Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([CH2:5][CH:6]([CH3:14])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH2:3][OH:4].[H][H]>C1CCCCC1>[CH:8]1([CH2:7][CH:6]([CH3:14])[CH2:5][CH:2]([CH3:1])[CH2:3][OH:4])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: [H][H]
Reactant: CC(CO)CC(C)Cc1ccccc1
Solvent: C1CCCCC1
Product: CC(CO)CC(C)CC1CCCCC1
Reaction time: 18 h
Yield: 97 %

Procedure:
100 g of 2,4-Dimethyl-5-phenyl-pentanol (obtained as described in EP 0 908 439) combined with 2 g Ru on aluminium oxide (Ru content: 5 wt. %) were hydrogenated in 80 ml cyclohexane at a hydrogen pressure of 22 bar and at a temperature of 105° C. After 18 hours the reaction was finished. The catalyst was removed and the product distilled. 100 g (content: 99.5%) of 5-cyclohexyl-2,4-dimethyl-pentanol were obtained.
Reaction SMILES: [N:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=O)=[CH:6][CH:5]=1)=[N+:2]=[N-:3].C(Cl)(=O)C(Cl)=O.[CH3:19][O:20][C:21](=[O:31])[CH2:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([NH2:30])=[CH:26][N:25]=1.CCN(C(C)C)C(C)C>C(Cl)Cl.C(OCC)(=O)C.CN(C=O)C>[CH3:19][O:20][C:21](=[O:31])[CH2:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([NH:30][C:8](=[O:10])[C:7]2[CH:6]=[CH:5][C:4]([N:1]=[N+:2]=[N-:3])=[CH:12][CH:11]=2)=[CH:26][N:25]=1
Reactant: [N-]=[N+]=Nc1ccc(C(=O)O)cc1
Reactant: COC(=O)COc1ccc(N)cn1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COC(=O)COc1ccc(NC(=O)c2ccc(N=[N+]=[N-])cc2)cn1
Reaction time: 0.33 h
Yield: 40.7 %

