Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH3:9][C:10]1[C:18]2[C:17](=[O:19])[NH:16][C:15]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[O:26][CH2:27][CH2:28][CH3:29])=[N:14][C:13]=2[N:12]([CH2:30][CH2:31][CH3:32])[N:11]=1>>[Br:1][C:24]1[CH:23]=[CH:22][C:21]([O:26][CH2:27][CH2:28][CH3:29])=[C:20]([C:15]2[NH:16][C:17](=[O:19])[C:18]3[C:10]([CH3:9])=[N:11][N:12]([CH2:30][CH2:31][CH3:32])[C:13]=3[N:14]=2)[CH:25]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CCCOc1ccccc1-c1nc2c(c(C)nn2CCC)c(=O)[nH]1
Product: CCCOc1ccc(Br)cc1-c1nc2c(c(C)nn2CCC)c(=O)[nH]1

Procedure:
The title compound was prepared from N-bromosuccinimide (4.9 g, 0.0276 mol) and 3-methyl-6-(2-n-propoxyphenyl)-1-n-propyl-1,5-dihydro-4H-pyrazolo-[3,4-d]pyrimidin-4-one (Example 18; 3.0 g, 0.0092 mol), following the procedure of Example 6, and was obtained as yellow crystals (1.11 g, 30%), m.p. 157-159° C., after crystallisation from ethyl acetate. Found: C,53.14; H,5.17; N,13.76. C18H21BrN4O2 requires C,53.34; H,5.22; N,13.82%.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([N:6]=[C:7]([O:14][CH3:15])[C:8]([O:12][CH3:13])=[N:9]2)=[C:4]([CH3:16])[CH:3]=1.[Br:17]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([N:6]=[C:7]([O:14][CH3:15])[C:8]([O:12][CH3:13])=[N:9]2)=[C:4]([CH2:16][Br:17])[CH:3]=1
Reactant: COc1nc2cc(Br)cc(C)c2nc1OC
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: COc1nc2cc(Br)cc(CBr)c2nc1OC

Procedure:
15 g (53 mmol) of 7-bromo-5-methyl-2,3-dimethoxy-quinoxaline, 9.9 g (1.05 equiv.) of N-bromosuccinimide and 0.87 g (0.1 equiv.) of azo-isobutyronitrile are dissolved in 100 ml of carbon tetrachloride and the solution is stirred at reflux for 24 hours. The solid is filtered off and the filtrate is diluted with dichloromethane, then washed once with each of water and brine. The organic phase is dried over magnesium sulfate and concentrated by evaporation. The residue is recrystallized from ethyl acetate and hexane. The title compound is obtained in the form of light-orange crystals.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([CH2:8][N:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12](=[O:19])[C:11]([C:20]([OH:22])=O)=[CH:10]2)[CH:5]=[CH:4][CH:3]=1.Cl.[CH3:24][NH:25][O:26][CH3:27].C(N(CC)CC)C.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O>O.C(#N)C>[CH3:27][O:26][N:25]([CH3:24])[C:20]([C:11]1[C:12](=[O:19])[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:9]([CH2:8][C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([Br:1])[N:7]=2)[CH:10]=1)=[O:22]
Reactant: O=C(O)c1cn(Cc2cccc(Br)n2)c2ccccc2c1=O
Reactant: CNOC
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: CC#N
Product: CON(C)C(=O)c1cn(Cc2cccc(Br)n2)c2ccccc2c1=O
Yield: 90.9 %

