:10])([CH3:9])[CH3:8])[N:6]=1.C(O[CH:14]=[C:15]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:16]([O:18][CH2:19][CH3:20])=[O:17])C>>[C:21]([C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:14][NH:1][C:2]1[S:3][CH:4]=[C:5]([C:7]([CH3:10])([CH3:9])[CH3:8])[N:6]=1)([O:23][CH2:24][CH3:25])=[O:22]
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: CC(C)(C)c1csc(N)n1
Product: CCOC(=O)C(=CNc1nc(C(C)(C)C)cs1)C(=O)OCC

Procedure:
2-Amino-4-(2-methyl-2-propyl)thiazole (15.6 g., 0.1 mole) and diethyl ethoxymethylenemalonate (23.8 g., 0.11 mole) were combined and heated on a steam bath for 2 hours. 2-(2,2-Dicarbethoxyethenylamino)-4-(2-methyl-2-propyl)thiazole was obtained as a wet solid on cooling and used directly in the next step.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[C:10]([N:17]3[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][O:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[CH2:19][CH2:18]3)[CH:11]=[CH:12][C:13]=2[N+:14]([O-])=O)[CH2:4][CH2:3]1.[C:33]([C:35]1[O:39][C:38]([C:40](O)=[O:41])=[CH:37][CH:36]=1)#[N:34].C(Cl)(=O)C(Cl)=O.CCN(C(C)C)C(C)C>[Pd].CCOC(C)=O.ClCCl>[C:33]([C:35]1[O:39][C:38]([C:40]([NH:14][C:13]2[CH:12]=[CH:11][C:10]([N:17]3[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][O:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[CH2:19][CH2:18]3)=[CH:9][C:8]=2[N:5]2[CH2:6][CH2:7][CH:2]([CH3:1])[CH2:3][CH2:4]2)=[O:41])=[CH:37][CH:36]=1)#[N:34]
Reactant: CC1CCN(c2cc(N3CCN(CCOC(=O)OC(C)(C)C)CC3)ccc2[N+](=O)[O-])CC1
Reactant: N#Cc1ccc(C(=O)O)o1
Agent: [Pd]
Agent: O=C(Cl)C(=O)Cl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC1CCN(c2cc(N3CCN(CCOC(=O)OC(C)(C)C)CC3)ccc2NC(=O)c2ccc(C#N)o2)CC1
Yield: 94.1 %

Procedure:
The procedure of Example 4, step (c) was followed using 156 mg (0.348 mmol) of carbonic acid tert-butyl ester 2-{4-[3-(4-methyl-piperidin-1-yl)-4-nitro-phenyl]-piperazin-1-yl}-ethyl ester (as prepared in the previous step), 78 mg of 10% palladium on carbon (50% by weight water), 52.5 mg (383 mmol) of 5-cyanofuran-2-carboxylic acid (as prepared in Example 1), 50.1 μL (0.575 mmol) of oxalyl chloride, and 121 μL (0.696 mmol) of DIEA. Chromatography on a 10-g silica SPE column with 5-20% EtOAc-dichloromethane afforded 176 mg (94%) of the title compound as a light yellow solid: 1H-NMR (CDCl3; 400 MHz): δ 9.60 (br s, 1H), 8.29 (d, 1H, J=8.9 Hz), 7.21, 7.24 (AB q, 2H, J=3.7 Hz), 6.79 (d, 1H, J=2.6 Hz), 6.71 (dd, 1H, J=8.9, 2.6 Hz), 4.23 (t, 2H, J=5.8 Hz), 3.16-3.19 (m, 4H), 2.97-3.00 (m, 2H), 2.67-2.75 (m, 8H), 1.82-1.84 (m, 4H), 1.50-1.65 (m, 1H), 1.46-1.58 (m, 2H, partially obscured by t-Bu peak), 1.49 (s, 9H), and 1.07 (d, 3H, J=6.2 Hz). Mass spectrum (ESI, m/z): Calcd. for C29H39N5O5, 538.3 (M+H) and 438.2 (M-BOC+2H), found 538.2, 438.2.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]([CH2:17][C:18]([F:21])([F:20])[F:19])[C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[C:7]([C:13]([F:16])([F:15])[F:14])[CH:6]=1.[CH3:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30][O:31][C:32]2[N:37]=[CH:36][C:35](O)=[CH:34][CH:33]=2)=[CH:26][CH:25]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>>[CH3:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30][O:31][C:32]2[N:37]=[CH:36][C:35]([O:1][CH2:2][CH2:3][N:4]([CH2:17][C:18]([F:19])([F:20])[F:21])[C:5]3[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[C:7]([C:13]([F:15])([F:16])[F:14])[CH:6]=3)=[CH:34][CH:33]=2)=[CH:26][CH:25]=1
Reactant: COc1ccc(COc2ccc(O)cn2)cc1
Reactant: N#Cc1ccc(N(CCO)CC(F)(F)F)cc1C(F)(F)F
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: COc1ccc(COc2ccc(OCCN(CC(F)(F)F)c3ccc(C#N)c(C(F)(F)F)c3)cn2)cc1