Procedure:
To a mixture of 4-azidobenzoic acid (200 mg, 1.23 mmol) and oxalyl chloride (5 mL) was added a catalytic quantity of DMF (50 μL). The reaction mixture was stirred for 20 minutes and was concentrated in vacuo. Benzene (20 mL) was added and the mixture was again concentrated in vacuo. The resulting residue was dissolved in DCM (5 mL) and was treated with (5-amino-pyridin-2-yloxy)-acetic acid methyl ester (242 mg, 1.33 mmol) followed by DIPEA (427 μL, 2.46 mmol). The reaction mixture was stirred for 15 h at ambient temperature before being diluted with DCM, washed with water and brine and dried over magnesium sulfate. Filtration and concentration in vacuo gave a residue that was taken up in a small portion of ethyl acetate (5 mL) and was precipitated through the addition of hexanes (50 mL). The solids were collected by vacuum filtration on a fritted glass funnel to afford 164 mg (41%) of (5-(4-azido-benzoylamino)pyridin-2-yloxy)acetic acid methyl ester as a solid: 1H NMR (300 MHz, DMSO-d6) δ 10.25 (bs, 1H), 8.39 (m, 1H), 8.00 (m, 3H), 7.24 (m, 2H), 6.92 (m, 1H), 4.87 (s, 2H), 3.63 (s, 3H); MS (EI) m/z 326.12 (M−H)−.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[C:9]([Cl:10])=[CH:8][CH:7]=[CH:6][C:5]=1[S:11]([N:14]([CH3:23])[CH2:15][CH2:16][N:17]1[CH2:21][CH2:20][NH:19][C:18]1=[O:22])(=[O:13])=[O:12].Br[CH2:25][CH2:26][C:27]1[CH:34]=[CH:33][C:30]([C:31]#[N:32])=[CH:29][CH:28]=1.Cl>CN(C)C=O.O>[Cl:3][C:4]1[C:9]([Cl:10])=[CH:8][CH:7]=[CH:6][C:5]=1[S:11]([N:14]([CH2:15][CH2:16][N:17]1[CH2:21][CH2:20][N:19]([CH2:25][CH2:26][C:27]2[CH:34]=[CH:33][C:30]([C:31]#[N:32])=[CH:29][CH:28]=2)[C:18]1=[O:22])[CH3:23])(=[O:13])=[O:12]
Reactant: N#Cc1ccc(CCBr)cc1
Reactant: CN(CCN1CCNC1=O)S(=O)(=O)c1cccc(Cl)c1Cl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CN(CCN1CCN(CCc2ccc(C#N)cc2)C1=O)S(=O)(=O)c1cccc(Cl)c1Cl
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
34 mg (0.84 mmol) of NaH (60%) were added to a solution of 290 mg (0.82 mmol) of 2,3-dichloro-N-methyl-N-[2-(2-oxoimidazolidin-1-yl)ethyl]benzenesulphonamide in 10 ml of dimethylformamide, and the mixture was stirred at room temperature for 10 minutes. 177 mg (0.84 mmol) of 4-(2-bromoethyl)benzonitrile were then added. The reaction mixture was stirred at 50° C. overnight. The mixture was then poured into water, 1 N HCl was added and the mixture was extracted with ethyl acetate. The combined organic extracts were washed with saturated sodium bicarbonate solution and saturated sodium chloride solution, dried over sodium sulphate and concentrated. The crude product obtained in this manner was purified by column chromatography on silica gel (mobile phase: dichloromethane/methanol 0-3%).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[O:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.[Br:13][CH2:14][CH2:15]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1.CCCCCC>[Br:13][CH2:14][CH2:15][O:10][C:7]1[CH:6]=[CH:5][C:4]([O:3][C:2]([F:11])([F:12])[F:1])=[CH:9][CH:8]=1
Reactant: Oc1ccc(OC(F)(F)F)cc1
Reactant: OCCBr
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCCCCC
Solvent: C1CCOC1
Product: FC(F)(F)Oc1ccc(OCCBr)cc1
Reaction time: 12 h
Yield: 103.7 %

Procedure:
4-(Trifluoromethoxy)phenol (15 g), 2-bromoethanol (7.76 g) and triphenylphosphine (22.1 g) were dissolved in tetrahydrofuran (250 ml). Diethyl azodicarboxylate (13.3 ml) was added dropwise to the stirred mixture and stirring was continued for 12 hours. The mixture was concentrated in vacuo to give a yellow oil. The oil was diluted with hexane to precipitate the triphenylphosphine oxide by-product which was removed by filtration. The filtrate was concentrated and purified on silica using 10% ether in hexane as eluant to give the product (18.35 g). 1H NMR (250 MHz, CDCl3) δ 3.63 (2H, t, J 6.1 Hz), 4.30 (2H, t, J 6.2 Hz), 6.84-6.95 (2H, m), 7.12-7.17 (2H, m).
Reaction SMILES: [NH2:1]/[C:2](/[C:9]([F:12])([F:11])[F:10])=[CH:3]\[C:4]([O:6][CH2:7][CH3:8])=[O:5].[H-].[Na+].[F:15][C:16]1[C:28]([N:29]=[C:30]=[O:31])=[CH:27][C:19]2[N:20]([CH2:24][C:25]#[CH:26])[C:21](=[O:23])[S:22][C:18]=2[CH:17]=1>CN(C)C=O.CN(C)C=O.C1(C)C=CC=CC=1>[CH2:7]([O:6][C:4]([CH:3]=[C:2]([NH:1][C:30](=[O:31])[NH:29][C:28]1[C:16]([F:15])=[CH:17][C:18]2[S:22][C:21](=[O:23])[N:20]([CH2:24][C:25]#[CH:26])[C:19]=2[CH:27]=1)[C:9]([F:10])([F:11])[F:12])=[O:5])[CH3:8]
Reactant: CCOC(=O)/C=C(\N)C(F)(F)F
Reactant: C#CCn1c(=O)sc2cc(F)c(N=C=O)cc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: C#CCn1c(=O)sc2cc(F)c(NC(=O)NC(=CC(=O)OCC)C(F)(F)F)cc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 18.51 g of ethyl 3-amino-4,4,4-trifluorocrotonate in 50 ml of dimethylformamide is added dropwise while stirring at 0° C. during 30 minutes to 4.41 g of a 55% sodium hydride dispersion in 100 ml of dimethylformamide and the mixture is stirred at room temperature for 2 hours. The reaction mixture is then cooled to -55° C. and treated during 3 minutes while stirring with a solution of 25.10 g of 6-fluoro-5-isocyanato-3-(2-propynyl)-2-benzothiazolinone in 200 ml of dimethylformamide/toluene (1:1). In so doing, the temperature of the reaction mixture rises to -15° C. and the mixture is subsequently stirred at room temperature for one hour. The thus-formed intermediate 5-{3-[2-(ethoxycarbonyl)-1-trifluoromethyl-vinyl]ureido}-6-fluoro-3-(2-propynyl)-2-benzothiazolinone is not isolated.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([OH:17])=O)[CH3:14])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.[NH2:18][CH:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22](C2C=NC=CC=2)[NH:21][C:20]1=[O:35]>>[F:8][C:6]1[CH:5]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([NH:18][CH:19]2[C:28]3[C:23](=[CH:24][CH:25]=[C:26]([C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)[CH:27]=3)[CH2:22][NH:21][C:20]2=[O:35])=[O:17])[CH3:14])=[O:11])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Reactant: NC1C(=O)NC(c2cccnc2)c2ccccc21
Product: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)NC1C(=O)NCc2ccc(-c3ccccc3)cc21

