Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:23]=[C:22](Cl)[CH:21]=[CH:20][C:3]=1[C:4]([NH:6][CH2:7][C:8]1[S:9][C:10]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:11][CH:12]=1)=[O:5].C1C=CC(CC(NCN[C@H](C(O)=O)CC2C=CC([N+]([O-])=O)=CC=2)=O)=CC=1.[S:51]1[CH:55]=[CH:54][N:53]=[CH:52]1>C1(C)C(C)=CC=CC=1.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>[NH2:1][C:2]1[N:23]=[C:22]([C:52]2[S:51][CH:55]=[CH:54][N:53]=2)[CH:21]=[CH:20][C:3]=1[C:4]([NH:6][CH2:7][C:8]1[S:9][C:10]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:11][CH:12]=1)=[O:5]
Reactant: c1cscn1
Reactant: Nc1nc(Cl)ccc1C(=O)NCc1ccc(Oc2ccccc2)s1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C(Cc1ccccc1)NCN[C@@H](Cc1ccc([N+](=O)[O-])cc1)C(=O)O
Solvent: Cc1ccccc1C
Product: Nc1nc(-c2nccs2)ccc1C(=O)NCc1ccc(Oc2ccccc2)s1
Temperature: 120 °C
Reaction time: 12 h
Yield: 19 %

Procedure:
To a solution of 2-amino-6-chloro-N-(5-phenoxy-thiophen-2-ylmethyl)-nicotinamide described in Example A-101 (101 mg, 0.281 mmol) in xylene (7 mL) were added 2-tributylstanyl thiazole (137 mg, 0.365 mmol) and tetrakis(triphenylphosphine)palladium(0) (81 mg, 0.070 mmol) under nitrogen atmosphere, and the solution was stirred for 12 hours at 120° C. The reaction mixture was concentrated, the obtained residue was purified by silica gel chromatography (toluene-ethyl acetate), then, the obtained residue was washed by hexane-ethyl acetate (20:1), and the title compound (22 mg, 0.054 mmol, 19%) was obtained.
Reaction SMILES: FC(F)(F)C(O)=O.[C:8]([C:10]1[CH:19]=[C:18]2[C:13]([CH:14]=[CH:15][C:16](=[O:26])[N:17]2[CH2:20][CH:21]2OCC[O:22]2)=[N:12][CH:11]=1)#[N:9].[OH-].[Na+]>>[C:8]([C:10]1[CH:19]=[C:18]2[C:13]([CH:14]=[CH:15][C:16](=[O:26])[N:17]2[CH2:20][CH:21]=[O:22])=[N:12][CH:11]=1)#[N:9]
Reactant: N#Cc1cnc2ccc(=O)n(CC3OCCO3)c2c1
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1cnc2ccc(=O)n(CC=O)c2c1
Temperature: 25 °C
Yield: 50.5 %

Procedure:
To 5 mL of 90% trifluoroacetic acid, 215 mg of 7-cyano-1-(1,3-dioxolan-2-ylmethyl)-1,5-naphthyridin-2(1H)-one was dissolved, and the resultant solution was stirred at 60° C. for 7 hours. After the reaction mixture was cooled to room temperature and alkalified with a 10% aqueous sodium hydroxide solution, the solvent was then distilled off under reduced pressure. The resultant residue was purified by silica gel column chromatography using silica gel; Silica Gel 60 made by KANTO CHEMICAL CO., INC., and an eluent of ethyl acetate:hexane=1:1, and washed with water to obtain 90 mg of (7-cyano-2-oxo-1,5-naphthyridin-1(2H)-yl)acetaldehyde as a light yellow solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:11]2[C:6](=[CH:7][C:8](Br)=[CH:9][CH:10]=2)[C:5](=[O:13])[CH2:4][CH2:3]1.[CH:15]([C:17]1[CH:27]=[CH:26][C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:19][CH:18]=1)=[CH2:16].CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>C(N(CC)CC)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:1][C:2]1([CH3:14])[CH2:3][CH2:4][C:5](=[O:13])[C:6]2[CH:7]=[C:8](/[CH:16]=[CH:15]/[C:17]3[CH:27]=[CH:26][C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:19][CH:18]=3)[CH:9]=[CH:10][C:11]1=2
Reactant: CC1(C)CCC(=O)c2cc(Br)ccc21
Reactant: C=Cc1ccc(C(=O)OCC)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc(/C=C/c2ccc3c(c2)C(=O)CCC3(C)C)cc1
Temperature: 95 °C

