Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:5][N:6]=[CH:7][C:8]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[C:15]([O:19][CH2:20][CH3:21])(=[O:18])[C:16]#[CH:17].C(O)(=O)C>C(#N)C.ClCCl>[CH2:20]([O:19][C:15]([C:16]1[C:7]([C:8]2[CH:9]=[CH:10][C:11]([F:14])=[CH:12][CH:13]=2)=[N:6][N:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[CH:17]=1)=[O:18])[CH3:21]
Reactant: CC(C)(C)NN=Cc1ccc(F)cc1
Reactant: C#CC(=O)OCC
Solvent: CC#N
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCOC(=O)c1cn(C(C)(C)C)nc1-c1ccc(F)cc1
Temperature: 50 °C
Reaction time: 24 h
Yield: 51 %

Procedure:
Add dropwise a solution of N-tert-butyl-N′-(4-fluorobenzylidene)hydrazine (Tetrahedron, 1986, 42, 4223-4234) (8.4 g, 43.2 mmol) in acetonitrile (43 mL) to a well stirred mixture of ethyl propiolate (4.4 mL, 43.2 mmol) and acetic acid (37 mL, 648 mmol) at RT. Warm the mixture at 50° C. for 2 days and at 60° C. for 1 day. Cool at RT and dilute with dichloromethane (250 mL). Wash the mixture with water (50 mL), a saturated aqueous solution of Na2CO3 (2×50 mL), dry (MgSO4), concentrate and purify (Biotage system eluting with CH2Cl2). Dissolve the yellow solid obtained in dichloromethane (43 mL) and acetic acid (37 mL) and bubble a stream of O2 at RT for 10 days. Dilute the mixture with dichloromethane (100 mL) and wash with a saturated aqueous solution of Na2CO3 (2×50 mL), dry (MgSO4) and concentrate and purify (Biotage system eluting with CH2Cl2) to provide the desired compound as yellow solid (6.4 g, 51% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:28]=[CH:29][C:30]=1[F:31])[NH:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([OH:27])=[CH:13][C:14]=2[O:16][CH2:17][C@H:18]2[CH2:22][CH2:21][CH2:20][N:19]2[C:23](=[O:26])[CH2:24][OH:25])[N:9]=[CH:8][N:7]=1.[CH2:32]([O:34][CH2:35][CH2:36]Br)[CH3:33]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:28]=[CH:29][C:30]=1[F:31])[NH:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([O:27][CH2:33][CH2:32][O:34][CH2:35][CH3:36])=[CH:13][C:14]=2[O:16][CH2:17][C@H:18]2[CH2:22][CH2:21][CH2:20][N:19]2[C:23](=[O:26])[CH2:24][OH:25])[N:9]=[CH:8][N:7]=1
Reactant: CCOCCBr
Reactant: O=C(CO)N1CCC[C@@H]1COc1cc(O)cc2ncnc(Nc3ccc(F)c(Cl)c3)c12
Product: CCOCCOc1cc(OC[C@H]2CCCN2C(=O)CO)c2c(Nc3ccc(F)c(Cl)c3)ncnc2c1
Yield: 48 %

Procedure:
The procedure described in Example 17 was repeated using 4-[3-chloro-4-fluoro-anilino]-5-{[(2R)-1-glycoloylpyrrolidin-2-yl]-methoxy}-quinazolin-7-ol (70 mg) and 2-bromoethyl ethyl ether (26 μl) to give the title compound as a white solid in 48% yield; NMR Spectrum (DMSO-d6 at 373 K) 9.80 (br s, 1H), 8.40 (s, 1H), 8.15 (m, 1H), 7.65 (m, 1H), 7.33 (m, 1H), 6.80 (m, 2H), 4.60 (m, 1H), 4.50 (m, 1H), 4.30-4.10 (m, 4H), 4.0 (m, 2H), 3.75 (t, 2H), 3.55 (q, 2H), 3.48-3.37 (m, 2H), 2.10-1.85 (m, 4H), 1.15 (t, 3H); Mass spectrum MH+ 519.
Reaction SMILES: [C:1](Cl)(=O)[CH3:2].[F:5][C:6]1[CH:7]=[C:8]([NH2:15])[C:9](=[CH:13][CH:14]=1)[C:10]([OH:12])=[O:11]>C(OC(=O)C)(=O)C>[F:5][C:6]1[CH:14]=[CH:13][C:9]2[C:10](=[O:12])[O:11][C:1]([CH3:2])=[N:15][C:8]=2[CH:7]=1
Reactant: CC(=O)Cl
Reactant: Nc1cc(F)ccc1C(=O)O
Solvent: CC(=O)OC(C)=O
Product: Cc1nc2cc(F)ccc2c(=O)o1
Reaction time: 1 h

