Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[N:7]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][OH:16])=[CH:10][CH:9]=2)[C:6]2[CH:17]=[CH:18][C:19](B3OC(C)(C)C(C)(C)O3)=[CH:20][C:5]=2[N:4]=1)[CH3:2].Br[C:31]1[CH:32]=[N:33][CH:34]=[N:35][CH:36]=1.C([O-])(O)=O.[Na+]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:1]([C:3]1[N:7]([C:8]2[CH:9]=[CH:10][C:11]([CH2:14][CH2:15][OH:16])=[CH:12][CH:13]=2)[C:6]2[CH:17]=[CH:18][C:19]([C:31]3[CH:32]=[N:33][CH:34]=[N:35][CH:36]=3)=[CH:20][C:5]=2[N:4]=1)[CH3:2]
Reactant: Brc1cncnc1
Reactant: CCc1nc2cc(B3OC(C)(C)C(C)(C)O3)ccc2n1-c1ccc(CCO)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CCc1nc2cc(-c3cncnc3)ccc2n1-c1ccc(CCO)cc1
Temperature: 70 °C
Reaction time: 17 h
Yield: 50.3 %

Procedure:
To a solution of 2-{4-[2-ethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzimidazol-1-yl]phenyl}ethanol (step 1, 100 mg, 0.26 mmol) and 5-bromopyrimidine (45 mg, 0.28 mmol) in 1,2-dimethoxyethane (3.5 ml) was added sat. NaHCO3 aq. (1.2 ml) and Pd(PPh3)4 (60 mg, 0.05 mmol). This mixture was stirred at 70° C. for 17 h. The reaction mixture was diluted with water and extracted with CH2Cl2 (3×10 ml). The organic layer was dried (MgSO4) and concentrated to give light brown oil. This mixture was purified by SiO2 preparative TLC (CH2Cl2/methanol=10/1) to afford 45 mg (50%) of the title compound.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[N:7]([C@H:9]1[CH2:14][CH2:13][C@H:12]([C:15]#[C:16][CH2:17][CH2:18][OH:19])[CH2:11][CH2:10]1)[CH3:8])([CH3:4])([CH3:3])[CH3:2].[CH3:21][S:22](Cl)(=[O:24])=[O:23].N1C=CC=CC=1.O>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:1]([O:5][C:6]([N:7]([CH3:8])[C@H:9]1[CH2:10][CH2:11][C@H:12]([C:15]#[C:16][CH2:17][CH2:18][O:19][S:22]([CH3:21])(=[O:24])=[O:23])[CH2:13][CH2:14]1)=[O:20])([CH3:3])([CH3:2])[CH3:4]
Reactant: CS(=O)(=O)Cl
Reactant: CN(C(=O)OC(C)(C)C)[C@H]1CC[C@H](C#CCCO)CC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: O
Product: CN(C(=O)OC(C)(C)C)[C@H]1CC[C@H](C#CCCOS(C)(=O)=O)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 2.66 g (9.44 mmol) of trans-[4-(4-Hydroxy-but-1-ynyl)-cyclohexyl]-methyl-carbamic acid tert-butyl ester in 75 ml CH2Cl2 was treated at 0° C. with 0.81 ml (10.38 mmol) methanesulfonylchloride, 1.14 ml (14.16 mmol) pyridine and 1.15 g (9.44 mmol) DMAP. The reaction mixture was stirred at RT for 3 h, water (19 ml) was added and the reaction was stirred for 5 min. After extraction with aqueous 10% KHSO4/Et2O (3×) the organic phases were washed with aqueous saturated NaHCO3 (2×), aqueous 10% NaCl, dried over Na2SO4 and evaporated to yield 3.57 g (quantitative) of trans-Methanesulfonic acid 4-[4-(tert-butoxycarbonyl-methyl-amino)-cyclohexyl]-but-3-ynyl ester, MS: 360 (MH+).