Procedure:
To a solution of 520.0 mg (2.00 mmol) of 3,4-dihydro-4,4-dimethyl-7-bromo-1(2H)-naphthalenone (Compound B) and 510.0 mg (2.90 mmol) of ethyl 4-vinylbenzoate in 4.0 ml of triethylamine (degassed by sparging with argon for 25 minutes), was added 124.0 mg (0.40 mmol) of tris(2-methylphenyl) phosphine, followed by 44.0 mg (0.20 mmol) of palladium(II)acetate. The resulting solution was heated to 95° C. for 2.5 hours, cooled to room temperature and concentrated under reduced pressure. Purification by column chromatography (10% EtOAc/hexanes) afforded the title compound as a colorless solid. 1H NMR (CDCl3): δ 8.19 (1H, d, J=2.0 Hz), 8.03 (2H, d, J=8.4 Hz), 7.69 (1H, dd, J=2.0, 8.2 Hz), 7.57 (2H, d, J=8.4 Hz), 7.45 (1H, d, J=8.2 Hz), 7.20 (2H, s), 4.39 (2H, q, J=7.1 Hz), 2.76 (2H, t, J=6.5 Hz), 2.04 (2H, t, J=6.5 Hz), 1.41(3H, t, J=7.1 Hz, and 6H, s).
Reaction SMILES: N.[CH2:2]1[O:23][CH:5]([C:6]2[C:7]([C:15]3[O:16][C:17]([N+:20]([O-:22])=[O:21])=[CH:18][CH:19]=3)=[N:8][N:9](C(OC)=O)[CH:10]=2)[O:4][CH2:3]1.Cl>O>[CH2:3]1[O:4][CH:5]([C:6]2[C:7]([C:15]3[O:16][C:17]([N+:20]([O-:22])=[O:21])=[CH:18][CH:19]=3)=[N:8][NH:9][CH:10]=2)[O:23][CH2:2]1
Reactant: COC(=O)n1cc(C2OCCO2)c(-c2ccc([N+](=O)[O-])o2)n1
Agent: Cl
Agent: N
Solvent: O
Product: O=[N+]([O-])c1ccc(-c2n[nH]cc2C2OCCO2)o1
Reaction time: 0.33 h
Yield: 79 %

Procedure:
Add 29 ml of concentrated ammonia solution (in 200 ml. of dimethylformamide and 50 ml of water) dropwise at room temperature to a suspension of 51 g of 1-methoxycarbonyl-3-(5-nitro-2-furyl)pyrazole-4-carboxaldehyde-ethyleneacetal. Stir for 20 minutes until dissolution takes place. Acidify with 2N hydrochloric acid to a pH of from 5 to 6 to throw down a precipitate. Add 50 ml of water dropwise, stir for a further 15 minutes at room temperture, draw off the precipitate and wash with water to obtain 3-(5-nitro-2-furyl)-1H-pyrazole-4-carboxaldehyde-ethyleneacetal [m.p. 166° to 167° C]with a yield of 79%.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([O:26][CH2:27][CH2:28][CH3:29])=[C:8]([C:10]2[NH:15][C:14](=[O:16])[C:13]3=[C:17]([CH3:25])[N:18]=[C:19]([CH:20]4[CH2:24][CH2:23][CH2:22][CH2:21]4)[N:12]3[N:11]=2)[CH:9]=1)([O-])=O>O1CCCC1.C(O)C.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([O:26][CH2:27][CH2:28][CH3:29])=[C:8]([C:10]2[NH:15][C:14](=[O:16])[C:13]3=[C:17]([CH3:25])[N:18]=[C:19]([CH:20]4[CH2:24][CH2:23][CH2:22][CH2:21]4)[N:12]3[N:11]=2)[CH:9]=1
Reactant: CCCOc1ccc([N+](=O)[O-])cc1-c1nn2c(C3CCCC3)nc(C)c2c(=O)[nH]1
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: CCCOc1ccc(N)cc1-c1nn2c(C3CCCC3)nc(C)c2c(=O)[nH]1