Procedure:
Following General Procedure D above using N-(3,5-difluorophenylacetyl)-L-alanine (Example B) and 4-amino-6-phenyl-1,2,3,4-tetrahydroisoquinoline-3-one (General Procedure 5-D), the title compound was prepared. The product was purified by LC 2000 chromatography, eluting with ethyl acetate.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13]([C:14]3[CH:19]=[CH:18][N:17]=[C:16]([Cl:20])[CH:15]=3)=[CH:12][C:11]([C:21](O)=[O:22])=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8].ClC1C=C(C2N(C3C=NC=CC=3)N=C(C([N:45]3[CH2:50][CH2:49][NH:48][C:47](=[O:51])[CH2:46]3)=O)C=2)C=C(F)C=1.O=C1CNCCN1>>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13]([C:14]3[CH:19]=[CH:18][N:17]=[C:16]([Cl:20])[CH:15]=3)=[CH:12][C:11]([C:21]([N:45]3[CH2:50][CH2:49][NH:48][C:47](=[O:51])[CH2:46]3)=[O:22])=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: O=C(O)c1cc(-c2ccnc(Cl)c2)n(-c2ccc(F)c(Cl)c2)n1
Reactant: O=C1CN(C(=O)c2cc(-c3cc(F)cc(Cl)c3)n(-c3cccnc3)n2)CCN1
Agent: O=C1CNCCN1
Product: O=C1CN(C(=O)c2cc(-c3ccnc(Cl)c3)n(-c3ccc(F)c(Cl)c3)n2)CCN1

Procedure:
100 mg (0.28 mmol) of the compound of Example 68A is reacted analogously to the synthesis of the compound of Example 4 with 30 mg (0.30 mmol) of 2-oxopiperazine. 111 mg (90% of theory) of the title compound is obtained.
Reaction SMILES: [CH2:1]([O:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([O:22][CH3:23])[N:12]2[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]Cl)=[C:8]([NH2:24])[N:7]=1)[CH2:2][CH2:3][CH3:4].[NH:25]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1>>[CH2:1]([O:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([O:22][CH3:23])[N:12]2[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][N:25]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)=[C:8]([NH2:24])[N:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: C1CCCNCC1
Reactant: CCCCOc1nc(N)c2nc(OC)n(CCCCCCCl)c2n1
Product: CCCCOc1nc(N)c2nc(OC)n(CCCCCCN3CCCCCC3)c2n1

