Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([N:6]2[C:10]3[N:11]=[C:12]([NH:15][C:16]4[CH:24]=[CH:23][C:19]([C:20](O)=[O:21])=[CH:18][N:17]=4)[N:13]=[CH:14][C:9]=3[CH:8]=[C:7]2[C:25](=[O:29])[N:26]([CH3:28])[CH3:27])[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:30]([O:34][C:35]([N:37]1[CH2:44][CH:43]2[O:45][CH:39]([CH2:40][NH:41][CH2:42]2)[CH2:38]1)=[O:36])([CH3:33])([CH3:32])[CH3:31]>>[C:30]([O:34][C:35]([N:37]1[CH2:38][CH:39]2[O:45][CH:43]([CH2:42][N:41]([C:20]([C:19]3[CH:18]=[N:17][C:16]([NH:15][C:12]4[N:13]=[CH:14][C:9]5[CH:8]=[C:7]([C:25](=[O:29])[N:26]([CH3:28])[CH3:27])[N:6]([CH:1]6[CH2:5][CH2:4][CH2:3][CH2:2]6)[C:10]=5[N:11]=4)=[CH:24][CH:23]=3)=[O:21])[CH2:40]2)[CH2:44]1)=[O:36])([CH3:33])([CH3:31])[CH3:32]
Reactant: CN(C)C(=O)c1cc2cnc(Nc3ccc(C(=O)O)cn3)nc2n1C1CCCC1
Reactant: CC(C)(C)OC(=O)N1CC2CNCC(C1)O2
Product: CN(C)C(=O)c1cc2cnc(Nc3ccc(C(=O)N4CC5CN(C(=O)OC(C)(C)C)CC(C4)O5)cn3)nc2n1C1CCCC1
Yield: 34 %

Procedure:
Following general amide formation method 1, 6-(7-Cyclopentyl-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-nicotinic acid (266 mg, 0.438 mmol, 1.0 eq) was combined with 9-Oxa-3,7-diaza-bicyclo[3.3.1]nonane-3-carboxylic acid tert-butyl ester (100 mg, 0.438 mmol, 1.0 eq) which gave 7-[6-(7-Cyclopentyl-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-pyridine-3-carbonyl]-9-oxa-3,7-diaza-bicyclo[3.3.1]nonane-3-carboxylic acid tert-butyl ester as a light pink powder (90 mg) in 34% yield. MS m/z 605.2 (M+H)+.
Reaction SMILES: [CH2:1]([N:4]1[C:12](=[O:13])[C:11]2[C:6](=[N:7][C:8](SC)=[N:9][CH:10]=2)[N:5]1[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[N:17]=1)[CH:2]=[CH2:3].[CH3:23][O:24][CH2:25][CH2:26][N:27]1[CH2:32][CH2:31][N:30]([C:33]2[CH:39]=[CH:38][C:36]([NH2:37])=[CH:35][CH:34]=2)[CH2:29][CH2:28]1>>[CH3:23][O:24][CH2:25][CH2:26][N:27]1[CH2:32][CH2:31][N:30]([C:33]2[CH:39]=[CH:38][C:36]([NH:37][C:8]3[N:7]=[C:6]4[N:5]([C:16]5[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[N:17]=5)[N:4]([CH2:1][C:2]#[CH:3])[C:12](=[O:13])[C:11]4=[CH:10][N:9]=3)=[CH:35][CH:34]=2)[CH2:29][CH2:28]1
Reactant: COCCN1CCN(c2ccc(N)cc2)CC1
Reactant: C=CCn1c(=O)c2cnc(SC)nc2n1-c1cccc(C)n1
Product: C#CCn1c(=O)c2cnc(Nc3ccc(N4CCN(CCOC)CC4)cc3)nc2n1-c1cccc(C)n1