Procedure:
Analogously to the procedure of example 42A 5.13 g (12.96 mmol) of the compound from example 43A are hydrogenated in tetrahydrofuran/ethanol (1:1) using 1.11 g of 10% Pd/C. The product is purified by silica gel chromatography using toluene and ethyl acetate as solvent gradient.
Reaction SMILES: [CH:1]12[NH:8][CH:5]([CH2:6][CH2:7]1)[CH2:4][CH2:3][CH2:2]2.C([O-])([O-])=O.[K+].[K+].[CH3:15][O:16][C:17](=[O:44])[CH2:18][C@H:19]1[C:23]2[CH:24]=[CH:25][C:26]([O:28][C@H:29]3[C:37]4[C:32](=[C:33]([CH2:42]Br)[C:34]([C:38]([F:41])([F:40])[F:39])=[CH:35][CH:36]=4)[CH2:31][CH2:30]3)=[CH:27][C:22]=2[O:21][CH2:20]1.O>CN(C)C=O.[Cl-].[Na+].O>[CH3:15][O:16][C:17](=[O:44])[CH2:18][C@H:19]1[C:23]2[CH:24]=[CH:25][C:26]([O:28][C@H:29]3[C:37]4[C:32](=[C:33]([CH2:42][N:8]5[CH:5]6[CH2:6][CH2:7][CH:1]5[CH2:2][CH2:3][CH2:4]6)[C:34]([C:38]([F:41])([F:39])[F:40])=[CH:35][CH:36]=4)[CH2:31][CH2:30]3)=[CH:27][C:22]=2[O:21][CH2:20]1
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c3ccc(C(F)(F)F)c4CBr)ccc21
Reactant: C1CC2CCC(C1)N2
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c3ccc(C(F)(F)F)c4CN3C4CCCC3CC4)ccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
8-Aza-bicyclo[3.2.1]octane (19 mg), KI (27 mg), and K2CO3 (45 mg) are added to a solution of {(S)-6-[(R)-4-bromomethyl-5-trifluoromethyl-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester (80 mg) in N,N-dimethylformamide (2 mL) at room temperature. The resulting mixture is stirred at room temperature overnight. Water and brine are added and the mixture is extracted with ethyl acetate. The combined extracts are dried (Na2SO4) and concentrated to give the crude title compound that is submitted to the next reaction step without further purification. LC (method 6): tR=0.93 min; Mass spectrum (ESI+): m/z=516 [M+H]+.
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[C:15]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][C@@H:24]3[CH3:29])[C:16]3[CH2:22][NH:21][CH2:20][CH2:19][C:17]=3[N:18]=2)=[CH:9][CH:8]=1)=[O:5])[CH3:2].Cl[C:31]([O:33][CH2:34][CH:35]([CH3:37])[CH3:36])=[O:32]>>[CH2:1]([NH:3][C:4](=[O:5])[NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[C:15]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][C@@H:24]3[CH3:29])[C:16]3[CH2:22][N:21]([C:31]([O:33][CH2:34][CH:35]([CH3:37])[CH3:36])=[O:32])[CH2:20][CH2:19][C:17]=3[N:18]=2)=[CH:9][CH:8]=1)[CH3:2]
Reactant: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CNCC3)cc1
Reactant: CC(C)COC(=O)Cl
Product: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CN(C(=O)OCC(C)C)CC3)cc1