Procedure:
A mixture of acetyl chloride (4.6 ml) and 4-fluoroanthranilic acid (5 g) in acetic anhydride (100 ml) was heated under reflux for 48 hours, cooled and filtered. The filtrate was added to ice/water, stirred for 1 hour and extracted with ethyl acetate. The extract was dried and the solvent removed under reduced pressure to give 7-fluoro-2-methyl-3,1-benzoxazin-4-one, m.p. 159°-160°. (Compound 2).
Reaction SMILES: [NH:1]([C:3]1[CH:7]=[C:6]([S:8][CH3:9])[N:5]([CH3:10])[N:4]=1)[NH2:2].C(O[CH:14]=[C:15]([C:18]#[N:19])[C:16]#[N:17])C>C(O)C>[NH2:19][C:18]1[N:1]([C:3]2[CH:7]=[C:6]([S:8][CH3:9])[N:5]([CH3:10])[N:4]=2)[N:2]=[CH:14][C:15]=1[C:16]#[N:17]
Reactant: CCOC=C(C#N)C#N
Reactant: CSc1cc(NN)nn1C
Solvent: CCO
Product: CSc1cc(-n2ncc(C#N)c2N)nn1C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 2.0 g (13.1 mmol) 3-Hydrazino-1-methyl-5-methylmercaptopyrazole and 1.8 g (14.4 mmol) ethoxymethylenemalononitrile in 25 ml ethanol was stirred for 30 minutes at room temperature and heated at boiling point for 3 hours. The reaction mixture was concentrated and the residue purified by silica gel chromatography (hexane/ethyl acetate 1:1).
Reaction SMILES: [CH2:1]([N:5]1[C:9](=[O:10])[C:8](=[CH:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([OH:20])=[O:19])=[CH:14][CH:13]=2)[NH:7][C:6]1=[O:21])[CH2:2][CH2:3][CH3:4].S(Cl)(Cl)=O.[CH3:26]O>>[CH2:1]([N:5]1[C:9](=[O:10])[C:8](=[CH:11][C:12]2[CH:13]=[CH:14][C:15]([C:18]([O:20][CH3:26])=[O:19])=[CH:16][CH:17]=2)[NH:7][C:6]1=[O:21])[CH2:2][CH2:3][CH3:4]
Reactant: CO
Reactant: CCCCN1C(=O)NC(=Cc2ccc(C(=O)O)cc2)C1=O
Solvent: O=S(Cl)Cl
Product: CCCCN1C(=O)NC(=Cc2ccc(C(=O)OC)cc2)C1=O
Temperature: 40 °C

