Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[C:9][CH:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]2)=[C:6]([Cl:23])[N:5]=[CH:4][N:3]=1.CC(C)([O-])C.[K+].C1OCCOCCOCCOCCOCCOC1>C1(C)C=CC=CC=1.C(OCC)(=O)C>[Cl:23][C:6]1[C:7]2[CH:8]=[C:9]([CH:10]3[CH2:11][CH2:12][N:13]([C:16]([O:18][C:19]([CH3:20])([CH3:22])[CH3:21])=[O:17])[CH2:14][CH2:15]3)[NH:1][C:2]=2[N:3]=[CH:4][N:5]=1
Reactant: CC(C)(C)OC(=O)N1CCC(C#Cc2c(N)ncnc2Cl)CC1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC(c2cc3c(Cl)ncnc3[nH]2)CC1
Temperature: 65 °C

Procedure:
To a solution of Example 1B (250 mg, 0.74 mmol), in toluene (5 mL), was added potassium tert-butoxide (249 mg, 2.22 mmol) followed by 18-crown-6 (15 mg, 0.057 mmol) and the mixture was heated under nitrogen at 65° C. for 12 hours. The mixture was cooled to room temperature, diluted with ethyl acetate, washed with water and brine, dried over sodium sulfate, filtered, concentrated and purified by column chromatography (silica gel, 40% ethyl acetate in hexane) to afford the title compound. LCMS: 337.1 (M+1)+.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[C:14]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2.Br[C:17]([CH3:22])([CH3:21])[C:18](Br)=[O:19].[Cl-].[Cl-].[Cl-].[Al+3]>C(=S)=S>[CH3:21][CH:17]1[C:18](=[O:19])[C:5]2=[CH:4][C:3]3[C:2]([CH3:15])([CH3:1])[C:14]4[C:9]([C:8]=3[CH:7]=[C:6]2[CH2:22]1)=[CH:10][CH:11]=[CH:12][CH:13]=4
Reactant: CC1(C)c2ccccc2-c2ccccc21
Reactant: CC(C)(Br)C(=O)Br
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: CC1Cc2cc3c(cc2C1=O)C(C)(C)c1ccccc1-3
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.8 %

Procedure:
A 2000 mL round flask was charged with 9,9-dimethyl-9H-fluorene (50 g, 257.4 mmol) and 2-bromo-2-methylpropanoyl bromide (61.0 g, 265.1 mmol), and then dissolved with 700 mL of carbon disulfide inputted thereto. Then, the reactor was cooled with ice water. Under nitrogen atmosphere, aluminum trichloride (85.8 g, 643.4 mmol) was slowly added thereto in ten lots over 2 hours. The mixture was stirred at room temperature for 8 hours, and then the reaction was terminated by addition of 500 mL of distilled water. The resultant mixture was diluted by adding 500 mL of methyl chloride and washed with 500 mL of distilled water three times. The organic layer was dried over magnesium sulfate, followed by removal of volatile materials and drying, and then recrystallized by using methyl chloride and methanol, to thereby obtain 64.0 g of 2,9,9-trimethyl-2,3-dihydrocyclopenta[b]fluoren-1(9H)-one (yield: 94.8%) as white solid.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[O:10][CH2:11][C:12]([OH:14])=O.ClC(OCC)=O.[Cl:21][C:22]1[CH:23]=[C:24]([CH:32]=[CH:33][C:34]=1[Cl:35])[CH2:25][N:26]([CH3:31])[CH2:27][CH2:28][CH2:29][NH2:30]>C(Cl)(Cl)Cl>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[O:10][CH2:11][C:12]([NH:30][CH2:29][CH2:28][CH2:27][N:26]([CH2:25][C:24]1[CH:32]=[CH:33][C:34]([Cl:35])=[C:22]([Cl:21])[CH:23]=1)[CH3:31])=[O:14]
Reactant: O=C(O)COc1nc2ccccc2o1
Reactant: CN(CCCN)Cc1ccc(Cl)c(Cl)c1
Agent: CCOC(=O)Cl
Solvent: ClC(Cl)Cl
Product: CN(CCCNC(=O)COc1nc2ccccc2o1)Cc1ccc(Cl)c(Cl)c1
Temperature: -15 °C
Yield: 42.3 %