Procedure:
Compound eu was prepared according to the procedure described in Example 5 by reacting (S)-1-ethyl-3-(4-(4-(3-methylmorpholino)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)phenyl)urea with isobutyl chloroformate. LC-MS: m/z=+497 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:5]2[CH2:6][CH2:7][CH2:8][O:9][C:4]=2[CH:3]=1.C([Li])CCC.[C:17](=[O:19])=[O:18]>[Pd].C(O)C.O1CCCC1>[F:1][C:2]1[CH:11]=[CH:10][C:5]2[CH2:6][CH2:7][CH2:8][O:9][C:4]=2[C:3]=1[C:17]([OH:19])=[O:18]
Reactant: Fc1ccc2c(c1)OCCC2
Reactant: O=C=O
Agent: [Pd]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCO
Product: O=C(O)c1c(F)ccc2c1OCCC2

Procedure:
Schema 5 illustrates the synthesis of an amino substituted 3,4-dihydro-2H-1-benzopyran, for example, 8-amino-5-chloro-3,4-dihydro-7-fluoro-2H-1-benzopyran, starting with the reaction of an appropriately halo-substituted phenol with 3-bromopropanol under basic conditions in acetone, yielding the corresponding substituted phenoxypropanol (XI). The propanol is oxidized with Jones reagent in water and acetone, giving an acid, for example, 3-(3-fluorophenoxy)propanecarboxylic acid (XII). The acid is in turn cyclized with phosphorous pentachloride and aluminium chloride in methylene chloride, affording the corresponding 3,4-dihydro-7-substituted-2H-1-benzopyran-4-one (XIII), which is then treated with sodium borohydride in methanol, yielding the appropriate 3,4-dihydro-7-substituted-4-hydroxy-2H-1-benzopyran, for example, 3,4-dihydro-7-fluoro-4-hydroxy-2H-1-benzopyran (XIV). The 4-hydroxybenzopyran is dehydrated with molecular sieves in the present of p-toluenesulfonic acid, yielding the corresponding 7-fluoro-2H-1-benzopyran (XV). This compound is then hydrogenated in the presence of 5% palladium on carbon in ethanol, yielding 3,4-dihydro-7-fluoro-2H-1 -benzopyran (XVI), which is in turn treated with n-butyllithium and carbon dioxide at -78° C. in tetrahydrofuran, affording the corresponding 3,4-dihydro-7-fluoro-2H-1-benzopyran-8-ylcarboxylic acid (XVII). The so-prepared acid is then refluxed with diphenylphosphoryl azide under mild basic conditions in t-butanol, giving the corresponding 1,1-dimethylethyl N-(3,4-dihydro-7-fluoro-2H-1-benzopyran-8-yl)carbamate (XVIII). The carbamate is then converted to the free amine by treating it with trifluoroacetic acid, yielding the 8-amino-3,4-dihydro-7-fluoro-2H-1-benzopyran intermediate (XIX). The intermediate benzopyran is optionally halogenated in the 5-position by treatment with, for example, N-chlorosuccinimide in N,N-dimethylformamide, yielding the desired 8-amino-5-chloro-3,4-dihydro-7-fluoro-2H-1-benzopyran (XX) intermediate. Examples 11 and 12 provide detailed descriptions of how these compounds are prepared.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]([CH2:16][C:17]([F:20])([F:19])[F:18])[C@H:10]([C:12]([O:14]C)=[O:13])[CH3:11])=[CH:5][C:4]=1[C:21]([F:24])([F:23])[F:22])#[N:2].[OH-].[Na+].Cl>C1COCC1.CO>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]([CH2:16][C:17]([F:18])([F:19])[F:20])[C@H:10]([C:12]([OH:14])=[O:13])[CH3:11])=[CH:5][C:4]=1[C:21]([F:22])([F:24])[F:23])#[N:2]
Reactant: COC(=O)[C@H](C)N(CC(F)(F)F)c1ccc(C#N)c(C(F)(F)F)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: C[C@@H](C(=O)O)N(CC(F)(F)F)c1ccc(C#N)c(C(F)(F)F)c1
Temperature: 60 °C
Yield: 82.8 %