Procedure:
3-n-Butyl-5-(4-carboxybenzylidene) hydantoin (5.8 g; 0.02 mole) was added gradually to a stirred mixture of thionylchloride (1.5 ml; ca 0.02 mole) in methanol (100 ml.) prepared at -10° C. The mixture was gradually warmed to 40° C. and after 1 hour was boiled under reflux for 3 hours. After cooling and storage in the refrigerator, a white solid formed and was filtered off, washed with cold methanol and dried. This solid was recrystallised from ethyl acetate to give the title compound. Yield 3.2 g; m.p. 212° C.
Reaction SMILES: CO[CH:3](OC)[N:4]([CH3:6])[CH3:5].[OH:9][C:10]1[CH:15]=[C:14]([CH3:16])[O:13][C:12](=[O:17])[CH:11]=1>O1CCOCC1>[CH3:6][N:4]([CH:3]=[C:11]1[C:10](=[O:9])[CH:15]=[C:14]([CH3:16])[O:13][C:12]1=[O:17])[CH3:5]
Reactant: Cc1cc(O)cc(=O)o1
Reactant: COC(OC)N(C)C
Solvent: C1COCCO1
Product: CC1=CC(=O)C(=CN(C)C)C(=O)O1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
N,N-dimethylformamide dimethyl acetal (150 ml) is added dropwise to a mixture of 4-hydroxy-6-methyl-2-pyrone (100 g) in dioxane (400 ml) at 0° C. over 20 minutes. The mixture is warmed to room temperature and stirred an additional 4 hours. The precipitated solid is filtered, washed with isopropanol and dried to give 85.0 g of the title compound. The filtrate is concentrated and isopropanol (300 ml) is added to the residue. This mixture is kept at 0° C. overnight to give an additional 18.8 g of the title compound. Physical characteristics are as follows:
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[CH3:10][O:11][C:12]1[CH:13]=[C:14]([CH:16]=[CH:17][C:18]=1[O:19][CH3:20])[NH2:15]>>[NH2:15][C:14]1[CH:13]=[C:12]([O:11][CH3:10])[C:18]([O:19][CH3:20])=[CH:17][C:16]=1[C:4]([C:3]1[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=1[Cl:1])=[O:5]
Reactant: COc1ccc(N)cc1OC
Reactant: O=Cc1ccccc1Cl
Product: COc1cc(N)c(C(=O)c2ccccc2Cl)cc1OC

Procedure:
(2-amino-4,5-dimethoxyphenyl)-(2-chlorophenyl)-methanone (Xx) was prepared by reacting 2-chlorobenzaldehyde with 0.0196 moles of 3,4-dimethoxy aniline in a manner analogous to Example 1. MH+/Z=292.
Reaction SMILES: CS(Cl)(=O)=O.[CH3:6][C:7]([OH:25])([CH:10]([C:21]([F:24])([F:23])[F:22])[CH2:11][S:12]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)(=[O:14])=[O:13])[CH2:8]O.C(N(CC)CC)C.C1CCN2C(=NCCC2)CC1>C(Cl)Cl>[CH3:6][C:7]1([CH:10]([C:21]([F:22])([F:23])[F:24])[CH2:11][S:12]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)(=[O:13])=[O:14])[O:25][CH2:8]1
Reactant: CC(O)(CO)C(CS(=O)(=O)c1ccccc1)C(F)(F)F
Agent: CS(=O)(=O)Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1(C(CS(=O)(=O)c2ccccc2)C(F)(F)F)CO1
Reaction time: 3.5 h
Yield: 82.1 %

Procedure:
Under an argon atmosphere, 1.45 ml (18.7 mmoles) of methanesulfonyl chloride was added under ice cooling to a solution of 3.90 g (12.5 mmoles) of the compound (18) and 6.10 ml (43.8 mmoles) of triethylamine in 25 ml of methylene chloride, and the mixture was stirred for 3.5 hours while the temperature was being returned to room temperature. To the reaction mixture was added 5.60 ml (37.4 mmoles) of 1,8-diazabicyclo[5,4,0]-7-undecene, and the mixture was stirred for 2.5 hours. The reaction mixture was poured into ice-dilute hydrochloric acid, and extracted with ether. The ether extract was washed with saturated aqueous sodium bicarbonate solution and aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (150 g; n-hexane:ethyl acetate=5:1 to 3:1 v/v) to give 3.02 g of the captioned compound (19) as a colorless oil.
Reaction SMILES: C(=[N:14][C:15]1[CH:16]=[CH:17][C:18]([F:30])=[C:19]([C:21]23[CH2:28][CH:27]2[CH2:26][O:25][CH2:24][C:23](=[S:29])[NH:22]3)[CH:20]=1)(C1C=CC=CC=1)C1C=CC=CC=1.Cl.C([O-])(O)=O.[Na+]>O1CCOCC1>[NH2:14][C:15]1[CH:16]=[CH:17][C:18]([F:30])=[C:19]([C:21]23[CH2:28][CH:27]2[CH2:26][O:25][CH2:24][C:23](=[S:29])[NH:22]3)[CH:20]=1
Reactant: Fc1ccc(N=C(c2ccccc2)c2ccccc2)cc1C12CC1COCC(=S)N2
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: Nc1ccc(F)c(C23CC2COCC(=S)N3)c1
Reaction time: 0.5 h
Yield: 255 %