Procedure:
To the solution of 54 mg (0.28 mmol) (1,3-benzoxazol-2-yloxy)acetic acid in 3 ml chloroform 28 mg (0.28 mmol) 4-methylmorpholine is added. The mixture is cooled to −15° C., 30 mg (0.28 mmol) ethyl chloroformate is dropped to it and the mixture is stirred under cooling for 15 minutes. Then the solution of 83 mg (0.34 mmol) N-(3,4-dichlorobenzyl)-N-(methyl)propane-1,3-diamine in 2 ml chloroform is added and the reaction mixture is stirred for 30 min under cooling and 1 hour at room temperature. The chloroform solution is extracted with 2×10 ml water, the organic phase is dried over sodium sulfate and evaporated in vacuum to obtain 50 mg title compound as an oil. LC/MS[MH+]=422 (C20H21Cl2N3O3 422.31).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([O:17][CH2:18][C:19]([O:21]CC)=O)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:24][O:25][CH2:26][CH2:27][NH2:28]>>[CH3:24][O:25][CH2:26][CH2:27][NH:28][C:19](=[O:21])[CH2:18][O:17][CH:14]1[CH2:13][CH2:12][N:11]([C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:10])[CH2:16][CH2:15]1
Reactant: COCCN
Reactant: CCOC(=O)COC1CCN(C(=O)OCc2ccccc2)CC1
Product: COCCNC(=O)COC1CCN(C(=O)OCc2ccccc2)CC1

Procedure:
A mixture of ethyl 1-benzyloxycarbonylpiperidine-4-oxyacetate (2.4 g) and 2-methoxyethylamine (5 ml) was heated on a steam bath for 6 hours. The amine was evaporated under reduced pressure and the residue was dissolved in ethyl acetate (10 ml), washed sequentially with dilute citric acid solution (5 ml), water (5 ml) and saturated aqueous sodium chloride (5 ml), dried (MgSO4) and concentrated. The residual oil was purified by flash column chromatography, eluting with hexane/ethyl acetate (1:3) to give N-2-methoxyethyl-1-benzyloxycarbonylpiperidine-4-oxyacetamide (500 mg) as a colourless oil. NMR: (d6DMSO): δ1.4-1.5(2H,m); 1.75-1.9(2H,m); 3.0-3.4(9H,m); 3.55(1H,m); 3.65-3.8(2H,m); 3.9(2H,s); 5.1(2H,s); 7.3(5H,m); 7.6(1H, br. t); m/e 351(M+H)+, 373 (M+Na)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH2:12][C:11](=O)[C:10]3[CH:14]=[C:15]([S:18][CH3:19])[CH:16]=[CH:17][C:9]=3[S:8][C:7]=2[CH:20]=1.C([OH:23])C.[BH4-].[Na+]>O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:12]3[CH2:11][CH:10]([OH:23])[CH:14]=[C:15]([S:18][CH3:19])[C:16]=3[CH:17]=[CH:9][S:8][C:7]=2[CH:20]=1
Reactant: COc1ccc2c(c1)Sc1ccc(SC)cc1C(=O)C2
Reactant: CCO
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Product: COc1ccc2c(c1)SC=CC1=C2CC(O)C=C1SC
Reaction time: 1.5 h

Procedure:
17.8 G. of 3-methoxy-8-(methylthio)-dibenzo[b,f]thiepin-10(11H)-one is suspended in 150 ml. of ethanol and reacted with 38 g. of sodium borohydride. The reaction mixture is stirred for 90 minutes, and subsequently treated with water and extracted with ether. The organic phase is washed with water, dried over magnesium sulfate and evaporated, whereby there is obtained 10,11-dihydro-3-methoxy-8-(methylthio)-dibenzo[d,f]thiepin-10-ol having a melting point of 122°-124°.
Reaction SMILES: [CH3:1][C:2]1([CH3:28])[N:7]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-])=O)[CH:10]=2)[C:6]2[CH:18]=[C:19]([C:21]3[CH:22]=[N:23][NH:24][C:25]=3[CH3:26])[S:20][C:5]=2[C:4](=[O:27])[NH:3]1>[Pt](=O)=O.C(O)C>[NH2:15][C:11]1[CH:10]=[C:9]([CH:14]=[CH:13][CH:12]=1)[CH2:8][N:7]1[C:6]2[CH:18]=[C:19]([C:21]3[CH:22]=[N:23][NH:24][C:25]=3[CH3:26])[S:20][C:5]=2[C:4](=[O:27])[NH:3][C:2]1([CH3:28])[CH3:1]
Reactant: Cc1[nH]ncc1-c1cc2c(s1)C(=O)NC(C)(C)N2Cc1cccc([N+](=O)[O-])c1
Agent: O=[Pt]=O
Solvent: CCO
Product: Cc1[nH]ncc1-c1cc2c(s1)C(=O)NC(C)(C)N2Cc1cccc(N)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 38.2 %