Procedure:
9.45 g (26.3 mmol) of 1-(6-bromo-pyridin-2-ylmethyl)-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid, 2.82 g (28.9 mmol) of N,O-dimethylhydroxylamine hydrochloride, 22 mL (16 g, 158 mmol) of triethylamine and 18.8 mL (20.1 g, 31.6 mmol) of 50% 1-propanephosphonic acid cyclic anhydride were sequentially added to 250 mL acetonitrile at rt. After 1 h 400 mL of water were added and the mixture was extracted two times with 300 mL DCM. Combined organic layers were evaporated and the residue purified on silica flash column using 0-15% methanol in EtOAc to give 9.62 g of the product as an off-white solid.
Reaction SMILES: [F:1][C@H:2]([C@H:4]1[CH2:8][O:7][C:6](=[O:9])[N:5]1[C:10]1[CH:15]=[CH:14][N:13]=[C:12](F)[N:11]=1)[CH3:3].[F:17][C:18]1[C:23]([C:24]([F:27])([F:26])[F:25])=[CH:22][CH:21]=[CH:20][C:19]=1[C:28]1[CH:29]=[N:30][C:31]([C@@H:34]([NH2:36])[CH3:35])=[N:32][CH:33]=1.CCN(C(C)C)C(C)C.O>CS(C)=O>[F:17][C:18]1[C:23]([C:24]([F:26])([F:25])[F:27])=[CH:22][CH:21]=[CH:20][C:19]=1[C:28]1[CH:33]=[N:32][C:31]([C@@H:34]([NH:36][C:12]2[N:11]=[C:10]([N:5]3[C@@H:4]([C@@H:2]([F:1])[CH3:3])[CH2:8][O:7][C:6]3=[O:9])[CH:15]=[CH:14][N:13]=2)[CH3:35])=[N:30][CH:29]=1
Reactant: C[C@H](N)c1ncc(-c2cccc(C(F)(F)F)c2F)cn1
Reactant: C[C@H](F)[C@H]1COC(=O)N1c1ccnc(F)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CS(C)=O
Product: C[C@H](Nc1nccc(N2C(=O)OC[C@@H]2[C@H](C)F)n1)c1ncc(-c2cccc(C(F)(F)F)c2F)cn1
Yield: 76.1 %

Procedure:
(R)-4-((S)-1-fluoroethyl)-3-(2-fluoropyrimidin-4-yl)oxazolidin-2-one (50 mg, 0.218 mmol) and (S)-1-(5-(2-fluoro-3-(trifluoromethyl)phenyl)pyrimidin-2-yl)ethanamine (75 mg, 0.262 mmol) were taken up in 3 mL DMSO. Hunig's base (57 uL, 0.327 mmol) was added. The mixture was heated to 110 C for 1.5 h. The reaction mixture was poured into 30 mL water, and extracted with EtOAc (2×30 mL). Organics were washed with 20 mL each water, and brine. Combined organics were dried over Na2SO4, filtered and concentrated on silica gel. Column chromatography (25-100% EtOAc/heptane) gave 82 mg white solid. 1H NMR (400 MHz, CDCl3) δ 8.91 (d, J=1.4 Hz, 2H), 8.25 (d, J=5.7 Hz, 1H), 7.79-7.61 (m, 2H), 7.52 (d, J=5.7 Hz, 1H), 7.44 (tt, J=7.7, 0.8 Hz, 1H), 6.12 (s, 1H), 5.32 (s, 1H), 5.08 (br s, 1H), 4.80 (dddd, J=26.5, 9.1, 3.4, 1.5 Hz, 1H), 4.58 (dd, J=8.8, 3.4 Hz, 1H), 4.44 (td, J=9.0, 1.3 Hz, 1H), 1.68 (d, J=8.8 Hz, 3H), 1.43-1.24 (m, 3H). HRMS (A) m/z 495.1611 (M+H)+. Anal. RP-HPLC tR=3.68 min. Purity 96%/100%.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[O:14][C@@H:9]2[C:10]([NH:12][CH3:13])=[O:11])=[CH:4][CH:3]=1.[NH2:15][C:16]1[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][C:17]=1[SH:23]>>[NH2:15][C:16]1[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][C:17]=1[S:23][C@H:8]([C:5]1[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=1)[C@H:9]([OH:14])[C:10]([NH:12][CH3:13])=[O:11]
Reactant: Cc1ccc(N)c(S)c1
Reactant: CNC(=O)[C@H]1O[C@@H]1c1ccc(C)cc1
Product: CNC(=O)[C@@H](O)[C@H](Sc1cc(C)ccc1N)c1ccc(C)cc1