Procedure:
Prepared similarly to Intermediate 38 from 2-(butyloxy)-9-(6-chlorohexyl)-8-(methyloxy)-9H-purin-6-amine and hexahydro-1H-azepine.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][C:2]1=[O:6].I[C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1.C(=O)([O-])[O-].[K+].[K+]>[Cu]>[CH3:15][O:14][C:11]1[CH:12]=[CH:13][C:8]([N:1]2[CH2:5][CH2:4][CH2:3][C:2]2=[O:6])=[CH:9][CH:10]=1
Reactant: O=C1CCCN1
Reactant: COc1ccc(I)cc1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1ccc(N2CCCC2=O)cc1

Procedure:
In step a of the overall synthesis, 2-pyrrolidinone and 4-iodoanisole are heated in the presence of copper powder and potassium carbonate to give the N-(4-methoxyphenyl)pyrrolidin-2-one, which in step b is treated with ethylmagnesium bromide Grignard reagent to give an aliphatic ketone after ring opening of the pyrrolidinone. This ketone is isolated and then undergoes ring closure to form the 3-hydroxy-1,2,5,6-tetrahydropyridin-2-one intermediate in steps c and d using ethyl oxalyl chloride and sodium hydroxide in step c and sodium ethoxide and ethanol in step d. The corresponding 3-methoxy intermediate is obtained in step e by treatment with 3-methyl-p-tolyltriazine, after which in step f the 4,5,6,7-tetrahydro-7-oxo-1H-pyrazolo[3,4-c]pyridine intermediate is obtained by ring closure using cyclopentyl hydrazine hydrochloride. The 4-methoxyphenyl N-protecting group is removed in step g by treatment with cerium (IV) ammonium nitrate to give the lactam intermediate, after which in step h the lactam intermediate is converted to the corresponding thiolactam intermediate by treatment with phosphorus pentasulfide. The tricyclic final product is prepared in steps i′, j and k by treatment with anhydrous hydrazine in step i, followed by treatment with 2-thiophene carbonyl chloride in step j and refluxing in step k.
Reaction SMILES: [C:1]([C:3]1([NH:6][C:7]([C@@H:9]2[CH2:13][C@@H:12]([S:14]([C:17]3[CH:22]=[CH:21][C:20](F)=[CH:19][C:18]=3[Cl:24])(=[O:16])=[O:15])[CH2:11][C@H:10]2[C:25]([N:27]2[CH2:30][C:29]([F:32])([F:31])[CH2:28]2)=[O:26])=[O:8])[CH2:5][CH2:4]1)#[N:2].[CH3:33][N:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1>>[C:1]([C:3]1([NH:6][C:7]([C@@H:9]2[CH2:13][C@@H:12]([S:14]([C:17]3[CH:22]=[CH:21][C:20]([N:37]4[CH2:38][CH2:39][N:34]([CH3:33])[CH2:35][CH2:36]4)=[CH:19][C:18]=3[Cl:24])(=[O:15])=[O:16])[CH2:11][C@H:10]2[C:25]([N:27]2[CH2:28][C:29]([F:32])([F:31])[CH2:30]2)=[O:26])=[O:8])[CH2:5][CH2:4]1)#[N:2]
Reactant: CN1CCNCC1
Reactant: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3ccc(F)cc3Cl)C[C@H]2C(=O)N2CC(F)(F)C2)CC1
Product: CN1CCN(c2ccc(S(=O)(=O)[C@@H]3C[C@@H](C(=O)NC4(C#N)CC4)[C@H](C(=O)N4CC(F)(F)C4)C3)c(Cl)c2)CC1