Procedure:
Synthesized as described in Example 27B from 4-[(2-hydroxyethyl)(2,2,2-trifluoroethyl)amino]-2-(trifluoromethyl)benzonitrile (Example 15B) and 6-({[4-(methyloxy)phenyl]methyl}oxy)-3-pyridinol (step B above) with the following exceptions: PPh3 was used instead of PBu3, and the reaction was started at 0° C., then allowed to proceed at rt: 1H NMR (400 MHz, CDCl3) δ 7.76 (d, J=3.3 Hz, 1H), 7.68 (d, J=8.9 Hz, 1H), 7.37 (m, 2H; AA′XX′), 7.18 (d, J=2.7 Hz, 1H), 7.15 (dd, J=8.9, 3.1 Hz, 1H), 7.00 (dd, J=8.9, 2.7 Hz, 1H), 6.90 (m, 2H; AA′XX′), 6.72 (d, J=8.9 Hz, 1H), 5.23 (s, 2H), 4.20 (t, J=5.1 Hz, 2H; overlapping 4.19), 4.19 (q, J=8.6 Hz, 2H; overlapping 4.20), 3.99 (t, J=5.2 Hz, 2H), 3.81 (s, 3H).
Reaction SMILES: [C:1]([C:4]1[C:5](=[O:22])[N:6]([CH2:18][CH:19]([CH3:21])[CH3:20])[N:7]=[C:8]([C:10]2[CH:15]=[CH:14][C:13](C)=[C:12](F)[CH:11]=2)[CH:9]=1)([OH:3])=[O:2].C(N1C(=O)C(C(OC)=O)=CC(C2C=CC=CC=2)=N1)C(C)C>>[C:1]([C:4]1[C:5](=[O:22])[N:6]([CH2:18][CH:19]([CH3:20])[CH3:21])[N:7]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:9]=1)([OH:3])=[O:2]
Reactant: Cc1ccc(-c2cc(C(=O)O)c(=O)n(CC(C)C)n2)cc1F
Agent: COC(=O)c1cc(-c2ccccc2)nn(CC(C)C)c1=O
Product: CC(C)Cn1nc(-c2ccccc2)cc(C(=O)O)c1=O
Yield: 82.5 %

Procedure:
Following the procedure of Example 1 (7), 2-isobutyl-4-methoxycarbonyl-6-phenyl-2H-pyridazin-3-one was reacted to yield the title compound as colorless fine-needles (yield: 82.5%).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:11]=[C:10]2[N:6]([N:7]=[C:8]([CH2:49][CH3:50])[N:9]2CC2C=CC(C3C=CC=CC=3C3N(C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)N=NN=3)=CC=2)[N:5]=1)[CH3:2].[CH2:51]([O:53][C:54]1[N:55]([CH2:64][C:65]2[CH:70]=[CH:69][C:68]([C:71]3[CH:76]=[CH:75][CH:74]=[CH:73][C:72]=3[C:77]3[N:81]([C:82]([C:95]4[CH:100]=[CH:99][CH:98]=[CH:97][CH:96]=4)([C:89]4[CH:94]=[CH:93][CH:92]=[CH:91][CH:90]=4)[C:83]4[CH:88]=[CH:87][CH:86]=[CH:85][CH:84]=4)[N:80]=[N:79][N:78]=3)=[CH:67][CH:66]=2)[N:56]2[C:60]([CH:61]=1)=[N:59][C:58]([CH2:62][CH3:63])=[N:57]2)[CH3:52]>>[CH2:51]([O:53][C:54]1[N:55]([CH2:64][C:65]2[CH:66]=[CH:67][C:68]([C:71]3[CH:76]=[CH:75][CH:74]=[CH:73][C:72]=3[C:77]3[N:81]([C:82]([C:83]4[CH:88]=[CH:87][CH:86]=[CH:85][CH:84]=4)([C:95]4[CH:96]=[CH:97][CH:98]=[CH:99][CH:100]=4)[C:89]4[CH:90]=[CH:91][CH:92]=[CH:93][CH:94]=4)[N:80]=[N:79][N:78]=3)=[CH:69][CH:70]=2)[N:56]2[C:60]([CH:61]=1)=[N:59][C:58]([CH2:62][CH3:63])=[N:57]2)[CH3:52].[CH2:1]([O:3][C:4]1[CH:11]=[C:10]2[N:6]([N:7]=[C:8]([CH2:49][CH3:50])[NH:9]2)[N:5]=1)[CH3:2]
Reactant: CCOc1cc2n(Cc3ccc(-c4ccccc4-c4nnnn4C(c4ccccc4)(c4ccccc4)c4ccccc4)cc3)c(CC)nn2n1
Agent: CCOc1cc2nc(CC)nn2n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: CCOc1cc2[nH]c(CC)nn2n1