Procedure:
Crude (1SR,7RS)-1-[5-(benzhydrylidene-amino)-2-fluoro-phenyl]-5-oxa-2-aza-bicyclo[5.1.0]octane-3-thione (intermediate B12A) (600 mg, 1.15 mmol) was dissolved in dioxane (15 ml) and 1 M HCl (1.44 ml, 1.44 mmol) was added at 23° C. After 30 min of stirring, the reaction mixture was poured on sat. NaHCO3-solution and extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and evaporated to give a dark green oil (740 mg), which was purified by silica gel column chromatography with dichloromethane/ethyl acetate to give the title compound as a light yellow solid (175 mg, 60%). MS (ISP): m/z=253.2 [(M+H)+].
Reaction SMILES: [Si:1]([O:8][CH2:9][C@H:10]1[O:14][C@@H:13]([N:15]2[CH:23]=[C:21]([CH3:22])[C:19](=[O:20])[NH:18][C:16]2=[O:17])[CH2:12][C@@H:11]1[OH:24])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[N:45]1[C:49](=[O:50])[C:48]2=[CH:51][CH:52]=[CH:53][CH:54]=[C:47]2[C:46]1=[O:55].CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1.CCOCC>[Si:1]([O:8][CH2:9][C@H:10]1[O:14][C@@H:13]([N:15]2[CH:23]=[C:21]([CH3:22])[C:19](=[O:20])[NH:18][C:16]2=[O:17])[CH2:12][C@@H:11]1[O:24][N:45]1[C:46](=[O:55])[C:47]2=[CH:54][CH:53]=[CH:52][CH:51]=[C:48]2[C:49]1=[O:50])([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:2])[CH3:3]
Reactant: Cc1cn([C@H]2C[C@H](O)[C@@H](CO[Si](C)(C)C(C)(C)C)O2)c(=O)[nH]c1=O
Reactant: O=C1c2ccccc2C(=O)N1O
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOCC
Product: Cc1cn([C@H]2C[C@H](ON3C(=O)c4ccccc4C3=O)[C@@H](CO[Si](C)(C)C(C)(C)C)O2)c(=O)[nH]c1=O
Temperature: 0 °C
Yield: 62 %

Procedure:
To a solution of 5'-O-t-butyldimethylsilylthymidine [1, 21.36 g, 60 mmol, prepared according to the procedure of Nair, et al., Org. Prep. Procedures Int. 1990, 22, 57 in dry THF (750 ml)], triphenylphosphine (17.28 g, 66 mmol) and N-hydroxyphthalimide (10.74 g, 66 mmol) were added. The solution was cooled to 0° C. and diisopropylazodicarboxylate (15.15 g, 75 mmol) was added dropwise over a period of 3 hr while stirring under nitrogen. The reaction mixture was then stirred at room temperature for 12 hr. The solution was evaporated and the residue was dissolved in CH2 Cl2 (750 ml), extracted with sat. NaHCO3 (200 ml), and water (200 ml), dried (MgSO4), filtered and concentrated to furnish yellow oily residue. Silica gel column chromatography (100% hexanes, and then hexanes:Et2O gradient to 90% Et2O) of the residue gave compound 2 as a colorless glass (18.68 g, 62%); 1H NMR (CDCl3) δ 0.05 [2s, 6, (CH3)2 ], 0.91 [s, 9, (CH3)3 ], 2.0 (s, 3, CH3), 2.5-2.65 (m, 2, 2'CH2), 4.05-4.2 (m, 2, 5'CH2), 4.25-4.35 (m, 1, 4'H), 5.0 (m, 1, 3'H), 6.15 (m, 1'H), 8.6 (br s, 1, NH), and aromatic protons. Anal. Calcd. for C24H3 N3O7Si: C, 57.46;H, 6.23; N, 8.37. found : C, 57.20; H, 6.26; N, 8.27.
Reaction SMILES: [Br:1][C:2]1[C:7]2[N:8]=[C:9](SC)[N:10]=[C:11]([NH:12][C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[CH:14]=3)[C:6]=2[C:5](=[O:22])[NH:4][CH:3]=1.C1C=C(Cl)C=C(C(OO)=O)C=1.[NH2:34][CH2:35][CH2:36][CH2:37][NH:38]C(=O)OC(C)(C)C.C(O)(C(F)(F)F)=O>>[NH2:34][CH2:35][CH2:36][CH2:37][NH:38][C:9]1[N:10]=[C:11]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[CH:14]=2)[C:6]2[C:5](=[O:22])[NH:4][CH:3]=[C:2]([Br:1])[C:7]=2[N:8]=1
Reactant: CC(C)(C)OC(=O)NCCCN
Reactant: CSc1nc(Nc2cccc(C)c2)c2c(=O)[nH]cc(Br)c2n1
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: O=C(O)C(F)(F)F
Product: Cc1cccc(Nc2nc(NCCCN)nc3c(Br)c[nH]c(=O)c23)c1