Procedure:
(2S,3R)-3-(4-Methylphenyl)-2,3-epoxy-N-methylpropionamide and 2-amino-5-methylthiophenol are treated in the same manner as in Reference Example 1-(2) to give (2R,3R)-3-(2-amino-5-methylphenylthio)-2-hydroxy-3-(4-methylphenyl)-N-methylpropionamide.
Reaction SMILES: [CH3:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[CH:4]=[CH:5][C:6](=O)[CH3:7].[CH2:13]([O:15][C:16](=[O:21])[CH2:17][C:18](=[NH:20])[NH2:19])[CH3:14].C(O)(C)C>C(O)C>[CH2:13]([O:15][C:16]([C:17]1[CH:4]([C:3]2[CH:9]=[CH:10][CH:11]=[CH:12][C:2]=2[CH3:1])[CH:5]=[C:6]([CH3:7])[NH:20][C:18]=1[NH2:19])=[O:21])[CH3:14]
Reactant: CC(=O)C=Cc1ccccc1C
Reactant: CCOC(=O)CC(=N)N
Solvent: CC(C)O
Solvent: CCO
Product: CCOC(=O)C1=C(N)NC(C)=CC1c1ccccc1C
Yield: 61 %

Procedure:
Upon heating a solution of 16.0 g of 2-methylbenzylideneacetone and 13.0 of amidinoacetic acid ethyl ester in 150 ml of ethanol for 2 hours, 2-amino-6-methyl-4-(2-methylphenyl)-1,4-dihydropyridine-3-carboxylic acid ethyl ester of melting point 159°C (isopropanol) is obtained. Yield: 61 percent of theory.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([OH:16])=O)=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.Cl.[NH2:43][CH2:44][C:45]1[CH:46]=[C:47]([CH:62]=[CH:63][CH:64]=1)[C:48]([NH:50][C:51]1[CH:60]=[C:59]2[C:54]([CH2:55][CH2:56][N:57]([CH3:61])[CH2:58]2)=[CH:53][CH:52]=1)=[O:49].CN1CCOCC1>CN(C=O)C>[CH3:61][N:57]1[CH2:56][CH2:55][C:54]2[C:59](=[CH:60][C:51]([NH:50][C:48]([C:47]3[CH:46]=[C:45]([CH:64]=[CH:63][CH:62]=3)[CH2:44][NH:43][C:14]([C:11]3[CH:10]=[CH:9][C:8]([C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([OH:1])[CH:3]=4)=[CH:13][CH:12]=3)=[O:16])=[O:49])=[CH:52][CH:53]=2)[CH2:58]1
Reactant: O=C(O)c1ccc(-c2cccc(O)c2)cc1
Reactant: CN1CCc2ccc(NC(=O)c3cccc(CN)c3)cc2C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CN1CCc2ccc(NC(=O)c3cccc(CNC(=O)c4ccc(-c5cccc(O)c5)cc4)c3)cc2C1