Procedure:
A mixture of 2,2-dimethyl-6-(5-methyl-1H-pyrazol-4-yl)-1-(3-nitrobenzyl)-2,3-dihydrothieno[3,2-d]pyrimidin-4(1H)-one (147 mg, 0.37 mmol), platinum(IV) oxide (15 mg) and ethanol (20 mL) was stirred at room temperature for 3 h under hydrogen atmosphere (1 atm). Then, the catalyst was removed by filtration. After removal of the solvent at reduced pressure, the residue was purified by column chromatography (Purif, silica gel, EtOAc to 90:10 EtOAc/MeOH), then crystallized from MeOH/EtOAc/hexane to give the title compound (52 mg, 38%) as a yellow solid:
Reaction SMILES: [CH2:1]([O:8][C:9]([C:18]1[CH:23]=[CH:22][C:21]([N:24]2[CH2:29][CH2:28][N:27]([C:30](=[O:33])[CH2:31]Br)[CH2:26][CH2:25]2)=[C:20](/[CH:34]=[CH:35]\[CH3:36])[CH:19]=1)([C:14]([F:17])([F:16])[F:15])[C:10]([F:13])([F:12])[F:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:37]1[C:46]2[C:41](=[N:42][CH:43]=[C:44]([C:47]3([CH3:54])[NH:51][C:50](=[O:52])[NH:49][C:48]3=[O:53])[CH:45]=2)[O:40][CH2:39][CH2:38]1>>[CH2:1]([O:8][C:9]([C:18]1[CH:23]=[CH:22][C:21]([N:24]2[CH2:29][CH2:28][N:27]([C:30](=[O:33])[CH2:31][N:49]3[C:48](=[O:53])[C:47]([C:44]4[CH:45]=[C:46]5[O:37][CH2:38][CH2:39][O:40][C:41]5=[N:42][CH:43]=4)([CH3:54])[NH:51][C:50]3=[O:52])[CH2:26][CH2:25]2)=[C:20]([CH:34]=[CH:35][CH3:36])[CH:19]=1)([C:14]([F:17])([F:16])[F:15])[C:10]([F:13])([F:12])[F:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C/C=C\c1cc(C(OCc2ccccc2)(C(F)(F)F)C(F)(F)F)ccc1N1CCN(C(=O)CBr)CC1
Reactant: CC1(c2cnc3c(c2)OCCO3)NC(=O)NC1=O
Product: CC=Cc1cc(C(OCc2ccccc2)(C(F)(F)F)C(F)(F)F)ccc1N1CCN(C(=O)CN2C(=O)NC(C)(c3cnc4c(c3)OCCO4)C2=O)CC1

Procedure:
(Z)-1-(4-{4-[2-(benzyloxy)-1,1,1,3,3,3-hexafluoropropan-2-yl]-2-(prop-1-en-1-yl)phenyl}piperazin-1-yl)-2-bromoethanone and 5-(2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-7-yl)-5-methylimidazolidine-2,4-dione were used for a similar reaction and treatment as Example 14-1, and the title compound was obtained as a yellow oil.
Reaction SMILES: [CH:1]1([C:4]2[S:8][C:7](=[NH:9])[N:6]([CH2:10][CH:11]3[CH2:15][CH2:14][CH2:13][O:12]3)[N:5]=2)[CH2:3][CH2:2]1.[CH2:16]([O:18][C:19]1[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=1[C:21](O)=[O:22])[CH3:17]>>[CH:1]1([C:4]2[S:8]/[C:7](=[N:9]\[C:21](=[O:22])[C:20]3[CH:24]=[CH:25][CH:26]=[CH:27][C:19]=3[O:18][CH2:16][CH3:17])/[N:6]([CH2:10][CH:11]3[CH2:15][CH2:14][CH2:13][O:12]3)[N:5]=2)[CH2:2][CH2:3]1
Reactant: N=c1sc(C2CC2)nn1CC1CCCO1
Reactant: CCOc1ccccc1C(=O)O
Product: CCOc1ccccc1C(=O)/N=c1\sc(C2CC2)nn1CC1CCCO1