Procedure:
The product was prepared from 8-bromo-4-[(3-methylphenyl)amino]-2-(methylthio)pyrido[4,3-d]pyrimidin-5(6H)-one using mCPBA/1,1-dimethylethyl (3-aminopropyl)carbamate and TFA sequences similar that described for Example 1 (Scheme 2). It was purified using reverse-phase HPLC.
Reaction SMILES: [CH2:1]([C:6]1[CH:7]=[N:8][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][C:21](Br)=[CH:20][CH:19]=3)=[CH:14][CH:13]=2)=[N:10][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH3:5].[Cu][C:26]#[N:27].C(N)CN>CN(C)C=O>[CH2:1]([C:6]1[CH:7]=[N:8][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][C:21]([C:26]#[N:27])=[CH:20][CH:19]=3)=[CH:14][CH:13]=2)=[N:10][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: N#C[Cu]
Reactant: CCCCCc1cnc(-c2ccc(-c3ccc(Br)cc3)cc2)nc1
Solvent: CN(C)C=O
Solvent: NCCN
Product: CCCCCc1cnc(-c2ccc(-c3ccc(C#N)cc3)cc2)nc1

Procedure:
1.5 G. of 5-n-pentyl-2-(4'-bromo-4-biphenylyl)-pyrimidine are heated at reflux for 22 hours with 2.5 g. of copper-(I) cyanide (content 70%) in 50 ml. of dimethylformamide. After cooling, 25 ml. of 10% aqueous ethylenediamine solution are added and, after stirring for a short time, the mixture is extracted with methylene chloride. The organic extract is shaken with a further 25 ml. of ethylenediamine solution and then washed until neutral. The crude concentrate is chromatographed on silica gel with toluene/1% acetone. Recrystallization of the pure fractions from ethyl acetate yields 5-n-pentyl-2-(4'-cyano-4-biphenylyl)-pyrimidine, having a melting point of 123.5°-124° C. and clearing point of 204.5°-205° C.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][PH:11](=[O:20])[O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[NH2:22][C@H:23]([C:31]([NH:33][C@H:34]([C:39]([O:41][CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)=[O:40])[CH2:35][CH:36]([CH3:38])[CH3:37])=[O:32])[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[C:14]1([CH2:13][O:12][P:11]([CH2:10][CH2:9][CH2:8][CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)([NH:22][C@H:23]([C:31]([NH:33][C@H:34]([C:39]([O:41][CH2:42][C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=2)=[O:40])[CH2:35][CH:36]([CH3:38])[CH3:37])=[O:32])[CH2:24][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)=[O:20])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CC(C)C[C@H](NC(=O)[C@@H](N)Cc1ccccc1)C(=O)OCc1ccccc1
Reactant: O=[PH](CCCCc1ccccc1)OCc1ccccc1
Agent: Cl
Product: CC(C)C[C@H](NC(=O)[C@H](Cc1ccccc1)NP(=O)(CCCCc1ccccc1)OCc1ccccc1)C(=O)OCc1ccccc1