Procedure:
45.3 mg of the entitled compound was obtained as a yellow solid in the same manner as in Example 113-1 to 113-2, for which, however, 2-allyl-1-(6-methylpyridin-2-yl)-6-(methylthio)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one was used in place of 2-allyl-1-[6-(1-hydroxy-1-methylethyl)-2-pyridinyl]-6-(methylthio)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one used in Example 113-1, and 4-[4-(2-methoxyethyl)piperazin-1-yl]aniline was used in place of 4-(4-methylpiperazin-1-yl)aniline used in Example 113-2.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[CH:4]=[CH:5][CH:6]1[O:11][CH2:10][CH2:9][N:8](C(OCC2C=CC=CC=2)=O)[CH2:7]1>[Pd]>[NH:8]1[CH2:9][CH2:10][O:11][CH:6]([CH2:5][CH2:4][C:3]([O:2][CH3:1])=[O:22])[CH2:7]1
Reactant: COC(=O)C=CC1CN(C(=O)OCc2ccccc2)CCO1
Agent: [Pd]
Product: COC(=O)CCC1CNCCO1
Yield: 87.4 %

Procedure:
Benzyl 2-(3-methoxy-3-oxoprop-1-en-1-yl)morpholine-4-carboxylate (6.47 g, 21.2 mmol) was reacted with Pd—C (10%, 0.65 g) according to the procedure as described in Example 34, Step C to give the title compound as colorless oil (3.21 g, 87%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [C:1]([C:5]1[C:14]([CH3:15])=[CH:13][C:8]2[NH:9][C:10]([SH:12])=[N:11][C:7]=2[CH:6]=1)([O:3][CH3:4])=[O:2].[OH-].[Na+].Cl.[CH3:19][O:20][C:21]1[C:22]([CH2:29]Cl)=[N:23][CH:24]=[CH:25][C:26]=1[O:27][CH3:28]>O.CO>[C:1]([C:5]1[C:14]([CH3:15])=[CH:13][C:8]2[NH:9][C:10]([S:12][CH2:29][C:22]3[C:21]([O:20][CH3:19])=[C:26]([O:27][CH3:28])[CH:25]=[CH:24][N:23]=3)=[N:11][C:7]=2[CH:6]=1)([O:3][CH3:4])=[O:2]
Reactant: COC(=O)c1cc2nc(S)[nH]c2cc1C
Reactant: COc1ccnc(CCl)c1OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COC(=O)c1cc2nc(SCc3nccc(OC)c3OC)[nH]c2cc1C
Reaction time: 1 h
Yield: 92 %

Procedure:
5-Carbomethoxy-6-methyl-2-mercapto-1H-benzimidazole (0.67 g, 0.003 mol) and NaOH (0.12g, 0.003 mol) in H2O (0.6 ml) were dissolved in CH3OH (15 ml). 3,4-dimethoxy-2-chloromethylpyridine hydrochloride, (=0.0036 mol) as a crude material in CH3OH (10 ml) and NaOH (0.144 g, 0.0036 mol) in H2O (0.72 ml) were added. The mixture was heated to reflux and the reflux was continued for 1 hour. CH3OH was evaporated off and the crude material was purified by chromatography on a silica column using CH2Cl2 --CH3OH (98-2) as eluent, giving (1.03 g, 92%) of the pure title compound.
Reaction SMILES: [CH:1]1([N:4]2[C:8]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)=[CH:7][N:6]([CH2:15][C:16]([OH:18])=O)[C:5]2=[O:19])[CH2:3][CH2:2]1.[CH:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22][C:21]=1[CH:30]([NH2:32])[CH3:31].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[CH:1]1([N:4]2[C:8]([C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=3)=[CH:7][N:6]([CH2:15][C:16]([NH:32][CH:30]([C:21]3[CH:22]=[CH:23][C:24]4[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=4)[CH:20]=3)[CH3:31])=[O:18])[C:5]2=[O:19])[CH2:2][CH2:3]1
Reactant: O=C(O)Cn1cc(-c2ccccc2)n(C2CC2)c1=O
Reactant: CC(N)c1ccc2ccccc2c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CC(NC(=O)Cn1cc(-c2ccccc2)n(C2CC2)c1=O)c1ccc2ccccc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
40 mg (0.155 mmol) of (3-cyclopropyl-2-oxo-4-phenyl-2,3-dihydro-1H-imidazol-1-yl)-acetic acid from Example 128A, 29.2 mg (0.17 mmol) of 1-(2-naphthyl)ethylamine, 38.6 mg (0.20 mmol) of EDC hydrochloride and 25.1 mg (0.19 mmol) of HOBt are dissolved in 1.5 ml of dry DMF and stirred overnight at RT. The crude product is purified by preparative HPLC [Method 10, with addition of 0.01 M hydrochloric acid in the water]. The target compound is obtained in a yield of 41 mg (63% of theory).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#N)=[C:4]([CH3:10])[CH:3]=1.CC(C[AlH]CC(C)C)C.CC[O:22]CC>C1COCC1>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:22])=[C:4]([CH3:10])[CH:3]=1
Reactant: Cc1cc(Cl)ccc1C#N
Reactant: CCOCC
Agent: CC(C)C[AlH]CC(C)C
Solvent: C1CCOC1
Product: Cc1cc(Cl)ccc1C=O
Reaction time: 1 h