Reaction SMILES: Cl.[OH:2][CH:3]1[O:11][C@H:10]([CH2:12][OH:13])[C@@H:8]([OH:9])[C@H:6]([OH:7])[C@H:4]1[NH2:5].C(N(CC)CC)C.[F:21][C:22]([F:29])([F:28])[C:23](OCC)=[O:24]>CO>[F:21][C:22]([F:29])([F:28])[C:23]([NH:5][C@@H:4]1[C@@H:6]([OH:7])[C@H:8]([OH:9])[C@@H:10]([CH2:12][OH:13])[O:11][CH:3]1[OH:2])=[O:24]
Reactant: CCOC(=O)C(F)(F)F
Reactant: N[C@H]1C(O)O[C@H](CO)[C@@H](O)[C@@H]1O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CO
Product: O=C(N[C@H]1C(O)O[C@H](CO)[C@@H](O)[C@@H]1O)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
160 g (0.742 mole) of D-(+)-glucosamine hydrochloride were dissolved in 2200 ml of methanol (99.6% purity), and 187.9 g (1.86 mole) of triethylamine were added to the resulting solution. 115.9 g of ethyl trifluoroacetate were then added dropwise to the resulting mixture, whilst ice-cooling, after which the mixture was stirred overnight at room temperature. At the end of this time, the mixture was concentrated by evaporation under reduced pressure, and then benzene (250 ml twice) and ethyl acetate (250 ml) were repeatedly added to the residue, which was then concentrated by evaporation under reduced pressure and then finally dried sufficiently in vacuo. The whole of the resulting crude trifluoroacetyl compound was used in the subsequent step (b) without purification.
Reaction SMILES: CN(C)CCN(C)C.C([Li])(CC)C.[CH:14]([C:18]1[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=[CH:27][C:19]=1[C:20]([N:22]([CH2:25][CH3:26])[CH2:23][CH3:24])=[O:21])([CH2:16][CH3:17])[CH3:15].[S:33](=[O:35])=[O:34].S(Cl)(Cl)(=O)=O.[OH-].[NH4+:42]>C1COCC1>[NH2:42][S:33]([C:27]1[CH:28]=[C:29]([O:31][CH3:32])[CH:30]=[C:18]([CH:14]([CH2:16][CH3:17])[CH3:15])[C:19]=1[C:20]([N:22]([CH2:25][CH3:26])[CH2:23][CH3:24])=[O:21])(=[O:35])=[O:34]
Reactant: O=S=O
Reactant: [NH4+]
Reactant: CCC(C)c1cc(OC)ccc1C(=O)N(CC)CC
Agent: CN(C)CCN(C)C
Agent: [Li]C(C)CC
Agent: [OH-]
Solvent: O=S(=O)(Cl)Cl
Solvent: C1CCOC1
Product: CCC(C)c1cc(OC)cc(S(N)(=O)=O)c1C(=O)N(CC)CC
Temperature: -10 °C
Reaction time: 0.25 h

Procedure:
To a solution of tetramethylethylenediamine (31 mL) in THF (500 mL) at -78° C. was added sec-butyllithium (170 mL, 1.1M), followed by 2-sec-butyl-4-methoxy-N,N-diethylbenzamide (45 g) in THF (150 mL). The mixture was stirred at -78° for 15 minutes, then at 0° C. for 30 minutes, then sulfur dioxide (50 mL) was condensed into the mixture at -78° C. The mixture was warmed to -10° C., sulfuryl chloride (17 mL) was added and then the mixture was slowly warmed to room temperature and stirred overnight. The reaction mixture was added to a solution of ammonium hydroxide (94 mL) in THF (200 mL), the mixture was filtered through a pad of silica/Na2SO4 /sand to afford 51.8 g of 2-aminosulfonyl-6sec-butyl-4-methoxy-N,N-diethylbenzamide.