Procedure:
(4-Phenylbutyl)phosphinic acid, phenylmethyl ester is reacted with L-phenylalanyl-L-leucine, phenylmethyl ester, hydrochloride according to the procedure of Example 1(c) to yield N-[N-[phenyl-methoxy(4-phenylbutyl)phosphinyl]-L-phenylalanyl]-L-leucine, phenylmethyl ester.
Reaction SMILES: [S:1]1[C:5]2[CH2:6][CH2:7][NH:8][CH2:9][CH2:10][C:4]=2[CH:3]=[CH:2]1.C(N(CC)CC)C.Cl[C:19]([O:21][CH2:22][CH3:23])=[O:20]>C1COCC1.O>[CH2:22]([O:21][C:19]([N:8]1[CH2:9][CH2:10][C:4]2[CH:3]=[CH:2][S:1][C:5]=2[CH2:6][CH2:7]1)=[O:20])[CH3:23]
Reactant: CCOC(=O)Cl
Reactant: c1cc2c(s1)CCNCC2
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)N1CCc2ccsc2CC1
Temperature: 25 °C
Yield: 77 %

Procedure:
To a solution of 5,6,7,8-tetrahydro-4H-thieno[2,3-d]azepine (951 mg, 5.03 mmol) in THF (20 ml) at 0° C. was added triethylamine (1526 mg, 15.09 mmol) and ethyl chloroformate (573 mg, 5.3 mmol). The reaction mixture was warmed to ambient temperature for 4 hours and then diluted with water (100 ml) and extracted with EtOAc (3×75 ml). The combined organic phases were washed with brine (100 ml), dried (MgSO4), and concentrated in vacuo to give the crude product as an oil. Purification by flash chromatography (gradient elution: 0 to 40% EtOAc in hexane) afforded the subtitled compound as an oil; yield 77%. 1H NMR (300 MHz, CDCl3) 6.96 (d, J=5 Hz, 1 H), 6.76 (d, J=5 Hz, 1 H), 4.18 (q, J=7 Hz, 2 H), 3.52-3.78 (m, 4 H), 2.78-3.08 (m, 4 H), 1.28 (t, J=7 Hz, 3 H); MS: ESI (positive): 226 (M+H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH:5]([C:12](=[O:14])[CH3:13])[CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH3:2].[H-].[Na+].[CH2:18](I)[CH2:19][CH3:20].[Na+].[Cl-]>CS(C)=O.O>[CH2:1]([O:3][C:4](=[O:15])[C:5]([C:12](=[O:14])[CH3:13])([CH2:18][CH2:19][CH3:20])[CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH3:2]
Reactant: CCOC(=O)CC(C(C)=O)C(=O)OCC
Reactant: CCCI
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CCCC(CC(=O)OCC)(C(C)=O)C(=O)OCC
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of 2-acetyl-succinic acid diethyl ester (30 g, 139 mmol) in DMSO (250 ml) is added NaH (5.8 g, 60% in mineral oil, 145 mmol) in 10 portions over a period of 1 hour. The resulting solution is stirred at room temperature for another 1.5 hours. PrI (17.1 ml, 174 mmol) is added slowly over the period of 45 minutes and the resulting solution is stirred at room temperature overnight. Water (500 ml) is added, the solution is saturated with NaCl and extracted with EtOAc (3×250 ml). The combined extracts are washed with brine (400 ml), dried over Na2SO4 and evaporated in vacuo. The resulting 2-acetyl-2-propyl-succinic acid diethyl ester is obtained as a yellow oil, which is used for the next step without further purification.
Reaction SMILES: [CH:1]([NH:4][CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1)([CH3:3])[CH3:2].O[CH2:12][C:13]#[N:14]>>[CH:5]1([N:4]([CH2:12][C:13]#[N:14])[CH:1]([CH3:3])[CH3:2])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1
Reactant: CC(C)NC1CCCCC1
Reactant: N#CCO
Product: CC(C)N(CC#N)C1CCCCC1