Procedure:
To a vial containing 3′-hydroxy-biphenyl-4-carboxylic acid (26 mg, 0.12 mmol) add a solution of HATU (2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyl uronium hexafluorophosphate) (57 mg, 0.15 mmol) in DMF (1 mL) followed by a solution of 3-aminomethyl-N-(2-methyl-1,2,3,4-tetrahydro-isoquinolin-7-yl)-benzamide dihydrochloride (37 mg, 0.10 mmol) and 4-methylmorpholine (0.044 mL, 0.40 mmol) in DMF (1 mL). Shake the reaction at rt for 24 h. Concentrate in vacuo to an oil. Dissolve the residue in 10% water in DMSO (0.9 mL) and purify by prep-HPLC (10% to 90%, CH3CN/H2O). Concentrate fractions to afford the desired product 3′-hydroxy-biphenyl-4-carboxylic acid 3-(2-methyl-1,2,3,4-tetrahydro-isoquinolin-7-ylcarbamoyl)-benzylamide as a solid in 45% yield (22 mg, 0.045 mmol). MS, electrospray (M+H) 492.4, rt 2.29 min.
Reaction SMILES: C([O:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([Cl:20])=[CH:16][C:17]=2[Cl:19])[N:12]=[C:11]([C:21]([O:23][CH2:24][CH2:25][N:26]2[CH2:30][CH2:29][CH2:28][CH2:27]2)=[O:22])[CH:10]=1)C1C=CC=CC=1.[BrH:31]>C(O)(=O)C>[BrH:31].[Cl:19][C:17]1[CH:16]=[C:15]([Cl:20])[CH:14]=[C:13]2[C:18]=1[C:9](=[O:8])[CH:10]=[C:11]([C:21]([O:23][CH2:24][CH2:25][N:26]1[CH2:30][CH2:29][CH2:28][CH2:27]1)=[O:22])[NH:12]2
Reactant: O=C(OCCN1CCCC1)c1cc(OCc2ccccc2)c2c(Cl)cc(Cl)cc2n1
Agent: Br
Solvent: CC(=O)O
Product: O=C(OCCN1CCCC1)c1cc(=O)c2c(Cl)cc(Cl)cc2[nH]1

Procedure:
Treatment of 2-(1-pyrrolidinyl)ethyl 4-benzyloxy-5,7-dichloroquinoline-2-carboxylate (0.65 g) with hydrogen bromide in acetic acid (5 ml, 48%) as described in Example 33d gave 2-(1-pyrrolidinyl)ethyl 5,7-dichloro-4-oxo-1,4-dihydroquinoline-2-carboxylate hydrobromide (0.3 g), m.p. 258° C. (dec). δ (250 MHz, DMSO-d6) 2.04 (4H, m, pyrrolidine-3,4-H), 3.18 (2H, m, CH2N) 3.68 (4H, m, pyrrolidine-2.5-H), 4.68 (2H, t, CO2CH2), 6.91 (1H, s, 3-H), 7.46 (1H, d, 6-H), 8.08 (1H, d, 8-H), 9.90 (2H, vbs, NH). (Found: C, 41.24; H, 3.68; N, 6.03%. C16H16Cl2N2O3. 1.35HBr requires C, 41.38; H, 3.76; N, 6.03%).
Reaction SMILES: [CH3:1][NH:2][CH:3]1[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.FC(F)(F)S(O[C:15]1[C:16]2[CH2:36][N:35]([C:37](=[O:39])[CH3:38])[CH2:34][CH2:33][C:17]=2[N:18]=[C:19]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]3[O:32][CH:31]=[N:30][CH:29]=3)=[CH:24][CH:23]=2)[N:20]=1)(=O)=O.S(C1C=CC(C)=CC=1)([O-])(=O)=O>>[CH:3]1([N:2]([CH3:1])[C:15]2[C:16]3[CH2:36][N:35]([C:37](=[O:39])[CH3:38])[CH2:34][CH2:33][C:17]=3[N:18]=[C:19]([NH:21][C:22]3[CH:27]=[CH:26][C:25]([C:28]4[O:32][CH:31]=[N:30][CH:29]=4)=[CH:24][CH:23]=3)[N:20]=2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: CNC1CCCCC1
Reactant: CC(=O)N1CCc2nc(Nc3ccc(-c4cnco4)cc3)nc(OS(=O)(=O)C(F)(F)F)c2C1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Product: CC(=O)N1CCc2nc(Nc3ccc(-c4cnco4)cc3)nc(N(C)C3CCCCC3)c2C1
Yield: 17 %