Procedure:
To a solution of methyl N-[4-cyano-3-(trifluoromethyl)phenyl]-N-(2,2,2-trifluoroethyl)alaninate (0.034 g, 0.11 mmol) in THF:methanol (1:1; 3 mL) was added 1N NaOH (1.1 ml, 1.1 mmol). The solution was heated at 60° C. for 30 min. Upon cooling, the solution was treated with 1N HCl (5 mL) and partitioned between ethyl acetate and saturated brine. The organic phase was washed with brine, dried (Na2SO4), and concentrated in vacuo to give 0.031 g (100% yield) of the desired product as a white solid: 1H NMR (400 MHz, CDCl3) δ 7.69 (d, J=8.8 Hz, 1H), 7.13 (d, J=2.7 Hz, 1H), 6.98 (dd, J=8.8, 2.7 Hz, 1H), 4.55 (q, J=7.2 Hz, 1H), 4.17-4.01 (m, 2H), 1.69 (d, J=7.2 Hz, 3H).
Reaction SMILES: FC(F)(F)C(O)=O.COC1C=C(OC)C=CC=1[CH2:12][N:13](C)[C:14]1[CH:19]=[CH:18][C:17]([S:20]([NH:23][C:24]2[S:25][CH:26]=[CH:27][N:28]=2)(=[O:22])=[O:21])=[C:16]([F:29])[CH:15]=1.C(Cl)Cl>>[F:29][C:16]1[CH:15]=[C:14]([NH:13][CH3:12])[CH:19]=[CH:18][C:17]=1[S:20]([NH:23][C:24]1[S:25][CH:26]=[CH:27][N:28]=1)(=[O:22])=[O:21]
Reactant: COc1ccc(CN(C)c2ccc(S(=O)(=O)Nc3nccs3)c(F)c2)c(OC)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNc1ccc(S(=O)(=O)Nc2nccs2)c(F)c1
Reaction time: 1 h
Yield: 43.2 %

Procedure:
Trifluoroacetic acid (1 mL, 0.01 mol) was added to a solution of the 4-[(2,4-dimethoxy-benzyl)-methyl-amino]-2-fluoro-N-thiazol-2-yl-benzenesulfonamide (0.22 g, 0.00050 mol) in methylene chloride (5.0 mL, 0.078 mol). The reaction solution was stirred for one hour then concentrated. The residue was partitioned between sat'd NaHCO3 and EtOAc. Organic layer was separated and the aq phase was extracted with EtOAc (2×). The combined organic layers were washed with water and brine, dried over Na2SO4. Evaporation of the solvent gave the crude product that was purified using Gilson preparative HPLC (reverse phase, Phenomenex 250×30 mm, 15 micron C18 column, 40 mL/min. Gradient, 85% A to 100% B over 25 min. Solvent A: 7800 water/200 acetonitrile/8 TFA. Solvent B: 7200 acetonitrile/800 water/8). Fractions were checked by LC/MS. The appropriate fractions were combined and dried on a lyophilizer to give the desired product as a pale yellow powder (62 mg, 43%).
Reaction SMILES: [N+:1]([C:4]1[CH:27]=[CH:26][C:7]([CH2:8][C:9]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=2)([C:13]([OH:15])=[O:14])C(O)=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].[Cl:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34]O.S(=O)(=O)(O)O>C1(C)C=CC=CC=1>[N+:1]([C:4]1[CH:27]=[CH:26][C:7]([CH2:8][CH:9]([CH2:16][C:17]2[CH:18]=[CH:19][C:20]([N+:23]([O-:25])=[O:24])=[CH:21][CH:22]=2)[C:13]([O:15][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][Cl:28])=[O:14])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=C(O)C(Cc1ccc([N+](=O)[O-])cc1)(Cc1ccc([N+](=O)[O-])cc1)C(=O)O
Reactant: OCCCCCCCl
Agent: O=S(=O)(O)O
Solvent: Cc1ccccc1
Product: O=C(OCCCCCCCl)C(Cc1ccc([N+](=O)[O-])cc1)Cc1ccc([N+](=O)[O-])cc1
Yield: 78.4 %