Procedure:
To a stirred −78° C. solution of 4-chloro-2-methylbenzonitrile (5.00 g, 32.98 mmol) in Et2O (190 mL) was added 1 M DIBAL in THF (66.0 mL) over 10 min. After 5 h additional 1M DIBAL in THF (3.30 mL) was added dropwise and the solution was stirred for 1 hour. The reaction was quenched with water followed by concentrated H2SO4 and stirred at ambient temperature for 16 h. The solution was extracted into Et2O, dried (Na2SO4) and reduced in vacuo. 4-Chloro-2-methylbenzaldehyde was isolated as a yellow oil. 1H NMR (CDCl3, 400 MHz) δ 2.59 (s, 3H), 7.19 (s, 1H), 7.26 (d, J=8.2 Hz, 1H), 7.66 (d, J=8.2 Hz, 1H), 10.15 (s, 1H).
Reaction SMILES: [H-].[Na+].[CH2:3]([O:6][C:7]([CH:9]([CH2:16][CH2:17][CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:10]([O:12][CH2:13][CH:14]=[CH2:15])=[O:11])=[O:8])[CH:4]=[CH2:5].Br[CH2:26][CH2:27][C:28]1[CH:35]=[CH:34][C:31]([C:32]#[N:33])=[CH:30][CH:29]=1.O>CN(C=O)C>[CH2:3]([O:6][C:7]([C:9]([CH2:26][CH2:27][C:28]1[CH:35]=[CH:34][C:31]([C:32]#[N:33])=[CH:30][CH:29]=1)([CH2:16][CH2:17][CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:10]([O:12][CH2:13][CH:14]=[CH2:15])=[O:11])=[O:8])[CH:4]=[CH2:5]
Reactant: C=CCOC(=O)C(CCCCC(=O)OCC)C(=O)OCC=C
Reactant: N#Cc1ccc(CCBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C=CCOC(=O)C(CCCCC(=O)OCC)(CCc1ccc(C#N)cc1)C(=O)OCC=C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 27923.2 %

Procedure:
6.37 g (159.27 mmol; content 60%) of sodium hydride are added in portions to a solution of 45.23 g (144.79 mmol) of 1-allyl 7-ethyl 2-allyloxycarbonylheptanedioate from Example 82A in 250 ml of DMF at 0° C. The reaction solution is then allowed to reach room temperature and is stirred for 30 min. The reaction solution is then cooled to 0° C. and, after addition of 36.50 g (173.75 mmol) of 4-(2-bromoethyl)benzonitrile from Example 8A in 250 ml DMF, stirred at this temperature for 30 min. The mixture is then stirred at room temperature overnight. Water is added dropwise to the reaction mixture and, after extraction three times with ethyl acetate, the combined organic phases are washed with saturated sodium chloride solution and dried over sodium sulfate. After filtration, the solvent is concentrated to dryness in vacuo. The resulting crude product is purified by flash chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate 10:1-4:1→1:1). 17.85 g (40.43 mol, 28% yield) of a colorless solid are obtained.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[C:7](I)[C:8]([F:12])=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:14]([NH:16][CH2:17][CH2:18][CH3:19])=[O:15].[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][C:22]=1B(O)O>>[CH2:17]([NH:16][C:14]([C:3]1[N:4]=[N:5][C:6]2[C:11]([C:2]=1[NH2:1])=[CH:10][CH:9]=[C:8]([F:12])[C:7]=2[C:22]1[CH:23]=[C:24]([O:27][CH3:28])[CH:25]=[CH:26][C:21]=1[Cl:20])=[O:15])[CH2:18][CH3:19]
Reactant: CCCNC(=O)c1nnc2c(I)c(F)ccc2c1N
Reactant: COc1ccc(Cl)c(B(O)O)c1
Product: CCCNC(=O)c1nnc2c(-c3cc(OC)ccc3Cl)c(F)ccc2c1N