Procedure:
1-(4-(Cyclohexyl(methyl)amino)-2-(4-(oxazol-5-yl)phenylamino)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)ethanone (12.6 mg, 17%) was prepared from N-methylcyclohexanamine and 6-acetyl-2-(4-(oxazol-5-yl)phenylamino)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl trifluoromethanesulfonate according to the general procedure for amine substitution of tosylate on pyrimidines.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:8]=[CH:7][C:5]=2[N:6]=1.[C:17]1([C:23]#[C:24][C:25](OCC)=[O:26])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[O:26]=[C:25]1[CH:24]=[C:23]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:6]2[C:2]([S:3][C:4]3[CH:10]=[C:9]([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:8]=[CH:7][C:5]=32)=[N:1]1
Reactant: CCOC(=O)Cc1ccc2nc(N)sc2c1
Reactant: CCOC(=O)C#Cc1ccccc1
Product: CCOC(=O)Cc1ccc2c(c1)sc1nc(=O)cc(-c3ccccc3)n12
Temperature: 200 °C
Yield: 25.8 %

Procedure:
A stirred mixture of 5 g of ethyl 2-aminobenzothiazole-6-acetate and 6 g of ethyl phenylpropiolate was heated at 200° C. in an oil bath for 1 hour and the crude mixture was then purified on a column of 200 g of silica using CHCl3 as eluant. The product obtained was highly colored and was crystallized from CHCl3 and crystallized from ethanol to obtain 1.99 g (26% yield) of ethyl 2-oxo-4-phenyl-2H-pyrimido[2,1-b]benzothiazole-8-acetate as orange plates.
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:21])[N:4]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)[N:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1.[CH:22]1([C:25](Cl)=[O:26])[CH2:24][CH2:23]1>>[Cl:1][C:2]1[C:3](=[O:21])[N:4]([C:14]2[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=2)[N:5]=[CH:6][C:7]=1[N:8]1[CH2:9][CH2:10][N:11]([C:25]([CH:22]2[CH2:24][CH2:23]2)=[O:26])[CH2:12][CH2:13]1
Reactant: O=c1c(Cl)c(N2CCNCC2)cnn1-c1ccc(Cl)cc1
Reactant: O=C(Cl)C1CC1
Product: O=C(C1CC1)N1CCN(c2cnn(-c3ccc(Cl)cc3)c(=O)c2Cl)CC1

Procedure:
Obtainable by general method 2 from 9.76 g (30.0 mmol) of the compound from Example 2A with 3.3 ml (36 mmol) of cyclopropylcarbonyl chloride.
Reaction SMILES: [C:1]1([CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=1)[OH:2].[OH-].[K+].F[C:12]1[C:17]([F:18])=[CH:16][C:15]([C:19]([F:22])([F:21])[F:20])=[CH:14][N:13]=1.Cl>CS(C)=O>[F:18][C:17]1[C:12]([O:2][C:1]2[CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=2)=[N:13][CH:14]=[C:15]([C:19]([F:21])([F:20])[F:22])[CH:16]=1
Reactant: Fc1cc(C(F)(F)F)cnc1F
Reactant: Oc1ccc(O)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: Oc1ccc(Oc2ncc(C(F)(F)F)cc2F)cc1
Temperature: 25 °C
Yield: 70.8 %