Procedure:
1.00 g (2.67 mmol) of 2,2-bis(4-nitrobenzyl)malonic acid and 1.42 ml (10.7 mmol) 6-chlorohexanol were suspended in 5.0 ml toluene. 1.0 ml sulphuric acid are added. The reaction mixture was subsequently allowed to react for 21.5 hours at refluxing temperature. The reaction mixture was partitioned between water and ethyl acetate; the organic phase was washed repeatedly with water, dried over magnesium sulfate, filtered and concentrated by rotary evaporation. Chromatography of the residue on 150 g silica gel using toluene:ethyl acetate 19:1 as eluant yielded 0.94 g (78%) 6-chlorohexyl 2-(4 -nitrobenzyl)-3-(4-nitrophenyl)propanoate as yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[N:7][CH:8]=[N:9][CH:10]=1)=[O:4].[BrH:11]>>[BrH:11].[CH3:1][O:2][C:3]([CH:5]1[CH2:10][NH:9][CH:8]=[N:7][CH2:6]1)=[O:4]
Reactant: COC(=O)c1cncnc1
Agent: Br
Product: COC(=O)C1CN=CNC1
Yield: 83 %

Procedure:
5-Methoxycarbonylpyrimidine (1.381 g, 10 mmol) in 143 ml 0.07158M HBr was hydrogenated at 26 psig over 600 mg Pd-on-carbon 10% in a Parr hydrogenator for three hours. The suspension was filtered and the filter rinsed twice with hot water (10 ml). The filtrate was evaporated in vacuo to give 1.86 g yellow oil (83%). The oil was crystallized from anhydrous ethanol/THF, and the hygroscopic crystals collected by decanting the solvents under a stream of nitrogen. Excess solvents were removed under vacuum in a drying pistol to yield 1.01 g (45%) white crystals mp 149°-153° C. (with the evolution of gas). Microanalysis calc.: C32.3, H 4.97, N 12.56; found: C 32.12, H 5.15, N 12.34. MHz nmr indicated product.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6](=[O:17])[S:7][C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10](Br)[CH:9]=2)=[O:4].[F:18][C:19]1[CH:20]=[C:21](B(O)O)[CH:22]=[CH:23][CH:24]=1>>[CH3:1][O:2][C:3]([C:5]1[C:6](=[O:17])[S:7][C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([C:23]1[CH:22]=[CH:21][CH:20]=[C:19]([F:18])[CH:24]=1)[CH:9]=2)=[O:4]
Reactant: OB(O)c1cccc(F)c1
Reactant: COC(=O)c1c(O)c2ccc(Br)cc2sc1=O
Product: COC(=O)c1c(O)c2ccc(-c3cccc(F)c3)cc2sc1=O