Procedure:
The product from Example 2A and 2-ethoxybenzoic acid (Aldrich) were processed using the method described in Example 2B to afford the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 0.95-1.02 (m, 2H) 1.13-1.19 (m, 2H) 1.32 (t, J=7.02 Hz, 3 H) 1.65-1.73 (m, 1H) 1.79-1.90 (m, 2H) 1.92-2.00 (m, 1H) 2.30-2.37 (m, 1H) 3.64 (dd, J=13.73, 7.63 Hz, 1H) 3.77 (dd, J=14.34, 7.32 Hz, 1H) 4.07 (q, J=7.02 Hz, 2H) 4.21 (dd, J=13.12, 4.58 Hz, 1H) 4.32-4.39 (m, 1H) 4.44 (dd, J=13.43, 7.63 Hz, 1H) 6.98 (td, J=7.63, 0.92 Hz, 1H) 7.08 (d, J=7.93 Hz, 1H) 7.40-7.45 (m, 1H) 7.77 (dd, J=7.63, 1.83 Hz, 1H); MS (ESI+) m/z 374 (M+H)+.
Reaction SMILES: [C:1]([C:9]1[O:10][C:11]2[CH:30]=[CH:29][CH:28]=[CH:27][C:12]=2[C:13]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=2)=[CH:16][CH:15]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[O:32][C:33](=[O:43])[CH:34]([CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)O>>[C:1]([C:9]1[O:10][C:11]2[CH:30]=[CH:29][CH:28]=[CH:27][C:12]=2[C:13]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:21]=[CH:22][C:23]([O:26][CH:34]([CH2:36][C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[C:33]([OH:43])=[O:32])=[CH:24][CH:25]=2)=[CH:16][CH:15]=1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(c1ccccc1)c1oc2ccccc2c1-c1ccc(-c2ccc(O)cc2)cc1
Reactant: COC(=O)C(O)Cc1ccccc1
Product: O=C(c1ccccc1)c1oc2ccccc2c1-c1ccc(-c2ccc(OC(Cc3ccccc3)C(=O)O)cc2)cc1

Procedure:
The title compound was prepared from 4′-(2-benzoyl-benzofuran-3-yl)-biphenyl-4-ol, and 3-phenyllactic acid methyl ester, in substantially the same manner, as described in Example 1, steps g-h, and was obtained as a yellow solid, mp 159-161° C.; MS m/e 538 (M+);
Reaction SMILES: [Cl:1][C:2]1[C:11]([O:12][CH3:13])=[C:10]([Cl:14])[CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][CH2:6][C:7]2=O.[C-]#N.[Li+].[C:19](P(=O)(OCC)OCC)#[N:20]>O1CCCC1>[C:19]([CH2:13][O:12][C:11]1[C:2]([Cl:1])=[C:3]2[C:8](=[CH:9][C:10]=1[Cl:14])[CH:7]=[CH:6][CH2:5][CH2:4]2)#[N:20]
Reactant: CCOP(=O)(C#N)OCC
Reactant: COc1c(Cl)cc2c(c1Cl)CCCC2=O
Agent: [C-]#N
Agent: [Li+]
Solvent: C1CCOC1
Product: N#CCOc1c(Cl)cc2c(c1Cl)CCC=C2
Temperature: -15 °C
Reaction time: 0.5 h
Yield: 95 %