Procedure:
In the same manner as described in Example 66, 1.02 g of 6-ethoxy-2-ethyl-1-[[2'-(N-triphenylmethyl-tetrazol-5-yl)biphenyl-4-yl]methyl]-1H-pyrazolo[1,5-b][1,2,4]triazole (compound 77a) and 1.22 g of 6-ethoxy-2-ethyl-5-[[2'-(N-triphenylmethyl-tetrazol-5-yl)biphenyl-4-yl]methyl]-5H-pyrazolo[1,5-b][1,2,4]triazole (compound 77b) were obtained from 1.80 g of 6-ethoxy-2-ethyl-1H-pyrazolo[1,5-b][1,2,4]triazole.
Reaction SMILES: C(OC([N:8]1[CH2:20][CH2:19][C:11]2([O:15][N:14]=[C:13]([C:16](O)=[O:17])[CH2:12]2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(Cl)CCl.C1C=CC2N(O)N=[N:31]C=2C=1.C(N)CC1C=CC=CC=1>CN(C=O)C.CCOC(C)=O>[O:15]1[C:11]2([CH2:19][CH2:20][NH:8][CH2:9][CH2:10]2)[CH2:12][C:13]([C:16]([NH2:31])=[O:17])=[N:14]1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CC(C(=O)O)=NO2
Reactant: On1nnc2ccccc21
Agent: NCCc1ccccc1
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: NC(=O)C1=NOC2(CCNCC2)C1
Reaction time: 4 h

Procedure:
To a solution of 8-(tert-butoxycarbonyl)-1-oxa-2,8-diazaspiro[4.5]dec-2-ene-3-carboxylic acid (300 mg, 1.06 mmol), EDC (242 mg, 1.26 mmol), HOBt (171 mg, 1.26 mmol) in DMF (4 mL) was added phenethylamine (159 μL, 1.26 mmol). After 4 h at room temperature, the reaction mixture was diluted with EtOAc (10 mL) and washed with H2O (1×5 mL) and brine (1×5 mL). The organic layer was dried over Na2SO4, filtered, and concentrated. The crude oil was taken up in CH2Cl2 (4 mL) and treated with TFA (2 mL). The reaction mixture was concentrated and the crude oil purified by reverse-phase chromatography (10-75% MeCN/H2O with 0.05% TFA) to give the N2-phenylethyl)-1-oxa-2,8-diazaspiro[4.5]dec-2-ene-3-carboxamide confirmed by MS (ESI+): cal'd [M+H]+ 288.2, obs'd 288.2.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH:9]=[N:10]O)=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1.[NH4+].[OH-].C([O-])(=O)C.[NH4+]>[Zn].CCO>[CH3:1][C:2]1[C:3]([CH2:9][NH2:10])=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: Cc1cnc(C=NO)c(C)c1
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cnc(CN)c(C)c1
Temperature: 55 °C
Reaction time: 20 h