Procedure:
7-(3-Fluoro-phenyl)-4-hydroxy-2-oxo-2H-thiochromene-3-carboxylic acid methyl ester was prepared from 7-bromo-4-hydroxy-2-oxo-2H-thiochromene-3-carboxylic acid methyl ester under conditions analogous to Example 7(a) using 3-fluoro-phenylboronic acid. 1H NMR (200 MHz, CDCl3): δ (ppm)=8.41 (d, 1H), 7.625-7.114 (m, 6H), 4.02 (s, 3H).
Reaction SMILES: CC(OC(/N=N/C(OC(C)C)=O)=O)C.[N:15]1([C:19](=[O:29])[CH2:20][C:21]2[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][C:22]=2[F:28])[CH2:18][CH2:17][CH2:16]1.[CH3:30][O:31][CH2:32][C:33]1[CH:34]=[CH:35][C:36]([N:39]2[CH2:44][CH2:43][CH:42]([C@H:45]3[CH2:47][C@H:46]3[CH2:48][CH2:49]O)[CH2:41][CH2:40]2)=[N:37][CH:38]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1(C)C=CC=CC=1>[N:15]1([C:19](=[O:29])[CH2:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][CH2:49][CH2:48][C@@H:46]3[CH2:47][C@@H:45]3[CH:42]3[CH2:43][CH2:44][N:39]([C:36]4[CH:35]=[CH:34][C:33]([CH2:32][O:31][CH3:30])=[CH:38][N:37]=4)[CH2:40][CH2:41]3)=[CH:23][C:22]=2[F:28])[CH2:18][CH2:17][CH2:16]1
Reactant: O=C(Cc1ccc(O)cc1F)N1CCC1
Reactant: COCc1ccc(N2CCC([C@H]3C[C@H]3CCO)CC2)nc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: COCc1ccc(N2CCC([C@H]3C[C@H]3CCOc3ccc(CC(=O)N4CCC4)c(F)c3)CC2)nc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
DIAD (38.2 μl, 0.196 mmol) was added to a stirred mixture of 1-(azetidin-1-yl)-2-(2-fluoro-4-hydroxyphenyl)ethanone (41.1 mg, 0.196 mmol), 2-[(1S,2R)-2-{1-[5-(methoxymethyl)pyridin-2-yl]piperidin-4-yl}cyclopropyl]ethanol (57 mg, 0.196 mmol), and triphenyl phosphine (51.5 mg, 0.196 mmol) in toluene (327 μl). The mixture was degassed (3×) and stirred at RT for 2 hours. The mixture was diluted with ethyl acetate (20 mL), washed with water (20 ml), the layers separated, the aqueous phase extracted with EtOAc (20 ml), the organic fractions combined, washed with brine (35 ml), dried over sodium sulfate, filtered and the volatiles removed in vac. The residue was purified by column chromatography on silica gel, Biotage 25 g, using a gradient eluant of 0-100% EtOAc/hexanes to afford the title compound. LC/MS (m/z): 482 (M+H)+. GPR119 Human EC50: 0.94 nM
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH3:7])=[C:5]([NH:8][C:9](=[O:16])OCC(Cl)(Cl)Cl)[O:4][N:3]=1.[F:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[N:25]=[C:26]([N:29]3[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]3)[S:27][CH:28]=2)=[CH:20][CH:19]=1.C(N(C(C)C)CC)(C)C.O>CS(C)=O>[CH3:1][C:2]1[C:6]([CH3:7])=[C:5]([NH:8][C:9]([N:32]2[CH2:33][CH2:34][N:29]([C:26]3[S:27][CH:28]=[C:24]([C:21]4[CH:22]=[CH:23][C:18]([F:17])=[CH:19][CH:20]=4)[N:25]=3)[CH2:30][CH2:31]2)=[O:16])[O:4][N:3]=1
Reactant: Fc1ccc(-c2csc(N3CCNCC3)n2)cc1
Reactant: Cc1noc(NC(=O)OCC(Cl)(Cl)Cl)c1C
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CS(C)=O
Product: Cc1noc(NC(=O)N2CCN(c3nc(-c4ccc(F)cc4)cs3)CC2)c1C
Temperature: 70 °C
Reaction time: 18 h
Yield: 50.1 %

Procedure:
A mixture of 2,2,2-trichloroethyl (3,4-dimethylisoxazol-5-yl)carbamate (240 mg, 0.834 mmol), 1-[4-(4-fluorophenyl)-1,3-thiazol-2-yl]piperazine (200 mg, 0.760 mmol) and diisopropylethylamine (0.265 ml, 1.52 mmol) in dimethylsulfoxide (2.5 ml) was stirred at 70° C. for 18 hours. Water was poured into the reaction solution, and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was recrystallized from a mixed solvent of hexane and tetrahydrofuran to give the desired product (153 mg, 50.2%) as a solid.
Reaction SMILES: I[CH:2]([CH3:4])[CH3:3].[S:5]1[CH:9]=[CH:8][C:7]2[CH:10]=[C:11]([CH2:14][C:15]#[N:16])[CH:12]=[CH:13][C:6]1=2.[OH-].[Na+]>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC>[CH:2]([CH:14]([C:11]1[CH:12]=[CH:13][C:6]2[S:5][CH:9]=[CH:8][C:7]=2[CH:10]=1)[C:15]#[N:16])([CH3:4])[CH3:3]
Reactant: N#CCc1ccc2sccc2c1
Reactant: CC(C)I
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Product: CC(C)C(C#N)c1ccc2sccc2c1
Yield: 62 %