Reaction SMILES: C([O:3][C:4](=[O:45])[CH2:5][CH2:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH2:18][C:19]([O:21]CC)=[O:20])[CH:15]=2)[CH:10]=[CH:9][C:8]=1[O:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][O:30][C:31]1[CH:41]=[CH:40][C:34]2[C:35](=[O:39])[CH2:36][CH2:37][O:38][C:33]=2[C:32]=1[CH2:42][CH2:43][CH3:44])C.O.[OH-].[Li+].S(=O)(=O)(O)O>C(OCC)(=O)C.O.O1CCCC1>[C:19]([CH2:18][O:17][C:14]1[CH:15]=[C:16]2[C:11]([CH:10]=[CH:9][C:8]([O:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][O:30][C:31]3[CH:41]=[CH:40][C:34]4[C:35](=[O:39])[CH2:36][CH2:37][O:38][C:33]=4[C:32]=3[CH2:42][CH2:43][CH3:44])=[C:7]2[CH2:6][CH2:5][C:4]([OH:45])=[O:3])=[CH:12][CH:13]=1)([OH:21])=[O:20]
Reactant: CCCc1c(OCCCCCOc2ccc3ccc(OCC(=O)OCC)cc3c2CCC(=O)OCC)ccc2c1OCCC2=O
Agent: O=S(=O)(O)O
Agent: [Li+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: CCCc1c(OCCCCCOc2ccc3ccc(OCC(=O)O)cc3c2CCC(=O)O)ccc2c1OCCC2=O
Temperature: 25 °C
Reaction time: 41.5 h
Yield: 102.3 %

Procedure:
A mixture of 0.86 g (1.39 mmol) of 2-[[5-[(3,4-dihydro-4-oxo-8-propyl-2H-1-benzopyran-7-yl)oxy]pentyl]oxy]-7-(2-ethoxy-2-oxoethoxy)-1-naphthalenepropanoic acid ethyl ester from the preceding example, 0.177 g (4.21 mmol) of lithium hydroxide monohydrate, 10.1 mL of tetrahydrofuran, and 10.1 mL of water was stirred at room temperature for 41.5 hr. A second saponification was carried out with 0.188 g (0.3 mmol) of the starting ester, 38 mg (0.9 mmol) of lithium hydroxide monohydrate, 2.2 mL of tetrahydrofuran and 2.2 mL of water. After combining the two reaction mixtures, 30 mL of 3N aqueous sulfuric acid was added, and the mixture was worked-up with ethyl acetate in the usual manner. The crude product was crystallized from hexane-ethyl acetate to give 0.803 g (84.3%) of the title compound as an off-white solid, mp 175°-177.5° C.
Reaction SMILES: [NH2:1][CH:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=2[NH:4][C:3]1=[O:19].[F:20][C:21]([F:32])([F:31])[C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=1)[C:25](O)=[S:26].C(Cl)CCl.C(N(CC)CC)C>CN(C=O)C>[C:9]1([C:7]2[C:6]3[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=3[NH:4][C:3](=[O:19])[CH:2]([NH:1][C:25](=[S:26])[C:24]3[CH:28]=[CH:29][CH:30]=[C:22]([C:21]([F:20])([F:31])[F:32])[CH:23]=3)[N:8]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: NC1N=C(c2ccccc2)c2ccccc2NC1=O
Reactant: OC(=S)c1cccc(C(F)(F)F)c1
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: O=C1Nc2ccccc2C(c2ccccc2)=NC1NC(=S)c1cccc(C(F)(F)F)c1
Temperature: 25 °C

Procedure:
3(RS)-Amino-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepin-2-one (80.0 mg, 0.318 mmole), 3-trifluoromethylthiobenzoic acid (70.7 mg, 0.318 mmole), HBT (43.0 mg, 0.318 mmole) and EDC (61.0 mg, 0.318 mmole) were combined in dry DMF (2 ml) and stirred at room temperature. The pH of the mixture was adjusted to 9.0-9.5 with triethylamine (64.4 mg, 0.636 mmole) and the mixture stirred for 10 minutes. The DMF was removed in vacuo, and the residue was treated with 10% citric acid and extracted with EtOAc. The combined organic fractions were washed with sodium carbonate solution, dried over Na2SO4, filtered, and evaporated to dryness in vacuo. The residue was crystallized from EtOAc to give the title compound which was dried in vacuo at 100° C.: (m.p. 230°-232° C.).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[CH:11]=[C:12]([CH:16]=[C:17]([O:19]CC4C=CC=CC=4)[CH:18]=3)[C:13]([OH:15])=O)=[CH:9][C:4]=2[O:3][CH2:2]1.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[NH2:51][C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1.C(N(CC)CC)C>ClCCl>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[CH:11]=[C:12]([CH:16]=[C:17]([OH:19])[CH:18]=3)[C:13]([NH:51][C:52]3[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=3)=[O:15])=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: Nc1ccccc1