Procedure:
The product from Example 96 (0.2 g) was dissolved in tetrahydrofuran (15 ml), cooled to -15° C. and treated with lithium cyanide (20 mg) and diethyl cyanophosphonate (0.2 ml). After 30 minutes, the reaction was quenched with water and extracted with ethyl acetate. The organic layer was separated, dried and the solvent evaporated. The residue was dissolved in benzene (30 ml) and a catalytic amount of p-toluenesulfonic acid was added. The reaction was refluxed for 30 minutes, quenched with 5% sodium bicarbonate, and extracted with ether. The organic layer was separated, dried and the solvent evaporated in vacuo affording the desired product in 95% yield.
Reaction SMILES: [OH:1][C:2]1[C:3]([C:14](=[O:16])[CH3:15])=[CH:4][C:5]2[CH2:6][CH2:7][CH2:8][C:9]([CH3:13])([CH3:12])[C:10]=2[CH:11]=1.[Br:17]N1C(=O)CCC1=O>CN(C)C=O.O>[Br:17][C:11]1[C:10]2[C:9]([CH3:12])([CH3:13])[CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[C:3]([C:14](=[O:16])[CH3:15])[C:2]=1[OH:1]
Reactant: CC(=O)c1cc2c(cc1O)C(C)(C)CCC2
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)c1cc2c(c(Br)c1O)C(C)(C)CCC2
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 1-(3-hydroxy-5,5-dimethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-ethanone (Compound A-88, 13.3 g, 61 mmol) in N,N-dimethylformamide (120 mL) was added N-bromosuccinimide (10.9 mg, 61 mmol). The mixture was stirred at room temperature for 16 h. The mixture was then diluted with water and extracted with diethyl ether. The combined ethereal layers were washed with water, brine, dried (Na2SO4), filtered and concentrated in vacuo. Recrystallization from diethyl ether and flash column chromatography (silica gel, 5% ethyl acetate in hexane) afforded the title compound as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][NH2:10])=[CH:4][CH:3]=1.[C:11]1([NH:17][C:18]([NH:20][CH2:21][CH2:22][CH2:23]Br)=[O:19])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+]>CC#N>[C:11]1([NH:17][C:18]([NH:20][CH2:21][CH2:22][CH2:23][NH:10][CH2:9][CH2:8][C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)=[O:19])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: NCCc1ccc(Cl)cc1
Reactant: O=C(NCCCBr)Nc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=C(NCCCNCCc1ccc(Cl)cc1)Nc1ccccc1
Temperature: 70 °C
Reaction time: 4.5 h
Yield: 44.4 %

Procedure:
2(4-Chlorophenyl)ethylamine (1.8 g, 12 mmol) was added to a mixture of N-phenylcarbamoyl-3-bromopropylamine (2.5 g, 9.7 mmol) and potassium carbonate (2.6 g, 19 mmol) in CH3CN (50 ml). The mixture was stirred at 70° C. for 4.5 h, and then filtered. The filtrate was concentrated under vacuum to dryness, and the residue was dissolved with chloroform, washed with water, 1N-HCl and brine. The organic layer was dried over sodium sulfate, filtered, and then concentrated under vacuum to dryness. The residue was chromatographed on silica gel (eluting with 2% methanol/chloroform) to afford N-phenylcarbamoyl-N′-[2-(4- chlorophenyl)ethyl]-1,3- diaminopropane (1.43 g, 45%): MS(ES+) m/e 332 M+; 1H NMR (400 MHz, CD3OD) δ 7.35-7.15 (m, 8H), 6.99 (m, 1H), 3.31 (m, 2H), 3.23 (m, 2H), 3.06 (t, J=7.1 Hz, 2H), 3.00 (m, 2H), 1.89 (m, 2H).
Reaction SMILES: [NH:1]([C:3]1[N:4]=[N:5][C:6]([Cl:9])=[CH:7][CH:8]=1)[NH2:2].[N+:10]([C:13]1[S:17][C:16](C=O)=[CH:15][CH:14]=1)([O-:12])=[O:11]>C(O)C>[N+:10]([C:13]1[S:17][C:16](=[N:2][NH:1][C:3]2[N:4]=[N:5][C:6]([Cl:9])=[CH:7][CH:8]=2)[CH2:15][CH:14]=1)([O-:12])=[O:11]
Reactant: O=Cc1ccc([N+](=O)[O-])s1
Reactant: NNc1ccc(Cl)nn1
Solvent: CCO
Product: O=[N+]([O-])C1=CCC(=NNc2ccc(Cl)nn2)S1