Procedure:
A mixture of 16.5 g (0.15 mol) of hydroquinone, 19.1 g (0.3 mol) of potassium hydroxide (88%) in 600 ml of dimethylsulfoxide is stirred at room temperature under a nitrogen atmosphere until everything is dissolved. A solution of 13.7 g (0.075 mol) of 2,3-difluoro-5-trifluoromethyl-pyridine in 25 ml of dimethylsulfoxide is added dropwise at a temperature of 15°-20°. The reaction mixture is then stirred at room temperature for 24 hours. Then it is poured into ice/water and the mixture is acidified with hydrochloric acid, extracted with methylene chloride, washed with water, dried over magnesium sulfate, filtered and evaporated to dryness. The residue crystallizes in hexane/ethyl acetate to yield 14.5 g (71%) of white crystals, melting at 97°.
Reaction SMILES: Cl.[O:2]1[CH2:8][CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[CH:9]([C:11]1[CH:16]=[CH:15][C:14]([C:17]#[C:18][C:19]2[CH:29]=[CH:28][C:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:21][CH:20]=2)=[CH:13][CH:12]=1)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl.C(O)(=O)C>[O:2]1[CH2:8][CH2:7][CH2:6][N:5]([CH2:9][C:11]2[CH:12]=[CH:13][C:14]([C:17]#[C:18][C:19]3[CH:20]=[CH:21][C:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:28][CH:29]=3)=[CH:15][CH:16]=2)[CH2:4][CH2:3]1
Reactant: C1CNCCOC1
Reactant: CCOC(=O)c1ccc(C#Cc2ccc(C=O)cc2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: O=C([O-])O
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1ccc(C#Cc2ccc(CN3CCCOCC3)cc2)cc1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 54.7 %

Procedure:
1,4-Oxazepane hydrochloride (1.6 g) and acetic acid (0.90 mL) were added to a chloroform (20 mL) solution of ethyl 4-[(4-formylphenyl)ethynyl]benzoate (2.1 g) as obtained in Example 5-(1), and the mixture was stirred for 3.5 hours at room temperature, and then for 2 hours at 60° C. Then, sodium triacetoxyborohydride (2.7 g) was added, and the mixture was stirred for 16 hours at room temperature. A saturated aqueous solution of sodium hydrogen carbonate was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with brine, and dried over anhydrous sodium sulfate. Then, the desiccant was filtered out, and the solvent was distilled off under reduced pressure. The resulting residue was purified by OH type silica gel chromatography (gradient elution with chloroform/methanol=100/0→93/7) to obtain ethyl 4-{[4-(1,4-oxazepan-4-ylmethyl)phenyl]ethynyl}benzoate (yellow solid) (1.5 g, 52%).
Reaction SMILES: Cl[C:2]1[C:3](=[O:15])[N:4]([C@H:9]([CH:12]2[CH2:14][CH2:13]2)[CH2:10][CH3:11])[CH:5]=[C:6]([Cl:8])[N:7]=1.[Cl:16][C:17]1[CH:18]=[C:19]2[C:23](=[C:24]([Cl:26])[CH:25]=1)[NH:22][CH2:21][CH2:20]2>>[Cl:8][C:6]1[N:7]=[C:2]([N:22]2[C:23]3[C:19](=[CH:18][C:17]([Cl:16])=[CH:25][C:24]=3[Cl:26])[CH2:20][CH2:21]2)[C:3](=[O:15])[N:4]([C@H:9]([CH:12]2[CH2:14][CH2:13]2)[CH2:10][CH3:11])[CH:5]=1
Reactant: CC[C@@H](C1CC1)n1cc(Cl)nc(Cl)c1=O
Reactant: Clc1cc(Cl)c2c(c1)CCN2
Product: CC[C@@H](C1CC1)n1cc(Cl)nc(N2CCc3cc(Cl)cc(Cl)c32)c1=O