Procedure:
Prepared from N-isopropylcyclohexylamine and hydroxyacetonitrile by a similar method to Preparation 24.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH2:8]O)[CH:5]=[CH:4][N:3]=1.S(Cl)([Cl:12])=O.C(Cl)Cl.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C>[Cl:12][CH2:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([CH3:1])[CH:7]=1
Reactant: Cc1cc(CO)ccn1
Reactant: O=S(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Cc1cc(CCl)ccn1
Temperature: 60 °C
Reaction time: 0.08 h

Procedure:
(2-Methyl-pyridin-4-yl)-methanol (40 mg, 0.33 mmol) described in Manufacturing Example 47-1-1, thionyl chloride (0.047 ml, 0.65 mmol) and methylene chloride (4.0 ml) were stirred for 5 minutes at 60° C. Sodium bicarbonate solution and ethyl acetate were added to separate the reaction solution, and the ethyl acetate layer was dried over sodium sulfate. The solvent was evaporated under a reduced pressure to obtain 4-chloromethyl-2-methyl-pyridine as a crude product.
Reaction SMILES: Cl[S:2]([CH:5]([C:9]1[CH:10]=[CH:11][C:12]2[O:16][CH2:15][CH2:14][C:13]=2[CH:17]=1)[C:6]([OH:8])=[O:7])(=[O:4])=[O:3].[CH2:18]([OH:20])[CH3:19].C(N(CC)CC)C.O>C(OCC)(=O)C>[CH2:18]([O:20][S:2]([CH:5]([C:9]1[CH:10]=[CH:11][C:12]2[O:16][CH2:15][CH2:14][C:13]=2[CH:17]=1)[C:6]([OH:8])=[O:7])(=[O:3])=[O:4])[CH3:19]
Reactant: CCO
Reactant: O=C(O)C(c1ccc2c(c1)CCO2)S(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: CCOC(C)=O
Product: CCOS(=O)(=O)C(C(=O)O)c1ccc2c(c1)CCO2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
α-Chlorosulfonyl(2,3-dihydro-5-benzofuranyl)acetic acid (5 mmole) is added to 30 ml of ethyl acetate. To this mixture is added 5 mmole of ethanol in 10 ml of ethyl acetate which contains 10 mmole of triethylamine. The mixture is stirred at room temperature for about 1 hour and 50 ml of water is added. The pH is adjusted to about 6.5 and the layers separated. The organic layer is dried over magnesium sulfate, filtered and evaporated to give ethoxysulfonyl(2,3-dihydro-5-benzofuranyl)acetic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([NH2:19])[CH:11]=[N:12][C:13]=2[O:14][CH:15]2[CH2:18][CH2:17][CH2:16]2)=[CH:4][CH:3]=1.[N:20]1[CH:25]=[CH:24][N:23]=[CH:22][C:21]=1[C:26](O)=[O:27]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([NH:19][C:26]([C:21]3[CH:22]=[N:23][CH:24]=[CH:25][N:20]=3)=[O:27])[CH:11]=[N:12][C:13]=2[O:14][CH:15]2[CH2:18][CH2:17][CH2:16]2)=[CH:4][CH:3]=1
Reactant: O=C(O)c1cnccn1
Reactant: Nc1cnc(OC2CCC2)c(-c2ccc(Cl)cc2)c1
Product: O=C(Nc1cnc(OC2CCC2)c(-c2ccc(Cl)cc2)c1)c1cnccn1

Procedure:
The title compound was synthesized in analogy to Example 42 g, using 5-(4-chloro-phenyl)-6-cyclobutoxy-pyridin-3-ylamine (example 78 d) and 2-pyrazinecarboxylic acid (CAN 98-97-5) as starting materials; MS (EI) 381.2(M+H)+.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:14]3[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=3)[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:30]2[CH:31]=[N:32][NH:33][CH:34]=2)O1>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[NH:32]1[CH:31]=[C:30]([C:2]2[CH:7]=[CH:6][C:5]([C:8]3([C:14]4[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=4)[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]3)=[CH:4][CH:3]=2)[CH:34]=[N:33]1
Reactant: N#Cc1ccc(C2(c3ccc(Cl)cc3)CCNCC2)cc1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: N#Cc1ccc(C2(c3ccc(-c4cn[nH]c4)cc3)CCNCC2)cc1
Temperature: 100 °C