Procedure:
3-Hydrazino-6-chloropyridazine was condensed with 5-nitro-2-thiophene-aldehyde in ethanol and the 3-(5-nitro-2-thienylidene-hydrazino)-6-chloropyridazine (m.p. 306° - 308°C. decomp.) thus obtained was cyclized in glacial acetic acid with lead tetraacetate to give 3-(5-nitro-2-thienyl)-6-chloro-s-triazolo[4,3-b]pyridazine (m.p. 215° - 217°C.) and this subsequently reacted with hydrazine hydrate in isopropanol.
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[C:6](NN)[N:5]=[C:4]([C:11]#[N:12])[C:3]=1[Cl:13].S(Cl)([Cl:17])(=O)=O>C(Cl)Cl>[NH2:1][C:2]1[C:7]([F:8])=[C:6]([Cl:17])[N:5]=[C:4]([C:11]#[N:12])[C:3]=1[Cl:13]
Reactant: O=S(=O)(Cl)Cl
Reactant: N#Cc1nc(NN)c(F)c(N)c1Cl
Solvent: ClCCl
Product: N#Cc1nc(Cl)c(F)c(N)c1Cl
Temperature: 25 °C
Reaction time: 40 h
Yield: 76 %

Procedure:
To a suspension of 4-amino-3-chloro-5-fluoro-6-hydrazinylpicolinonitrile (9.04 g, 44.8 mmol) in CH2Cl2 (150 mL) was added sulfuryl chloride (7.20 mL, 89 mmol). The mixture was stirred at room temperature for 40 h. The solvent was removed under reduced pressure, and the residue was partitioned with saturated aqueous sodium bicarbonate (NaHCO3) and EtOAc. The organic phase was separated, dried over Na2SO4, and filtered. The solution was concentrated and the residue was purified by silica gel chromatography to give the product (7.01 g, 76%) as an off-white solid: 1H NMR (300 MHz, DMSO-d6) δ 7.55 (s, 2H); 13C NMR (101 MHz, DMSO-d6) δ 143.26 (d, J=259.2 Hz, C5), 142.69 (d, J=14.0 Hz, C4), 135.53 (d, J=17.6 Hz. C6), 126.07 (d, J=4.4 Hz, C2), 120.14 (d, J=4.3 Hz, C3), 114.36 (s, CN); 19F NMR (376 MHz, DMSO-d6) δ −132.30 (s); ESIMS m/z 203 ([M+H]+), 206.
Reaction SMILES: C([Li])CCC.[Br:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH3:15])=[CH:9][CH:8]=1.Br[C:17]1[CH:18]=[CH:19][C:20]2[O:24][CH2:23][C:22](=O)[C:21]=2[CH:26]=1.Cl>O1CCCC1.O>[Br:6][C:7]1[CH:12]=[CH:11][C:10]2[O:13][CH:14]=[C:15]([C:17]3[CH:26]=[CH:21][C:20]([O:24][CH2:23][CH3:22])=[CH:19][CH:18]=3)[C:9]=2[CH:8]=1
Reactant: O=C1COc2ccc(Br)cc21
Reactant: CCOc1ccc(Br)cc1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: CCOc1ccc(-c2coc3ccc(Br)cc23)cc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 45.4 %