Procedure:
The title compound was prepared in analogy to example 127 using (1R,2R,4R)-4-(2-chloro-4-fluoro-benzenesulfonyl)-2-(3,3-difluoro-azetidine-1-carbonyl)-cyclopentanecarboxylic acid-(1-cyano-cyclopropyl)-amide (example 119 step 4) and N-methylpiperazine. White solid (81%). MS (EI): 570.2 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[NH:7][C@@H:8]([C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([C:18]([C:20]2[CH:21]=[N:22][C:23](Cl)=[CH:24][CH:25]=2)=[O:19])[C:12]=1[F:27])[CH2:9][CH3:10])([CH3:4])([CH3:3])[CH3:2].[NH3:29]>CO>[C:1]([O:5][C:6](=[O:28])[NH:7][C@@H:8]([C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([C:18]([C:20]2[CH:21]=[N:22][C:23]([NH2:29])=[CH:24][CH:25]=2)=[O:19])[C:12]=1[F:27])[CH2:9][CH3:10])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC[C@@H](NC(=O)OC(C)(C)C)c1ccc(Cl)c(C(=O)c2ccc(Cl)nc2)c1F
Reactant: N
Solvent: CO
Product: CC[C@@H](NC(=O)OC(C)(C)C)c1ccc(Cl)c(C(=O)c2ccc(N)nc2)c1F
Yield: 51 %

Procedure:
Step 2 {(R)-1-[4-Chloro-3-(6-chloro-pyridine-3-carbonyl)-2-fluoro-phenyl]-propyl}-carbamic acid tert-butyl ester (6.4 g, 15 mmol) was suspended in 7M NH3 in MeOH (32 mL) and split over 4 Reacti-vials and all heated at 100 degC overnight. The mixture was then evaporated down and purified by silica column, eluting 20-100% EtOAc in petroleum ether to give {(R)-1-[3-(6-amino-pyridine-3-carbonyl)-4-chloro-2-fluoro-phenyl]-propyl}-carbamic acid tert-butyl ester (3.1 g, 7.6 mmol, 51%). [MH]+ 408
Reaction SMILES: [CH3:1][C:2]1[C:3]([NH:14][C:15]([NH2:17])=S)=[C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.O.O.O.C([O-])(=O)C.[Pb+2].C([O-])(=O)C.[OH-].[K+]>O>[CH3:1][C:2]1[C:3]([NH:14][C:15]#[N:17])=[C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cccc(-c2ccccc2)c1NC(N)=S
Agent: CC(=O)[O-]
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: Cc1cccc(-c2ccccc2)c1NC#N

Procedure:
A mixture of N-(3-methyl-2-biphenylyl)thiourea (11.3 g), lead acetate trihydrate (17.7 g), potassium hydroxide (26.1 g) and water (50 ml) was heated at 90°-95° C. for 30 minutes to give 3-methyl-2-biphenylylcyanamide as a yellow oil.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[Br:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][O:18][CH2:19][C:20]#[CH:21]>>[Br:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][O:18][CH2:19][C:20]#[C:21][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1
Reactant: C#CCOCCCCCCBr
Reactant: O=[N+]([O-])c1ccc(Br)nc1
Product: O=[N+]([O-])c1ccc(C#CCOCCCCCCBr)nc1