Procedure:
The title compound was prepared from 4-amino-7-fluoro-8-iodo-N-propylcinnoline-3-carboxamide (250 mg, 0.67 mmol) and 2-chloro-5-methoxyphenyl boronic acid (279 mg, 1.50 mmol) according to Method A to afford a solid (181 mg, 72%). 1H NMR (500.333 MHz, CDCl3) δ 8.41 (s, 1H), 7.90 (dd, J=9.1, 5.1 Hz, 1H), 7.49 (t, J=8.7 Hz, 1H), 7.41 (dd, J=6.9, 2.7 Hz, 1H), 6.94-6.92 (m, 2H), 3.79 (s, 3H), 3.44 (q, J=6.7 Hz, 2H), 1.65 (sextet, J=7.2 Hz, 2H), 0.99 (t, J=7.3 Hz, 3H). MS APCI, m/z=389/391 (M+H). HPLC 2.13 min.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]1[CH2:11][CH:12]3[N:17]([CH3:18])[CH:16]([C:5]2=1)[CH2:15][CH2:14][CH2:13]3.[C:19]([C:21]1[CH:22]=[CH:23][C:24]([CH3:27])=[N:25][CH:26]=1)#[CH:20]>>[CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7](/[CH:20]=[CH:19]/[C:21]1[CH:26]=[N:25][C:24]([CH3:27])=[CH:23][CH:22]=1)[C:6]1[CH2:11][CH:12]3[N:17]([CH3:18])[CH:16]([C:5]2=1)[CH2:15][CH2:14][CH2:13]3
Reactant: C#Cc1ccc(C)nc1
Reactant: Cc1ccc2[nH]c3c(c2c1)C1CCCC(C3)N1C
Product: Cc1ccc2c(c1)c1c(n2/C=C/c2ccc(C)nc2)CC2CCCC1N2C

Procedure:
The coupling of 2,12-dimethyl-6,7,8,9,10,11-hexahydro-5H-7,11-epiminocycloocta[b]indole (110 mg, 0.458 mmol; Example 114A) and 5-ethynyl-2-methylpyridine (107 mg, 0.915 mmol; prepared as described in International Publication No. WO2005090333) was performed according to the procedure described in Example 20 to give the title compound as the minor of two alkene isomers: 1H NMR (300 MHz, methanol-d4) δ ppm 1.30-1.53 (m, 2H), 1.73-1.88 (m, 2H), 1.97-2.17 (m, 2H), 2.43 (s, 3H), 2.53 (s, 3H), 2.55 (s, 3H), 2.88 (d, J=18 Hz, 1H), 3.40-3.51 (m, 1H), 3.56 (br. s, 1H), 4.41 (s, 1H), 6.88 (d, J=15 Hz, 1H), 7.10 (dd, J=8, 1 Hz, 1H), 7.24 (s, 1H), 7.30 (d, J=8 Hz, 1H), 7.67 (d, J=8 Hz, 1H), 7.74 (d, J=15 Hz, 1H), 7.97 (dd, J=8, 2 Hz, 1H), 8.53 (d, J=2 Hz, 1H); MS (DCI/NH3) m/z 358 (M+H)+.
Reaction SMILES: [CH2:1]=O.Cl.[CH2:4]([NH:6][CH2:7][CH3:8])[CH3:5].[CH2:9]([P:11]([OH:13])[OH:12])[CH3:10].Cl>O>[CH2:9]([P:11]([CH2:1][N:6]([CH2:7][CH3:8])[CH2:4][CH3:5])(=[O:13])[OH:12])[CH3:10]
Reactant: CCP(O)O
Reactant: CCNCC
Reactant: C=O
Agent: Cl
Solvent: O
Product: CCN(CC)CP(=O)(O)CC