Procedure:
4.95 ml (15% solution in n-hexane) of n-butyllithium are added to a solution, cooled to −78° C., of 1.03 ml (7.23 mmol) of 4-bromophenetole in 35 ml of tetrahydrofuran under nitrogen, and the mixture is stirred at −78° C. for one hour. A solution of 1.4 g (6.6 mmol) of 5-bromobenzofuran-3-one is subsequently added dropwise at such a rate that the temperature does not rise above −70° C., stirring is continued at −78° C. for one hour, the reaction mixture is then allowed to come to room temperature stirred at room temperature for a further 15 hours, finally 10 ml of 1N hydrochloric acid are added, and stirring is continued for a further one hour. After addition of 20 ml of water, the tetrahydrofuran is stripped off in vacuo, and the aqueous mixture remaining is extracted three times with 10 ml of diethyl ether each time. After the combined organic phases have been washed with 10 ml of saturated sodium chloride solution and after drying over sodium sulfate, the solvent is stripped off in a rotary evaporator, and the crude product is purified by column chromatography on silica gel (petroleum ether/ethyl acetate 98:2), giving 0.95 g of 5-bromo-3-(4-ethoxyphenyl)-benzofuran as colourless oil; LC/MS: 318 (M+H);
Reaction SMILES: [CH3:1][O:2][CH2:3][C@H:4]([CH3:54])[CH2:5][O:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C@@H:14]2[C@@H:19]([O:20][CH2:21][C:22]3[CH:23]=[CH:24][C:25]4[O:30][CH2:29][CH2:28][N:27]([CH2:31][CH2:32][CH2:33][O:34][CH3:35])[C:26]=4[CH:36]=3)[CH2:18][N:17]([S:37]([C:40]3[CH:45]=[CH:44][C:43]([CH3:46])=[CH:42][CH:41]=3)(=[O:39])=[O:38])[C@H:16]([CH2:47][C:48]([CH3:53])([CH3:52])[C:49]([OH:51])=O)[CH2:15]2)=[CH:10][CH:9]=1.[CH3:55][NH2:56]>>[CH3:1][O:2][CH2:3][C@H:4]([CH3:54])[CH2:5][O:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C@@H:14]2[C@@H:19]([O:20][CH2:21][C:22]3[CH:23]=[CH:24][C:25]4[O:30][CH2:29][CH2:28][N:27]([CH2:31][CH2:32][CH2:33][O:34][CH3:35])[C:26]=4[CH:36]=3)[CH2:18][N:17]([S:37]([C:40]3[CH:45]=[CH:44][C:43]([CH3:46])=[CH:42][CH:41]=3)(=[O:38])=[O:39])[C@H:16]([CH2:47][C:48]([CH3:53])([CH3:52])[C:49]([NH:56][CH3:55])=[O:51])[CH2:15]2)=[CH:10][CH:9]=1
Reactant: COCCCN1CCOc2ccc(CO[C@H]3CN(S(=O)(=O)c4ccc(C)cc4)[C@H](CC(C)(C)C(=O)O)C[C@@H]3c3ccc(COC[C@@H](C)COC)cc3)cc21
Reactant: CN
Product: CNC(=O)C(C)(C)C[C@@H]1C[C@H](c2ccc(COC[C@@H](C)COC)cc2)[C@@H](OCc2ccc3c(c2)N(CCCOC)CCO3)CN1S(=O)(=O)c1ccc(C)cc1

Procedure:
According to general procedure D, 1.0 mmol of 3-[(2S,4R,5R)-4-[4-((S)-3-methoxy-2-methyl-propoxymethyl)-phenyl]-5-[4-(3-methoxy-propyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-1-(toluene-4-sulfonyl)-piperidin-2-yl]-2,2-dimethyl-propionic acid are reacted with methylamine (8M in EtOH) to afford the title compound as yellow oil. Rf=0.25 (EtOAc/heptane 3:1); Rt=5.36 (gradient I).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]#[N:11])[CH:5]=[CH:6][C:7]=1[Cl:8].C[Si]([N-][Si](C)(C)C)(C)C.[Na+].Br[CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25]>C1COCC1.C(OCC)C>[CH2:27]([O:26][C:24](=[O:25])[CH2:23][C:9]([C:10]#[N:11])([C:4]1[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=1)[CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH3:28]
Reactant: N#CCc1ccc(Cl)c(Cl)c1
Reactant: CCOC(=O)CBr
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCOC(=O)CC(C#N)(CC(=O)OCC)c1ccc(Cl)c(Cl)c1
Temperature: 20 °C
Reaction time: 3 h
Yield: 82.7 %