Reactant: O=C(O)c1cc(OCc2ccccc2)cc(-c2ccc3c(c2)OCO3)c1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Nc1ccccc1)c1cc(O)cc(-c2ccc3c(c2)OCO3)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 76 %

Procedure:
3-Benzo[1,3]dioxol-5-yl-5-benzyloxy-benzoic acid (500 mg), PyBroP (1.2 eq.), aniline (1.1 eq.), and triethylamine (2 eq.) were combined in dichloromethane (5 mL) and stirred at room temperature overnight. The reaction mixture was diluted with dichloromethane and washed with water. White solid which precipitated in dichloromethane layer was collected by filtration (493 mg). This material was dissolved in THF and hydrogenated over 10% Pd/C (50 mg) in Parr apparatus for 5 h. The catalyst was removed by filtration and the filtrate was concentrated under reduced pressure and purified on a silica gel column using ethyl acetate and hexanes to yield 362 mg of title compound (76% yield after 2 steps).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:17])=[C:6]([C@:8]2([CH3:16])[C@@H:13]([F:14])[CH2:12][O:11][C:10]([NH2:15])=[N:9]2)[CH:7]=1.[C:18]([C:20]1[CH:21]=[CH:22][C:23]([C:26](O)=[O:27])=[N:24][CH:25]=1)#[N:19]>>[NH2:15][C:10]1[O:11][CH2:12][C@H:13]([F:14])[C@:8]([C:6]2[CH:7]=[C:2]([NH:1][C:26]([C:23]3[CH:22]=[CH:21][C:20]([C:18]#[N:19])=[CH:25][N:24]=3)=[O:27])[CH:3]=[CH:4][C:5]=2[F:17])([CH3:16])[N:9]=1
Reactant: N#Cc1ccc(C(=O)O)nc1
Reactant: C[C@]1(c2cc(N)ccc2F)N=C(N)OC[C@@H]1F
Product: C[C@]1(c2cc(NC(=O)c3ccc(C#N)cn3)ccc2F)N=C(N)OC[C@@H]1F

Procedure:
The condensation of (4R,5R)-4-(5-amino-2-fluoro-phenyl)-5-fluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine (intermediate A8.2) and 5-cyano-pyridine-2-carboxylic acid (CAS 53234-55-2) following procedure I yielded the title compound as a crystalline white solid. MS (ISP): m/z=372.2 [M+H]+.
Reaction SMILES: [CH3:1][O:2][CH:3]([C:7]1[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=1)[CH2:4][CH2:5]Cl.[CH3:14][CH:15]([CH3:31])[C:16]([NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH:20]=1)=[O:17].C(N(C(C)C)CC)(C)C.N>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.O1CCOCC1.C(Cl)(Cl)Cl>[CH3:1][O:2][CH:3]([C:7]1[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=1)[CH2:4][CH2:5][N:28]1[CH2:29][CH2:30][CH:25]([C:21]2[CH:20]=[C:19]([NH:18][C:16](=[O:17])[CH:15]([CH3:14])[CH3:31])[CH:24]=[CH:23][CH:22]=2)[CH2:26][CH2:27]1
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Reactant: COC(CCCl)c1ccc(C)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: N
Agent: [I-]
Solvent: C1COCCO1
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: COC(CCN1CCC(c2cccc(NC(=O)C(C)C)c2)CC1)c1ccc(C)cc1
Temperature: 90 °C
Reaction time: 72 h
Yield: 21.2 %

Procedure:
A mixture of 3-methoxy-3-(p-tolyl)-1-chloropropane (24.9 mg, 0.126 mmol), 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide (28.3 mg, 0.126 mmol), diisopropylethylamine (0.50 mL) and catalytic amount of tetrabutylammonium iodide in dioxane (2.0 mL) was stirred at 90° C. for 72 hrs. Chromatography using silica preparative TLC plates [2.5% of NH3 (2.0 M in methanol) in CHCl3] gave the desired product (10.9 mg, 21.2% yield) as a thick oil: 1H NMR (400 MHz, CDCl3) δ 7.44 (s, 1H), 7.38 (m, 1H), 7.3-7.1 (m, 5H), 6.96 (d, 1H, J=7.4 Hz), 4.18 (apparent dd, 1H, J=5.6, 7.9 Hz), 3.24 (d, 1H, J=8.2 Hz), 3.2 (s, 3H), 3.11 (m, 2H, J=10.1 Hz), 2.49 (m, 4H), 2.35 (s, 3H), 2.3-2.1 (m, 3H), 1.92 (d, 4H), 1.25 (d, 6H, J=7.1 Hz); ESMS m/e: 409.4 (M+H)+.