Procedure:
A three-neck round-bottom flask with fitted KPG stirrer, reflux condenser and dropping funnel is initially charged with 44.0 g of paraformaldehyde (95%), 105.5 g of demineralized water and 233.4 g of diethylamine hydrochloride, followed by the addition of 100.1 g of ethylphosphonous acid (96.3%) (prepared according to example 1) during 6 h at 110° C. with stirring. The pH of the reaction solution is adjusted to below 1 with 8 g of 37% hydrochloric acid. After one hour of refluxing, a solution of ethyldiethylaminomethylphosphinic acid is obtained.
Reaction SMILES: N#CBr.[C:4](=[O:7])([O-])[O-].[Na+].[Na+].NCCN1CCC(NC2[N:24]([CH2:25][C:26]3C=CC(F)=[CH:28][CH:27]=3)[C:23]3[CH:33]=[CH:34][CH:35]=[CH:36][C:22]=3[N:21]=2)CC1>O1CCCC1>[O:7]1[CH:4]=[CH:28][CH:27]=[C:26]1[CH2:25][NH:24][C:23]1[C:22]([NH2:21])=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: NCCN1CCC(Nc2nc3ccccc3n2Cc2ccc(F)cc2)CC1
Reactant: O=C([O-])[O-]
Agent: N#CBr
Agent: [Na+]
Solvent: C1CCOC1
Product: Nc1ccccc1NCc1ccco1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a stirred mixture of 5.3 parts of cyanogen bromide, 106. parts of anhydrous sodium carbonate and 45 parts of tetrahydrofuran was added dropwise a solution of 18.35 parts of N-[1-(2-aminoethyl)-4-piperidinyl]-1-[(4-fluorophenyl)methyl]-1H-benzimidazol-2-amine in tetrahydrofuran at a temperature between -10° C. and -20° C. Upon completion, stirring was continued for 2 hours at -10° C. After heating to 0° C., the whole was filtered and the filtrate was evaporated, yielding 19 parts (100%) of [2[4-[[1-[(4-fluorophenyl)methyl]-1H-benzimidazol-2-yl]amino]-1-piperidinyl]ethyl]cyanimide as a residue (187).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:31])=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][CH:9]2[C:28]([OH:30])=O)[CH:5]=[CH:6][CH:7]=1.CCN(C(C)C)C(C)C.[NH2:41][C:42]1[CH:51]=[CH:50][C:45]([C:46]([O:48][CH3:49])=[O:47])=[C:44]([O:52][CH2:53][CH3:54])[CH:43]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>ClCCl>[Cl:1][C:2]1[C:3]([F:31])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:25])([CH3:26])[CH3:27])[NH:10][C@H:9]2[C:28]([NH:41][C:42]2[CH:51]=[CH:50][C:45]([C:46]([O:48][CH3:49])=[O:47])=[C:44]([O:52][CH2:53][CH3:54])[CH:43]=2)=[O:30])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Reactant: CCOc1cc(N)ccc1C(=O)OC
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOc1cc(NC(=O)[C@@H]2N[C@@H](CC(C)(C)C)[C@](C#N)(c3ccc(Cl)cc3F)[C@H]2c2cccc(Cl)c2F)ccc1C(=O)OC
Reaction time: 1.5 h
Yield: 107.4 %

Procedure:
To a solution of rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (60.8 mg, 0.13 mmol) in dichloromethane (3 mL) were added DIPEA (89.0 mg, 0.69 mmol), methyl 4-amino-2-ethoxybenzoate (50.9 mg, 0.26 mmol) and HATU (90.8 mg, 0.24 mmol). (The acid, DIPEA, and HATU were added in thirds at 20 min intervals). After 90 min, the reaction was diluted with dichloromethane, washed with water and saturated sodium chloride and purified by silica gel chromatography with ethyl acetate and hexanes to give racemic methyl 4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-2-ethoxybenzoate (90 mg, with minor impurity) as a light brown oil.
Reaction SMILES: [CH3:1][Si:2]([CH3:18])([CH3:17])[CH2:3][CH2:4][O:5][CH2:6][N:7]1[C:11]2[CH:12]=[N:13][NH:14][C:15](=[O:16])[C:10]=2[CH:9]=[CH:8]1.C(=O)([O-])O.[Na+].S([O-])(O)=O.[Na+].[Cl-:29].[Na+]>C(OCC)(=O)C.C(#N)C>[Cl:29][C:9]1[C:10]2[C:15](=[O:16])[NH:14][N:13]=[CH:12][C:11]=2[N:7]([CH2:6][O:5][CH2:4][CH2:3][Si:2]([CH3:18])([CH3:17])[CH3:1])[CH:8]=1
Reactant: C[Si](C)(C)CCOCn1ccc2c(=O)[nH]ncc21
Reactant: [Cl-]
Agent: O=C([O-])O
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: C[Si](C)(C)CCOCn1cc(Cl)c2c(=O)[nH]ncc21
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 65 %