Procedure:
3,4-Dichlorophenylacetonitrile (10 g, 53.75 mmol) was stirred mechanically in THF (50 mL) at -78° C. and treated dropwise with sodium bis-(trimethylsilyl)amide (108 mL, 1 M; 2 eq.). The reaction slurry was allowed to warm to 20° C. and stirred for 3 hours. The solution was cooled to -78° C. and the slurry was treated with ethyl bromoacetate (12 mL, 107 mmol, 2 eq.). The slurry was again allowed to warm to 20° C. and stirred 18 hours. The slurry was dissolved in ethyl ether and washed with water and brine. The organic phase was dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was chromatographed on silica gel (400 g) with 20% ethyl acetate to give 15.85 g (82%) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][N:12]([CH2:14][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][N:16]2C(OC(C)(C)C)=O)[CH3:13])=[CH:7][CH:6]=1)=[O:4].Cl>ClCCl.O1CCOCC1>[CH3:13][N:12]([CH2:11][C:8]1[CH:7]=[CH:6][C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:10][CH:9]=1)[CH2:14][CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][NH:16]1
Reactant: COC(=O)c1ccc(CN(C)CC2CCCCN2C(=O)OC(C)(C)C)cc1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: COC(=O)c1ccc(CN(C)CC2CCCCN2)cc1
Reaction time: 8 h

Procedure:
A solution of 1,1-dimethylethyl 2-(((4-(methoxycarbonyl)phenylmethyl)(methyl)amino)methyl)piperidine-1-carboxylate in dichloromethane (6 mL) was treated with a solution of 4 N hydrochloric acid in dioxane (6 mL). The reaction was stirred overnight. Solvent was removed under reduced pressure and the product, methyl 4-((methyl(piperidin-2-ylmethyl)amino)methyl)benzoate, was isolated as the hydrochloride salt.
Reaction SMILES: [C-:1]#[N:2].[K+].CS(O[CH2:9][CH2:10][CH:11]([C:24]1[S:28][C:27]([Br:29])=[N:26][CH:25]=1)[C:12]1[C:20]2[C:15](=[C:16]([CH2:21][S:22][CH3:23])[CH:17]=[CH:18][CH:19]=2)[NH:14][CH:13]=1)(=O)=O.O>CN(C=O)C>[Br:29][C:27]1[S:28][C:24]([CH:11]([C:12]2[C:20]3[C:15](=[C:16]([CH2:21][S:22][CH3:23])[CH:17]=[CH:18][CH:19]=3)[NH:14][CH:13]=2)[CH2:10][CH2:9][C:1]#[N:2])=[CH:25][N:26]=1
Reactant: [C-]#N
Reactant: CSCc1cccc2c(C(CCOS(C)(=O)=O)c3cnc(Br)s3)c[nH]c12
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CSCc1cccc2c(C(CCC#N)c3cnc(Br)s3)c[nH]c12
Temperature: 80 °C
Reaction time: 5 h

Procedure:
14 mg (0.21 mmol) of potassium cyanide were added to 50 mg (0.11 mmol) of the compound from Example 69A in 1 ml of DMF. The mixture was stirred at 80° C. for 5 h, water was added to the reaction solution, and the aqueous phase was extracted twice with dichloromethane. The combined organic phases were dried over sodium sulfate, the solid was filtered off, and the solvents were removed. The crude product was purified by preparative HPLC (mobile phase: acetonitrile/water gradient). 38 mg (89% of theory) of the target compound were obtained.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:10])[CH:4]=[CH:5][C:6]([Cl:9])=[CH:7][CH:8]=1.[CH2:11]=[C:12]1[O:16][C:14](=[O:15])[CH2:13]1>>[Cl:9][C:6]1[CH:5]=[CH:4][C:3](=[O:10])[C:2]([NH:1][C:14](=[O:15])[CH2:13][C:12](=[O:16])[CH3:11])=[CH:8][CH:7]=1
Reactant: C=C1CC(=O)O1
Reactant: Nc1ccc(Cl)ccc1=O
Product: CC(=O)CC(=O)Nc1ccc(Cl)ccc1=O
Temperature: 100 °C

Procedure:
A mixture of 2-amino-5-chloro-2,4,6-cycloheptatrien-1-one (1.55 g, described in example 9) and diketene (5 ml) were heated at 100° C. for 1 hr. The mixture was cooled and then purified by chromatography on silica gel using chloroform as the eluant. The appropriate fractions were pooled and the residue was crystallized from diethyl ether to give 650 mg of 1-[(4-chloro-7-oxo-1,3,5-cycloheptatrien-1-yl)amino]-1,3-butanedione, nmr (DMSO-d6) δ2.17 (s, 3H), 3.85 (s, 2H), 7.3 (m, 3H), 8.7 (d, 1H), 10.75 (s, 1H).