Procedure:
4-[4-(4-chloro-phenyl)-piperidin-4-yl]-benzonitrile was reacted with 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole following the procedure set out in Example 1, but using tetrakis(triphenylphosphine) palladium (0) as the catalyst and heating at 100° C. for 15 minutes, to obtain the title compound. LCMS (PS-A3) Rt 6.68 min [M+H]+ 329. 1H NMR (Me-d3-OD) δ 2.65-2.73 (4H, m), 2.77-2.85 (4H, m), 3.75 (3H, s), 7.46 (2H, d), 7.59 (2H, d), 7.68 (2H, d), 7.71 (2H, d), 8.42 (2H, br. s).
Reaction SMILES: [CH:1]([C@:3]12[CH2:41][CH2:40][C@@H:39]([C:42]([CH3:44])=[CH2:43])[C@@H:4]1[C@@H:5]1[C@@:18]([CH3:21])([CH2:19][CH2:20]2)[C@@:17]2([CH3:22])[C@@H:8]([C@:9]3([CH3:38])[C@@H:14]([CH2:15][CH2:16]2)[C:13]([CH3:24])([CH3:23])[C:12]([C:25]2[CH:37]=[CH:36][C:28]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])=[CH:27][CH:26]=2)=[CH:11][CH2:10]3)[CH2:7][CH2:6]1)=O.C(O)(=O)C.[NH2:49][CH2:50][CH2:51][N:52]1[CH2:57][CH2:56][N:55]([C:58]([O:60][C:61]([CH3:64])([CH3:63])[CH3:62])=[O:59])[CH2:54][CH2:53]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.C([O-])(O)=O.[Na+]>[C:32]([O:31][C:29]([C:28]1[CH:27]=[CH:26][C:25]([C:12]2[C:13]([CH3:24])([CH3:23])[C@H:14]3[C@:9]([CH3:38])([CH2:10][CH:11]=2)[C@@H:8]2[C@:17]([CH3:22])([C@@:18]4([CH3:21])[C@H:5]([CH2:6][CH2:7]2)[C@H:4]2[C@H:39]([C:42]([CH3:44])=[CH2:43])[CH2:40][CH2:41][C@:3]2([CH2:1][NH:49][CH2:50][CH2:51][N:52]2[CH2:57][CH2:56][N:55]([C:58]([O:60][C:61]([CH3:64])([CH3:63])[CH3:62])=[O:59])[CH2:54][CH2:53]2)[CH2:20][CH2:19]4)[CH2:16][CH2:15]3)=[CH:37][CH:36]=1)=[O:30])([CH3:35])([CH3:34])[CH3:33]
Reactant: CC(C)(C)OC(=O)N1CCN(CCN)CC1
Reactant: C=C(C)[C@@H]1CC[C@]2(C=O)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC(C)(C)C)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: C=C(C)[C@@H]1CC[C@]2(CNCCN3CCN(C(=O)OC(C)(C)C)CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC(C)(C)C)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of tert-butyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-formyl-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate (0.1 g, 0.167 mmol) in DCE (2 ml) was added acetic acid (0.019 ml, 0.334 mmol) and 4-N-(2-Aminoethyl)-1-N-Boc-piperazine (0.077 g, 0.334 mmol). The mixture was stirred at rt for 2 h then to the mixture was added sodium triacetoxyborohydride (0.177 g, 0.835 mmol). The mixture was stirred for 3 days at rt then was diluted with 7 ml of sat. NaHCO3 and was extracted with dichloromethane (3×7 ml). The combined organic layers were dried with Na2SO4. The drying agent was removed by filtration and the filtrate was concentrated under reduced pressure. The crude product was used in the next step without further purification. LCMS: m/e 812.3 (M+H)+, 3.30 min (method 6).