Procedure:
To 150 ml of acetonitrile solution containing 2.99 g (11.3 mmol) of 1-(2-trimethylsilylethoxymethyl)-1,5-dihydropyrrolo[2,3-d]pyridazin-4-one obtained in Reference example 16-(b) was added 1.42 g (10.6 mmol) of N-chlorosuccineimide, the mixture was stirred at room temperature for 3.5 hours, 0.53 g (4.0 mmol) of N-chlorosuccineimide was further added to the mixture and the resulting mixture was stirred for 24 hours. After completion of the reaction, to the reaction mixture were added a saturated aqueous solution of sodium hydrogencarbonate, 5% sodium hydrogen sulfite and ethyl acetate, and the mixture was stirred for 1 hour. Then, a saturated aqueous solution of sodium chloride was added to the solution and the liquids were separated. The organic layer after separation was further washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The obtained residue was applied to silica gel column chromatography (Eluent; toluene:ethyl acetate=9:1→7:3 (V/V)), and the fractions containing the desired compound were concentrated under reduced pressure to obtain 2.20 g of the title compound as a white solid. (Yield: 65%)
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]([CH2:11][CH3:12])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.C([O-])([O-])=O.[K+].[K+].[C:19]1([C:21](=[CH:23][CH:24]=[CH:25][CH:26]=1)[OH:22])[OH:20]>CN(C=O)C>[CH2:11]([N:4]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH2:3][CH2:2][O:20][C:19]1[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=1[OH:22])[CH3:12]
Reactant: Oc1ccccc1O
Reactant: CCN(CCCl)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCN(CCOc1ccccc1O)c1ccccc1
Temperature: 80 °C
Reaction time: 6 h
Yield: 57.4 %

Procedure:
A mixture of compound 3a (500 mg, 2.7 mmol), K2CO3 (750 mg, 5.4 mmol), KI (90 mg, 0.54 mmol) in DMF (50 mL) was bubbled with argon for 10 min Catechol (600 mg, 5.4 mmol) was added to the mixture under argon. The reaction mixture was heated and stirred at 80° C. for 6 hr. After cooling to room temperature, the solvent was evaporated and the residue was quenched with 100 mL water. The mixture was adjusted pH to ˜7 with diluted hydrochloric acid. The mixture was then extracted with EtOAc and the combined organic layer was washed with water and then brine and dried over Na2SO4. The solvent was evaporated and the residue was purified by silica gel column chromatography with CH2Cl2 to provide the compound 19 (400 mg, 1.55 mmol, 57%) as a white solid. 1H NMR (DMSO-d6, 400 MHz) δ 8.86 (s, 1H), 7.15 (t, J=8 Hz, 2H), 6.90 (d, J=8 Hz, 1H), 6.78 (m, 5H), 6.57 (t, J=7.2 Hz, 1H), 4.07 (t, J=6.0 Hz, 2H), 3.68 (t, J=6.0 Hz, 2H), 3.45 (q, J=6.8 Hz, 2H), 1.10 (t, J=6.8 Hz, 3H); 13C NMR (CDCl3, 100 MHz): δ 148.00, 146.35, 145.81, 129.47, 122.24, 120.06, 117.24, 115.04, 112.86, 67.44, 49.79, 45.65, 12.19; HRMS (ESI, positive) m/z calcd. for C16H20NO2 [M+H]+: 258.1494, found: 258.1465; calcd. for C16H19NO2Na [M+Na]+: 280.1313, found: 280.1345.
Reaction SMILES: NC1(C2C=CC(C3C(C4C=CC=CC=4)=CC4N(CCC#N)C(=O)COC=4N=3)=CC=2)CCC1.C(OC(=O)[NH:39][C:40]1([C:44]2[CH:49]=[CH:48][C:47]([C:50]3[C:51]([C:63]4[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=4)=[CH:52][C:53]4[N:58]([CH3:59])[C:57](=O)[CH:56]([CH3:61])[O:55][C:54]=4[N:62]=3)=[CH:46][CH:45]=2)[CH2:43][CH2:42][CH2:41]1)(C)(C)C>>[NH2:39][C:40]1([C:44]2[CH:45]=[CH:46][C:47]([C:50]3[C:51]([C:63]4[CH:64]=[CH:65][CH:66]=[CH:67][CH:68]=4)=[CH:52][C:53]4[N:58]([CH3:59])[CH:57]=[C:56]([CH3:61])[O:55][C:54]=4[N:62]=3)=[CH:48][CH:49]=2)[CH2:41][CH2:42][CH2:43]1
Reactant: CC1Oc2nc(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(-c3ccccc3)cc2N(C)C1=O
Agent: N#CCCN1C(=O)COc2nc(-c3ccc(C4(N)CCC4)cc3)c(-c3ccccc3)cc21
Product: CC1=CN(C)c2cc(-c3ccccc3)c(-c3ccc(C4(N)CCC4)cc3)nc2O1
Yield: 112.5 %