Procedure:
2-Bromo-5-nitropyridine (6.4 g) and 1-bromo-6-[(2-propynyl)oxy]hexane (6.39 g) were treated as in Intermediate 20 to give, after FCC eluting with hexane-ether (2:1), the title compound as a brown oil (7 g), t.l.c. (hexane-ether 5:1) Rf 0.22.
Reaction SMILES: Cl.[CH:2]1([N:9]2[CH2:14][CH2:13][C:12]3([O:19][C:18](=[O:20])[NH:17][C:16]4[CH:21]=[CH:22][CH:23]=[CH:24][C:15]3=4)[CH2:11][CH2:10]2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[H-].[Na+].[CH3:27]I>CN(C)C=O.O>[CH:2]1([N:9]2[CH2:14][CH2:13][C:12]3([O:19][C:18](=[O:20])[N:17]([CH3:27])[C:16]4[CH:21]=[CH:22][CH:23]=[CH:24][C:15]3=4)[CH2:11][CH2:10]2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: O=C1Nc2ccccc2C2(CCN(C3CCCCCC3)CC2)O1
Reactant: CI
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CN1C(=O)OC2(CCN(C3CCCCCC3)CC2)c2ccccc21
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
1′-cycloheptylspiro[benzo[d][1,3]oxazine-4,4′-piperidin]-2(1H)-one hydrochloride (compound No. 5) (188 mg, 0.54 mmol) was suspended in anhydrous dimethylformamide (4.0 mL), treated with sodium hydride (48 mg, 60% dispersion in mineral oil, 1.2 mmol) and stirred at room temperature for 10 minutes under nitrogen. The reaction mixture was then treated with a solution of methyl iodide (92 mg, 0.65 mmol) in anhydrous dimethylformamide (1.0 mL) and stirred at room temperature for 1 hour. The reaction mixture was diluted with water (50 mL), and the product was extracted in dichloromethane (2×50 mL). The pooled extracts were washed with water (2×10 mL), saturated NaHCO3, (2×10 mL) and saturated brine (2×10 mL); then dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure to afford crude 1′-cycloheptyl-1-methylspiro[benzo[d][1,3]oxazine-4,4′-piperidin]-2(1H)-one (compound no. 65) free base as a colorless oil.
Reaction SMILES: C(OC([N:8]1[CH2:11][CH:10]([N:12]2[CH2:15][C:14]([F:17])([F:16])[CH2:13]2)[CH2:9]1)=O)(C)(C)C>C(Cl)Cl.C(O)(C(F)(F)F)=O>[F:16][C:14]1([F:17])[CH2:15][N:12]([CH:10]2[CH2:11][NH:8][CH2:9]2)[CH2:13]1
Reactant: CC(C)(C)OC(=O)N1CC(N2CC(F)(F)C2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: FC1(F)CN(C2CNC2)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 36.5 %

Procedure:
A 10 mL round-bottomed flask was charged with a solution of 3,3-difluoro-[1,3′]biazetidinyl-1′-carboxylic acid tert-butyl ester (0.15 g, 0.61 mmol) in DCM/TFA (3 mL/3 mL) The reaction mixture was stirred for 3 h at room temperature. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge. The cartridge was washed with MeOH and the desired product was eluted using 2 M NH3 in MeOH to give 3,3-Difluoro-[1,3′]biazetidinyl as a colourless oil (0.033 g, 37%). 1H NMR (300 MHz, CDCl3): δ 3.73-3.55 (m, 8H), 3.57-3.43 (m, 1H), 2.77 (s, 1H)
Reaction SMILES: B(Br)(Br)Br.[CH2:5]([N:8]([CH:18]1[CH2:27][CH2:26][C:25]2[C:20](=[CH:21][CH:22]=[CH:23][C:24]=2[O:28]C)[CH2:19]1)[CH2:9][CH2:10][O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:6][CH3:7]>ClCCl.C(Cl)(Cl)Cl>[O:11]([CH2:10][CH2:9][N:8]([CH2:5][CH2:6][CH3:7])[CH:18]1[CH2:27][CH2:26][C:25]2[C:24]([OH:28])=[CH:23][CH:22]=[CH:21][C:20]=2[CH2:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CCCN(CCOc1ccccc1)C1CCc2c(cccc2OC)C1
Agent: BrB(Br)Br
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: CCCN(CCOc1ccccc1)C1CCc2c(O)cccc2C1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a mixture of 1.0M Boron tribromide in dichloromethane in 20 ML chloroform was added dropwise the product of Example 1 (80 mg, 0.236 mmol) in chloroform and stirred at room temperature of 15 min. After workup, the crude mixture was subjected to flash chromatography (Silica: 8.2 pet ether/EtOAc). The product showed characteristic peaks at: NMR (300 MHz, CDCl3) δ7.3-6.6(m, 8H), 4.0(t, 2H), 3.1-2.5(m,9H), 2.1(m, 1H), 1.7-1.4 (m, 3H), 0.9(t, 3H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([Cl:8])[CH:5]=[C:4](Cl)[N:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)(O)[O-].[Na+].[CH3:34][O:35][C:36](=[O:55])[C:37]1[CH:42]=[C:41](B2OC(C)(C)C(C)(C)O2)[C:40]([CH3:52])=[CH:39][C:38]=1[O:53][CH3:54]>C(OCC)(=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.COCCOC.O>[CH3:34][O:35][C:36](=[O:55])[C:37]1[CH:42]=[C:41]([C:4]2[CH:5]=[C:6]([Cl:8])[N:7]=[C:2]([NH2:1])[N:3]=2)[C:40]([CH3:52])=[CH:39][C:38]=1[O:53][CH3:54]
Reactant: COC(=O)c1cc(B2OC(C)(C)C(C)(C)O2)c(C)cc1OC
Reactant: Nc1nc(Cl)cc(Cl)n1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])O
Solvent: COCCOC
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(-c2cc(Cl)nc(N)n2)c(C)cc1OC
Temperature: 80 °C
Reaction time: 0.17 h
Yield: 53.3 %