Procedure:
Prepared in a similar fashion as described for Example 413 using 3,5-dichloro-1-[(1S)-1-cyclopropylpropyl]-2(1H)-pyrazinone and 5,7-dichloroindoline as the starting materials. mp 157–159° C.; 1H NMR (300 MHz, CDCl3): δ 7.15 (s, 1 H), 7.09 (s, 1 H), 6.99 (s, 1 H), 4.34–4.24 (m, 2 H), 4.08–3.99 (m, 0.5 H), 3.11 (t, J=7.9 Hz, 2 H), 2.42–2.36 (m, 0.5 H), 2.16–2.00 (m, 1 H), 1.94–1.74 (m, 1 H), 1.07–0.99 (m, 1 H), 0.94–0.86 (m, 3 H), 0.80–0.71 (m, 1 H), 0.53–0.42 (m, 2 H), 0.36–0.20 (m, 1 H); HRMS (ESI) calcd for C18H19N3OCl3 (M+H)+: 398.0594; found m/z 398.0602.
Reaction SMILES: [CH2:1]([C:5]1[C:6]([CH3:17])=[N:7][CH:8]=[N:9][C:10]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:2][CH2:3][CH3:4].[Br:18]Br>CC(O)=O>[Br:18][CH2:17][C:6]1[C:5]([CH2:1][CH2:2][CH2:3][CH3:4])=[C:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:9]=[CH:8][N:7]=1
Reactant: BrBr
Reactant: CCCCc1c(C)ncnc1-c1ccccc1
Solvent: CC(=O)O
Product: CCCCc1c(CBr)ncnc1-c1ccccc1

Procedure:
A solution of 5-butyl-4-methyl-6-phenyl-pyrimidine (320 mg, 1.14 mmol) and Br2 (0.08 ml, 1.48 mmol) in AcOH (2 mL) is stirred at 80° C. for 2 hours. After cooling, the solution is concentrated. The residue is then partitioned between Et2O and half saturated aqueous NaHCO3. The layers are separated, and the aqueous layer is reextracted once with Et2O. The combined extracts are dried over Na2SO4 and concentrated. The residue is purified by flash chromatography on silica gel. Elution with 3:1 hexanes-EtOAc affords 4-bromomethyl-5-butyl-6-phenyl-pyrimidine and a small amount of an unidentified impurity. 1H NMR (CDCl3, 300 MHz) δ 9.08 (s, 1H), 7.47 (s, 5H), 4.57 (s, 2H), 2.79-2.74 (m, 2H), 1.52-1.42 (m, 2H), 1.38-1.20 (m, 2H), 0.80 (t, J=7.41Hz, 3H) ppm.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([CH3:15])[C:6]([C:12]([OH:14])=O)=[CH:7][CH:8]=2)[N:3]=1.[CH:16]([NH2:19])([CH3:18])[CH3:17].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.Cl>CC#N.O>[CH:16]([NH:19][C:12]([C:6]1[C:5]([CH3:15])=[C:4]2[C:9]([CH:10]=[CH:11][C:2]([CH3:1])=[N:3]2)=[CH:8][CH:7]=1)=[O:14])([CH3:18])[CH3:17]
Reactant: CC(C)N
Reactant: Cc1ccc2ccc(C(=O)O)c(C)c2n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: Cc1ccc2ccc(C(=O)NC(C)C)c(C)c2n1
Temperature: 0 °C
Reaction time: 18 h
Yield: 92.6 %

Procedure:
A mixture of 2,8-dimethylquinoline-7-carboxylic acid (0.20 g, 0.994 mmol), isopropylamine (0.102 mL, 1.19 mmol) and HATU (0.491 g, 1.29 mmol) in anhydrous MeCN (5 mL) under a nitrogen atmosphere was cooled to 0° C. in an ice bath. To the cooled mixture was added dropwise DIEA (0.69 mL, 3.98 mmol) and the resulting mixture stirred at ambient temperature for 18 hours. The mixture was diluted with water, neutralized with aqueous 1N HCl and extracted with ethyl acetate. The combined organic extracts were washed with water and brine, dried (MgSO4), filtered and concentrated under reduced pressure. The residue was purified by reverse phase chromatography (Biotage SP4, 25M C-18, 5-60% MeCN—H2O) to afford N-isopropyl-2,8-dimethylquinoline-7-carboxamide (0.223 g, 93%).
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:4]=[C:5]([CH:17]=[CH:18][CH:19]=1)[C:6]([C:8]1[N:16]=[CH:15][CH:14]=[CH:13][C:9]=1[C:10](Cl)=[O:11])=[O:7].Cl.[CH3:23][NH:24][CH3:25].C(N(CC)CC)C>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH3:23][N:24]([CH3:25])[C:10](=[O:11])[C:9]1[CH:13]=[CH:14][CH:15]=[N:16][C:8]=1[C:6](=[O:7])[C:5]1[CH:17]=[CH:18][CH:19]=[C:3]([C:2]([F:21])([F:20])[F:1])[CH:4]=1
Reactant: O=C(Cl)c1cccnc1C(=O)c1cccc(C(F)(F)F)c1
Reactant: CNC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CN(C)C(=O)c1cccnc1C(=O)c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 4.5 h