Reaction SMILES: Cl.[F:2][C:3]([F:22])([F:21])[O:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:16][CH2:15][CH:14]3[CH2:17][NH:18][CH2:19][CH:13]3[C:12]2=[O:20])=[CH:7][CH:6]=1.[C:23]1([CH2:29][C:30](Cl)=[O:31])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.CCN(CC)CC.C(Cl)Cl>C(Cl)Cl.CO>[C:23]1([CH2:29][C:30]([CH:17]2[CH:14]3[CH:13]([C:12](=[O:20])[N:11]([C:8]4[CH:9]=[CH:10][C:5]([O:4][C:3]([F:2])([F:21])[F:22])=[CH:6][CH:7]=4)[CH2:16][CH2:15]3)[CH2:19][NH:18]2)=[O:31])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=C(Cl)Cc1ccccc1
Reactant: O=C1C2CNCC2CCN1c1ccc(OC(F)(F)F)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CO
Product: O=C(Cc1ccccc1)C1NCC2C(=O)N(c3ccc(OC(F)(F)F)cc3)CCC21
Temperature: 25 °C
Reaction time: 12 h
Yield: 44.8 %

Procedure:
5-(4-Trifluoromethoxy-phenyl)-octahydro-pyrrolo[3,4-c]pyridin-4-one, hydrochloride (80 mg, 0.24 mmol), 2-phenylacetyl chloride (74 mg, 0.48 mmol) and Et3N (0.12 g, 1.2 mmol) were added to DCM (10 mL), and the mixture was stirred for 12 h at ambient temperature. The product (45 mg, 46%) was obtained by prep-TLC (eluting with DCM/MeOH=25/1). 1H NMR (300 MHz, CDCl3): δ 7.34-7.23 (m, 9H), 3.90-3.54 (m, 7H), 3.23-3.20 (m, 2H), 2.78-2.75 (m, 1H), 2.07-2.02 (m, 1H), 1.83 (bs, 1H); LC-MS: [M+1]+ 418.7.
Reaction SMILES: FC(F)(F)C(O)=O.C(O[C:13]([N:15]1[CH2:36][CH2:35][C:18]2[N:19]=[C:20]([NH:23][C:24](=[O:34])[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[O:31][CH2:32][CH3:33])[N:21]=[CH:22][C:17]=2[CH2:16]1)=[O:14])(C)(C)C.CCN(C(C)C)C(C)C.[Cl:46][C:47]1[CH:51]=[CH:50][S:49][C:48]=1C(O)=O.CCN=C=NCCCN(C)C.C1C=NC2N(O)N=NC=2C=1>C(Cl)Cl>[Cl:46][C:47]1[CH:51]=[CH:50][S:49][C:48]=1[C:13]([N:15]1[CH2:36][CH2:35][C:18]2[N:19]=[C:20]([NH:23][C:24](=[O:34])[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[O:31][CH2:32][CH3:33])[N:21]=[CH:22][C:17]=2[CH2:16]1)=[O:14]
Reactant: CCOc1ccccc1C(=O)Nc1ncc2c(n1)CCN(C(=O)OC(C)(C)C)C2
Reactant: O=C(O)c1sccc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2cccnc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: CCOc1ccccc1C(=O)Nc1ncc2c(n1)CCN(C(=O)c1sccc1Cl)C2
Temperature: 0 °C
Reaction time: 2 h
Yield: 50.5 %

Procedure:
Trifluoroacetic acid 3.6 ml (49 mmol) was added to a solution of 2-(2-ethoxy-benzoylamino)-7,8-dihydro-5H-pyrido[4,3-d]pyrimidine-6-carboxylic acid tert-butyl ester 300 mg (0.753 mmol) in CH2Cl2 (10 ml) under nitrogen as inert gas and stirring was performed for 2 h at RT. After removal of the solvent, the intermediate (2-ethoxy-N-(5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-2-yl)-benzamide trifluoroacetate) was dissolved in CH2Cl2 (10 ml) and DIPEA 225 μl and 3-chlorothiophene-2-carboxylic acid 129 mg (0.791 mmol) were added. After cooling the reaction mixture to 0° C., EDCI 158 mg (0.828 mmol) and HOAt 15 mg (0.11 mmol) were added. The reaction mixture was stirred for 1 h at 0° C. and then overnight at RT. After removal of the solvent, purification was performed by means of column chromatography and the product N-[6-(3-chloro-thiophene-2-carbonyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-2-yl]-2-ethoxy-benzamide 170 mg (0.38 mmol, 51% of theoretical) was obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[C:4](=[O:14])[N:3]=1.N1C=CN=C1.[CH2:20]([NH2:23])[CH:21]=[CH2:22].C1C[O:27][CH2:26]C1>C(Cl)Cl>[CH2:20]([NH:23][C:26]([NH:1][C:2]1[CH:7]=[CH:6][N:5]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[C:4](=[O:14])[N:3]=1)=[O:27])[CH:21]=[CH2:22]
Reactant: CCCCCCn1ccc(N)nc1=O
Reactant: C1CCOC1
Reactant: C=CCN