Procedure:
2-Iodopropane (5.10 g, 0.03 mol) was added to a well stirred mixture of benzo(b)thiophene-5-acetonitrile (2.62 g, 0.015 mol), tetrabutylammonium hydrogen sulphate (5.10 g, 0.015 mol), sodium hydroxide (47% w/w, 1.72 cm3, 0.03 mol) and the mixture was refluxed for 6 hr. with vigorous stirring. The organic layer was washed with water, dried (Na2SO4), filtered and the solvent was removed. The residue was chromatographed on silica using toluene as the eluant and the component with RF 0.52 was isolated as α-isopropylbenzo(b)thiophene-5-acetonitrile (2.00 g, 0.0093 mol, 61.9%).
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([CH2:21][CH3:22])[C:5]([NH:10][C@@H]2C3C(=CC=CC=3)C[C@@H]2O)=[N:6][C:7]=1[CH2:8][CH3:9].C(C1C(N[CH:34]2[C:43]3[C:38](=[CH:39][CH:40]=[C:41]([O:44][CH3:45])[CH:42]=3)[CH2:37][CH2:36][CH2:35]2)=NC(CC)=CN=1)C>>[Br:1][C:2]1[N:3]=[C:4]([CH2:21][CH3:22])[C:5]([NH:10][CH:34]2[C:43]3[C:38](=[CH:39][CH:40]=[C:41]([O:44][CH3:45])[CH:42]=3)[CH2:37][CH2:36][CH2:35]2)=[N:6][C:7]=1[CH2:8][CH3:9]
Reactant: CCc1cnc(CC)c(NC2CCCc3ccc(OC)cc32)n1
Reactant: CCc1nc(N[C@@H]2c3ccccc3C[C@@H]2O)c(CC)nc1Br
Product: CCc1nc(NC2CCCc3ccc(OC)cc32)c(CC)nc1Br

Procedure:
Following the procedure for the preparation of (1R,2S)-1-[(5-bromo-3,6-diethylpyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-ol but substituting 3,6-diethyl-N-(7-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)pyrazin-2-amine and making non-critical variations provided the title compound as a oil: 1H NMR (400 MHz, CDCl3) δ 7.08, 6.88, 6.81, 5.36, 4.52, 3.76, 2.79, 2.56, 2.08, 1.91, 1.31; (FAB) calcd for C19H24BrN3O+H 390.0, found 390.0.
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][CH:13]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[CH:19][C:18]=2[O:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2Br)[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4]>CN(C=O)C>[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][CH:13]([N:16]2[C:17]3[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[CH:19][C:18]=3[O:25][C:26]3[C:31]2=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2ccc(C#N)cc2Oc2ccccc2Br)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(N2c3ccccc3Oc3cc(C#N)ccc32)CC1
Temperature: 120 °C

Procedure:
To a suspension of sodium hydride (0.1-1 g; 0.74 mmol) in DMF (5 mL) was added a solution of 4-[2-(2-bromophenoxy)-4-cyanophenylamino]-piperidine-1-carboxylic acid tert-butyl ester, 3a (0.35 g; 0.74 mmol) in DMF (3 mL). The mixture was heated to 120° C. for 90 min and allowed to cool to rt. The mixture was poured into ice-water and a precipitate formed. The solid was separated via filtration, dried to yield 4-(3-cyanophenoxazin-10-yl)-piperidine-1-carboxylic acid tert-butyl ester, 4a. MS m/z (M+Na) 413.9. The material was used as such for the next reaction.