Procedure:
2-Amino-4,6-dichloropyrimidine (246 mg, 1.5 mmol), palladium acetate (17 mg, 0.07 mmol), triphenylphosphine (59 mg, 0.22 mmol), sodium bicarbonate (168 mg, 2.0 mmol), 1,2-dimethoxyethane (2.5 ml), and water (1.0 ml) were placed in a reaction vessel. The resulting mixture was stirred at 80° C. for 10 minutes. A 1,2-dimethoxyethane (2.5 ml) solution of 2-methoxy-4-methyl-5-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)benzoic acid methyl ester (294 mg, 1.0 mmol) obtained in Step 3 above was added dropwise to the mixture. The resulting mixture was stirred at 80° C. for 14 hours. The reaction solution was diluted with ethyl acetate (100 ml), and washed three times with water (40 ml), and then with a saturated aqueous sodium chloride solution (40 ml). The washed ethyl acetate solution was dried over anhydrous sodium sulfate (10 g). After filtration, the filtrate was concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (developing solvent: n-hexane:ethyl acetate=2:1) to yield 5-(2-amino-6-chloropyrimidin-4-yl)-2-methoxy-4-methylbenzoic acid methyl ester (Compound 1-2) (164 mg) as a yellow solid material.
Reaction SMILES: [C:1]1(=[O:16])[N:5]([CH2:6]/[C:7](/[CH3:10])=[CH:8]/[F:9])[C:4](=[O:11])[C:3]2=[CH:12][CH:13]=[CH:14][CH:15]=[C:2]12.[Br:17]NC(=O)CCC(N)=O>C(Cl)(Cl)(Cl)Cl>[F:9]/[CH:8]=[C:7](\[CH2:10][Br:17])/[CH2:6][N:5]1[C:4](=[O:11])[C:3]2=[CH:12][CH:13]=[CH:14][CH:15]=[C:2]2[C:1]1=[O:16]
Reactant: C/C(=C\F)CN1C(=O)c2ccccc2C1=O
Reactant: NC(=O)CCC(=O)NBr
Solvent: ClC(Cl)(Cl)Cl
Product: O=C1c2ccccc2C(=O)N1C/C(=C/F)CBr