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: C=CCNC(=O)Nc1ccn(CCCCCC)c(=O)n1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 4-amino-1-hexyl-1H-pyrimidin-2-one (C) (1.00 g, 5.13 mmol) in dry CH2Cl2 (7 ml) was added N,N carbonyl diimidazole (1.31 g, 5.13 mmol) and the solution was stirred at room temperature for 16 h. The solvent was evaporated and the residue redissolved in dry chloroform. Hexane was then added to precipitate the intermediate, which was dried in vacuo and used directly without further purification. To a solution of the resulting imidazole intermediate (1.0 g, 3.47 mmol) in dry THF (20 ml) was added allyl amine (0.40 ml, 5.33 mmol). The solution was stirred at room temperature for 16 h. the solvent was evaporated in vacuo and the residue was redissolved in chloroform and washed with water and brine. The organic phase was combined and dried over MgSO4 and the solvent evaporated under vacuo to afford crude G, which was purified via flash silica gel chromatography (CHCl3/MeOH, 7:1) to give pure compound M (0.262 g, 30% from the amine)
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]([OH:13])=O)=[CH:5][CH:4]=1)#[N:2].[N-]1C=CN=C1.[NH2:19][C:20]1[C:21]([NH:30][CH3:31])=[N:22][CH:23]=[C:24]([CH:29]=1)[C:25]([O:27][CH3:28])=[O:26]>O1CCCC1.CN(C)C=O.C(OCC)(=O)C>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([CH2:9][CH2:10][C:11]([NH:19][C:20]2[C:21]([NH:30][CH3:31])=[N:22][CH:23]=[C:24]([CH:29]=2)[C:25]([O:27][CH3:28])=[O:26])=[O:13])=[CH:7][CH:8]=1)#[N:2]
Reactant: CNc1ncc(C(=O)OC)cc1N
Reactant: N#Cc1ccc(CCC(=O)O)cc1
Agent: c1c[n-]cn1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CNc1ncc(C(=O)OC)cc1NC(=O)CCc1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A solution of 2.6 g (15 mMol) of 3-(4-cyanophenyl)propionic acid in 25 ml of absolute tetrahydrofuran was mixed with 2.4 g (15 mMol) of N,N'-carbonyldiimidazole and stirred for 20 minutes at room temperature. Then the imidazolide was mixed with a solution of 2.3 g (13 mMol) of methyl 5-amino-6-methylamino-nicotinate in 25 ml of dimethylformamide and heated for 3 hours to 100° C. After the removal of the solvent in vacuo the crude product obtained was taken up in ethyl acetate, the organic phase was washed with water and after drying over sodium sulphate it was again freed from solvent. The residue obtained was purified by flash chromatography (silica gel; gradient: dichloromethane to dichloromethane/ethanol=19:1). Yield: 2.1 g (50% of theory) of beige solid Rf value: 0.54 (silica gel; ethyl acetate/ethanol/ammonia=90:10:1)
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]([C:25]#[N:26])[C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li+].CC([N-]C(C)C)C.[Br:35][C:36]1[CH:43]=[CH:42][CH:41]=[CH:40][C:37]=1[CH2:38]Br>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([C:14]([C:25]#[N:26])([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:23])([F:24])[F:22])=[CH:17][CH:16]=2)[CH2:38][C:37]2[CH:40]=[CH:41][CH:42]=[CH:43][C:36]=2[Br:35])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: BrCc1ccccc1Br
Reactant: CC(C)(C)OC(=O)N1CCC(C(C#N)c2ccc(C(F)(F)F)cc2)CC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(C(C#N)(Cc2ccccc2Br)c2ccc(C(F)(F)F)cc2)CC1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 64.6 %

Procedure:
To a solution of the above nitrile (280 mg, 0.76 mmol) in THF at −78° C. was added freshly prepared LDA (0.32M, 2.6 mL, 0.83 mmol). The resulting mixture was stirred for 30 min. at −78° C. and 2-bromobenzyl bromide (570 mg, 2.28 mmol) in THF (1 mL) was added. The reaction was stirred for 3 hours at 0° C. and quenched with saturated aqueous NH4Cl (20 mL) to give 4-[2-(2-bromo-phenyl)-1-cyano-1-(4-trifluoromethyl-phenyl)-ethyl]-piperidine-1-carboxylic acid tert-butyl ester (264 mg, 65%) as a white foam after work-up and purification.