Procedure:
Following the procedure for 3-(6-(4-(1-aminocyclobutyl)phenyl)-2-oxo-7-phenyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-1-yl)propanenitrile, tert-butyl(1-(4-(1,3-dimethyl-2-oxo-7-phenyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl)phenyl)cyclobutyl)carbamate (40 mg, 0.08 mmol) was reacted to afford the title compound (34.5 mg). 1H NMR (500 MHz, CH3OD) 7.56 (s, 1H), 7.42 (d, 2H), 7.38 (d,2H), 7.31 (m, 3H), 7.24 (m, 2H), 5.06 (q, 1H), 3.44 (s, 3H), 2.73-2.77 (m, 2H), 2.53-2.59 (m, 2H), 2.20-2.26 (m, 1H), 1.95-1.97 (m, 1H), 1.67 (d, 3H). LCMS (Method D): RT=0.85 min, M+H+=400.2.
Reaction SMILES: N1CCCC1.[OH:6][C:7]1[C:8]([C:16](=[O:18])[CH3:17])=[CH:9][C:10]2[O:14][CH2:13][O:12][C:11]=2[CH:15]=1.[C:19]1([CH2:25][CH2:26][N:27]2[CH2:32][CH2:31][C:30](=O)[CH2:29][CH2:28]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[ClH:34]>CO.C(O)C>[ClH:34].[C:19]1([CH2:25][CH2:26][N:27]2[CH2:32][CH2:31][C:30]3([CH2:17][C:16](=[O:18])[C:8]4[CH:9]=[C:10]5[O:14][CH2:13][O:12][C:11]5=[CH:15][C:7]=4[O:6]3)[CH2:29][CH2:28]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CC(=O)c1cc2c(cc1O)OCO2
Reactant: O=C1CCN(CCc2ccccc2)CC1
Agent: Cl
Solvent: CO
Solvent: CCO
Solvent: C1CCNC1
Product: O=C1CC2(CCN(CCc3ccccc3)CC2)Oc2cc3c(cc21)OCO3
Reaction time: 0.17 h
Yield: 38 %