Procedure:
A mixture of 1-phthalimido-2-methyl-3-fluoro-2-propene (prepared in Step E) (2.09 g) and N-bromosuccinamide (1.78 g) in carbon tetrachloride (100 ml) was refluxed for 45 min. The cooled mixture is filtered and the filtrate is washed with water, dried and evaporated to leave an almost colorless oil. Chromatography (silica; 20% ether in light petroleum) followed by recrystallization of the major fractions from EtOAc/light petroleum gives:
Reaction SMILES: Cl[CH2:2][O:3][C:4](=[O:24])[C:5]([CH3:23])([CH3:22])[CH2:6][O:7][C:8](=[O:21])[C@H:9]([CH:18]([CH3:20])[CH3:19])[NH:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12].[I-:25].[Na+]>C(#N)C>[I:25][CH2:2][O:3][C:4](=[O:24])[C:5]([CH3:23])([CH3:22])[CH2:6][O:7][C:8](=[O:21])[C@H:9]([CH:18]([CH3:20])[CH3:19])[NH:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12]
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)OCC(C)(C)C(=O)OCCl
Reactant: [I-]
Agent: [Na+]
Solvent: CC#N
Product: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)OCC(C)(C)C(=O)OCI
Yield: 94.9 %

Procedure:
2,2-Dimethyl-3-(N-Boc-L-valyloxy)propionic acid chloromethyl ester (3.6 g, 10 mmole) was dissolved in acetonitrile (50 ml). Sodium iodide (2.1 g, 14 mmole) was added to the solution. After reaction at 70° C. for 2 hr, the reaction mixture was filtered and the residue was dissolved in methylene chloride (20 ml) and refiltered. The solution was dried and gave 4.34 g of the titled product.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[NH2:6].O=[C:8]([CH3:21])[CH:9]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:10](OCC)=[O:11]>CN(C=O)C.C(N(CCCC)CCCC)CCC.O.ClCCl>[CH3:21][C:8]1[N:1]2[CH:5]=[CH:4][N:3]=[C:2]2[N:6]=[C:10]([OH:11])[C:9]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: Nc1ncc[nH]1
Reactant: CCOC(=O)C(C(C)=O)c1ccccc1
Solvent: CCCCN(CCCC)CCCC
Solvent: O
Solvent: CN(C)C=O
Product: Cc1c(-c2ccccc2)c(O)nc2nccn12
Temperature: 180 °C

Procedure:
A solution of 3.8 g 1H-imidazol-2-ylamine and 6 g ethyl 3-oxo-2-phenylbutanoate was suspended in a mixture of 32 mL DMF and 32 mL N,N-dibutylbutan-1-amine and heated by microwave irradiation to 180° C. for 10 h. The reaction mixture was diluted with water and dichloromethane, the phases separated, the aqueous layer extracted twice with dichloromethane, the combined organic layers were dried over Na2SO4 and concentrated to give the crude product. The crude product was purified by column chromatography (silica gel, dichloromethane/methanol).
Reaction SMILES: ClC1C=CC(C(=O)CCC2C3C(=CC=CC=3)C=CC=2)=CC=1.[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29][CH2:30]/[C:31](/[C:38]2[C:47]3[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=3)[CH:41]=[CH:40][CH:39]=2)=[CH:32]/[C:33]([O:35][CH2:36][CH3:37])=[O:34])=[CH:25][CH:24]=1>>[Cl:22][C:23]1[CH:24]=[CH:25][C:26]([CH2:29][CH2:30]/[C:31](/[C:38]2[C:47]3[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=3)[CH:41]=[CH:40][CH:39]=2)=[CH:32]\[C:33]([O:35][CH2:36][CH3:37])=[O:34])=[CH:27][CH:28]=1
Reactant: CCOC(=O)/C=C(/CCc1ccc(Cl)cc1)c1cccc2ccccc12
Agent: O=C(CCc1cccc2ccccc12)c1ccc(Cl)cc1
Product: CCOC(=O)/C=C(\CCc1ccc(Cl)cc1)c1cccc2ccccc12

Procedure:
By a procedure similar to that of example 1.85.3, starting from 1-(4-chlorophenyl)-3-(1-naphthalenyl)propan-1-one, (Z)-ethyl 5-(4-chlorophenyl)-3-(1-naphthalenyl)pent-2-enoate and (E)-ethyl 5-(4-chlorophenyl)-3-(1-naphthalenyl)pent-2-enoate were obtained as colourless oils.