Reaction SMILES: [C:1]([Si:5](Cl)([CH3:7])[CH3:6])([CH3:4])([CH3:3])[CH3:2].[OH:9][C@@H:10]([CH2:15][O:16][CH2:17][CH3:18])[C:11]([O:13][CH3:14])=[O:12].N1C=CN=C1>CN(C=O)C>[Si:5]([O:9][C@@H:10]([CH2:15][O:16][CH2:17][CH3:18])[C:11]([O:13][CH3:14])=[O:12])([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:7])[CH3:6]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CCOC[C@H](O)C(=O)OC
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CCOC[C@H](O[Si](C)(C)C(C)(C)C)C(=O)OC
Temperature: 25 °C
Reaction time: 20 h
Yield: 57.6 %

Procedure:
A solution of tert-butylchlorodimethylsilane (17.71 g, 117.52 mmol) in dry DMF (50 mL) was added dropwise to a stirred solution of (S)-methyl 2-hydroxy-3-ethoxypropanoate (14.51 g, 97.94 mmol) and 1H-imidazole (13.33 g, 195.87 mmol) in dry DMF (70 mL) at 20° C., over a period of 2 minutes. The resulting solution was stirred at ambient temperature for 20 hours. The reaction mixture was concentrated and diluted with EtOAc (500 mL), washed sequentially with water (4×100 mL) and saturated brine (100 mL). The organic layer was dried (MgSO4) and evaporated. The residue was purified by flash silica chromatography, elution gradient 20 to 50% EtOAc in isohexane to afford methyl (2S)-2-(tert-butyl-dimethylsilyl)oxy-3-ethoxypropanoate (14.8 g, 57%). 1H NMR (400 MHz, CDCl3) δ 0.10 (6H, d), 0.93 (9H, s), 1.19 (3H, t), 3.50-3.65 (3H, m), 3.57-3.73 (1H, m), 3.75 (3H, s), 4.37-4.40 (1H, m), 7.18 (2H, d).
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:13]=[CH:12][CH:11]=[CH:10][C:6]=1[C:7]([NH2:9])=O)[CH2:2][CH3:3].[CH3:14][O:15][S:16]([OH:19])(=[O:18])=[O:17].C(OC1C=CC=CC=1C(N)=[NH:26])C>>[CH3:14][O:15][S:16]([OH:19])(=[O:18])=[O:17].[CH2:1]([O:4][C:5]1[CH:13]=[CH:12][CH:11]=[CH:10][C:6]=1[C:7]([NH2:26])=[NH:9])[CH2:2][CH3:3]
Reactant: CCOc1ccccc1C(=N)N
Reactant: CCCOc1ccccc1C(N)=O
Agent: COS(=O)(=O)O
Product: CCCOc1ccccc1C(=N)N
Yield: 74 %

Procedure:
The title compound (74% yield) was prepared from 2-n-propoxybenzamide in a manner similar to that described for the preparation of 2-ethoxybenzamidine methyl sulfate in Preparation 6 above.