Procedure:
Pyrrolidine (83 ml, 71 mg, 1 mmol) was added to a mixture of 1-(6-hydroxy-1,3-benzodioxol-5-yl)-ethanone [prepared as described by K. Fukui and M. Nakayama, Bull. Chem: Soc. Jap., 1963, 37, 300.] (180 mg, 1 mmol) in methanol (1 ml). The mixture was stirred for 10 minutes, then 1-(2-phenylethyl)-4-piperidinone (203 mg, 1 mmol) in methanol (1 ml) was added and the mixture was heated under reflux for 1.5 hours. The mixture was cooled, the solvent was evaporated under reduced pressure and aqueous sodium hydrogen carbonate (saturated, 20 ml) was added. The mixture was extracted with dichloromethane (3×20 ml) and the combined organic fractions were dried (Na2SO4) and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with CH2Cl2 /MeOH/NH3 (Aq.) (98:2:0.2) to give a yellow glass which was suspended in ethanol (5 ml) and treated with ethanolic HCl (6N, 0.5 ml). The mixture was stirred for 1 hour, cooled and the precipitate was collected and dried in vacuo to give the title compound as a white solid (153 mg, 38%), m.p.>285° C.
Reaction SMILES: [F:1][C@H:2]1[CH2:19][C@@:17]2([CH3:18])[C@@H:13]([CH2:14][CH2:15][C:16]2=[O:20])[C@H:12]2[C@H:3]1[C:4]1[CH:5]=[CH:6][C:7]([OH:27])=[CH:8][C:9]=1[CH2:10][C@H:11]2[CH2:21][CH2:22][CH2:23][CH2:24]CI.[F:28][C:29]([C:34]([F:49])([F:48])[C:35]([F:47])([F:46])[C:36]([F:45])([F:44])[C:37]([F:43])([F:42])[C:38]([F:41])([F:40])[F:39])=[CH:30][CH2:31][NH:32][CH3:33].[CH3:50]N1CCCC1=O>>[F:28][C:29]([C:34]([F:48])([F:49])[C:35]([F:46])([F:47])[C:36]([F:44])([F:45])[C:37]([F:42])([F:43])[C:38]([F:39])([F:40])[F:41])=[CH:30][CH2:31][N:32]([CH3:50])[CH2:33][CH2:24][CH2:23][CH2:22][CH2:21][C@@H:11]1[CH2:10][C:9]2[CH:8]=[C:7]([OH:27])[CH:6]=[CH:5][C:4]=2[C@@H:3]2[C@@H:12]1[C@H:13]1[C@@:17]([CH2:19][C@@H:2]2[F:1])([CH3:18])[C:16](=[O:20])[CH2:15][CH2:14]1
Reactant: CN1CCCC1=O
Reactant: C[C@]12C[C@H](F)[C@@H]3c4ccc(O)cc4C[C@@H](CCCCCI)[C@H]3[C@@H]1CCC2=O
Reactant: CNCC=C(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Product: CN(CC=C(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)CCCCC[C@@H]1Cc2cc(O)ccc2[C@@H]2[C@@H]1[C@@H]1CCC(=O)[C@@]1(C)C[C@@H]2F
Temperature: 80 °C
Reaction time: 1 h

Procedure:
880 mg of 11β-fluoro-3-hydroxy-7α-(5-iodopentyl)-estra-1,3,5(10)-trien-17-one and 2.23 g of (3,4,4,5,5,6,6,7,7,8,8,8-dodecafluor-oct-2-enyl)-methyl-amine are dissolved in 20 ml of N-methylpyrrolidone and stirred for 1 hour at a bath temperature of 80° C. After the reaction solution is cooled to room temperature, the batch is added to saturated common salt solution, extracted with diethyl ether, dried and concentrated by evaporation in a vacuum. 2.47 g of 7α-{5-[(3,4,4,5,5,6,6,7,7,8,8,8-dodecafluor-oct-2-enyl)-methyl-amino]-pentyl}-11β-fluoro-3-hydroxy-estra-1,3,5(10)-trien-17-one is obtained as a crude product, which is used without purification in the next stage.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[CH2:3][NH:4][C:5](=S)[NH:6][C:7]1[N:11]=[CH:10][N:9]([CH2:12][CH2:13][CH2:14][CH2:15][C:16]#[N:17])[N:8]=1.[NH3:21]>CO.C(#N)C>[F:1][C:2]([F:20])([F:19])[CH2:3][N:4]=[C:5]([NH2:21])[NH:6][C:7]1[N:11]=[CH:10][N:9]([CH2:12][CH2:13][CH2:14][CH2:15][C:16]#[N:17])[N:8]=1
Reactant: N#CCCCCn1cnc(NC(=S)NCC(F)(F)F)n1
Reactant: N
Solvent: CC#N
Solvent: CO
Product: N#CCCCCn1cnc(NC(N)=NCC(F)(F)F)n1
Reaction time: 1.5 h

Procedure:
This nitrile (3.6 g.) in MeOH (80 ml.) and acetonitrile (5 ml.) was treated with mercuric oxide (3.06 g.) and methanolic ammonia (15 ml.). After stirring for 1.5 hours the black suspension was filtered through diatomaceous earth and the filtrates evaporated to give a white solid. The solid was washed with ether and filtered to give 5-[3-(2-[2,2,2-trifluoroethyl]guanidino)-1,2,4-triazol-1-yl]valeronitrile (2.87 g.) as a white solid, m.p. 200°-201° after recrystallisation from EtOH.