Procedure:
3,5-Dimethyl-pyridine-2-carbaldehyde oxime (3.15 g, 21.0 mmol), NH4OH (105 mL), ammonium acetate (3.24 g, 42.0 mmol), zinc dust (8.24 g, 126 mol) and EtOH (35 mL) were combined and warmed to 55° C. The mixture was stirred for 20 h, then cooled to ambient temperature and filtered through a celite pad to remove the zinc. The celite pad was thoroughly washed with methanol. The filtrate was concentrated in vacuo and the resulting aqueous mixture was extracted with CH2Cl2 (8×250 mL). The aqueous layer was basified to pH 14 with 10 N NaOH and extracted further with CH2Cl2/i-PrOH, 95:5 (5×250 mL). The combined organic layers were dried over Na2SO4 and concentrate in vacuo. Purification by flash chromatography on silica gel (CH2Cl2/MeOH/NH4OH, 95:4:1) afforded C-(3,5-dimethyl-pyridin-2-yl)-methylamine as an orange oil. 1H NMR (CDCl3) δ 2.26 (s, 3H), 2.28 (s, 3H), 3.91 (s, 2H), 7.24 (s, 1H), 8.23 (s, 1H).
Reaction SMILES: [CH:1]#[CH:2].[Cl:3][SiH:4]([CH:6]([SiH:11]([Cl:13])[Cl:12])[Si:7]([Cl:10])([Cl:9])[Cl:8])[Cl:5]>>[Cl:5][Si:4]1([Cl:3])[CH:2]=[CH:1][Si:11]([Cl:12])([Cl:13])[CH:6]1[Si:7]([Cl:8])([Cl:10])[Cl:9]
Reactant: C#C
Reactant: Cl[SiH](Cl)C([SiH](Cl)Cl)[Si](Cl)(Cl)Cl
Product: Cl[Si](Cl)(Cl)C1[Si](Cl)(Cl)C=C[Si]1(Cl)Cl
Reaction time: 10 h
Yield: 81.4 %

Procedure:
Hydrosilation of acetylene with bis(dichlorosilyl)trichlorosilylmethane in the presence of H2PtCl6. To a 50 ml, three-necked, dried, flask equipped with a magnetic stirrer was added 200 μl of a 0.1 M H2PtCl6 /isopropyl alcohol (IPA) solution. The flask was placed under dry nitrogen atmosphere and the IPA removed under vacuum. Then, 6.29 g of bis(dichlorosilyl)trichlorosilylmethane and 25 ml of dried benzene were added to the flask forming a solution. The solution was maintained at reflux temperature and acetylene gas fed into the solution at a rate of 90 ml per minute for 10 hours. The resulting products were vacuum distilled at 67 Pa to yield 6.36 g of 1,1,3,3-tetrachloro-2-trichlorosilyl-1,3-disilacyclopent-4-ene (TCD-GC are 81.4%) (TCD-GC =gas chromatography using a thermal conductivity detector) and 1,1,3,3-tetrachloro-2-trichlorosilyl-1,3-disilacyclopentane (TCD-GC 4.2%) as a mixture. The structure of 1,1,3,3-tetrachloro-2-trichlorosilyl-1,3-disilacyclopent-4-ene was confirmed by 1H-NMR (CDCl3, ppm): 1.52 (s, 1H, SiCHSi), 7.42 (s, 2H, CH=CH).
Reaction SMILES: [CH3:1][N:2]([CH3:32])[C:3]([C:5]1[C:13]2=[C:14]([C:18]3[CH:23]=[CH:22][C:21]([O:24]CC4C=CC=CC=4)=[CH:20][CH:19]=3)[C:15]([CH2:16][CH3:17])=[C:11]3[N:12]2[C:7](=[CH:8][CH:9]=[CH:10]3)[CH:6]=1)=[O:4]>C(O)C>[CH3:32][N:2]([CH3:1])[C:3]([C:5]1[C:13]2=[C:14]([C:18]3[CH:19]=[CH:20][C:21]([OH:24])=[CH:22][CH:23]=3)[C:15]([CH2:16][CH3:17])=[C:11]3[N:12]2[C:7](=[CH:8][CH:9]=[CH:10]3)[CH:6]=1)=[O:4]
Reactant: CCc1c(-c2ccc(OCc3ccccc3)cc2)c2c(C(=O)N(C)C)cc3cccc1n32
Solvent: CCO
Product: CCc1c(-c2ccc(O)cc2)c2c(C(=O)N(C)C)cc3cccc1n32
Yield: 113 %

Procedure:
4-Ethyl-3-(4-benzyloxyphenyl)pyrrolo[2,1,5-cd]indolizine-2-carboxylic acid dimethlamide was hydrogenated by the general synthetic principles outlined in example 12, to afford 4-ethyl-3-(4-hydroxyphenyl)pyrrolo[2,1,5-cd]indolizine-2-carboxylic acid dimethylamide as a yellow gum in 113% yield (ethanol incl.). 1H-NMR (CDCl3, 300 MHz) δ: 1.43 (t, 3H); 2.56 (s, 3H); 2.98 (s, 3H); 3.19 (q, 2H); 7.00 (d, 2H); 7.33 (s, 1H); 7.49 (d, 2H); 7.68 (dd, 1H); 7.96 (d, 2H).