Procedure:
The product from step (i) above was dissolved in dry toluene (10 ml). Dimethylamine hydrochloride (1.3 g) was added followed by triethylamine (1.94 g). The mixture was then stirred at room temperature for 4.5 hours. The mixture was diluted with ethyl acetate and washed successively with ethyl acetate and washed successively with 2N sodium carbonate, 2N hydrochloric acid then water. The organic phase was dried then evaporated to yield a red-brown gum which was triturated in hexane to yield the title product as a beige solid (0.64 g), m.p.100°-103° C.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH2:11]([O:18][C@H:19]1[C@H:24]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C@@H:23]([O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C@@:22]([C:43]2[CH:48]=[CH:47][C:46]([CH3:49])=[C:45]([CH2:50][C:51]3[S:52][C:53]([C:56]4[CH:61]=[CH:60][C:59]([F:62])=[CH:58][CH:57]=4)=[CH:54][CH:55]=3)[CH:44]=2)([O:41][CH3:42])[O:21][C@@H:20]1[CH2:63][OH:64])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C>ClCCl>[CH2:11]([O:18][C@H:19]1[C@H:24]([O:25][CH2:26][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[C@@H:23]([O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C@@:22]([C:43]2[CH:48]=[CH:47][C:46]([CH3:49])=[C:45]([CH2:50][C:51]3[S:52][C:53]([C:56]4[CH:57]=[CH:58][C:59]([F:62])=[CH:60][CH:61]=4)=[CH:54][CH:55]=3)[CH:44]=2)([O:41][CH3:42])[O:21][C@@H:20]1[CH:63]=[O:64])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CO[C@@]1(c2ccc(C)c(Cc3ccc(-c4ccc(F)cc4)s3)c2)O[C@H](CO)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: ClCCl
Product: CO[C@@]1(c2ccc(C)c(Cc3ccc(-c4ccc(F)cc4)s3)c2)O[C@H](C=O)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 101 %

Procedure:
Oxalyl chloride (0.27 mL, 3.12 mmol) was dissolved in 8 mL dichloromethane and cooled to −78° C. The reaction mixture was stirred for 15 minutes before 4 mL solution of dimethyl sulfoxide (0.36 mL, 5.04 mmol) in dichloromethane were added. Then 8 mL solution of [(2R,3R,4S,5R,6S)-3,4,5-tribenzyloxy-6-[3-[[5-(4-fluorophenyl)-2-thienyl]methyl]-4-methyl-phenyl]-6-methoxy-tetrahydropyran-2-yl]methanol 9g (1.8 g, 2.4 mmol) in dichloromethane were dropwise added. The reaction mixture was stirred for 30 minutes. Then triethylamine (1.66 mL, 12 mmol) was added before the reaction mixture was warmed to room temperature and stirred for 1 hour. Thereafter, the reaction mixture was partitioned after 12 mL 1 M hydrochloric acid were added, the organic extract was combined, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain the title compound (2S,3S,4S,5R,6S)-3,4,5-tribenzyloxy-6-[3-[[5-(4-fluorophenyl)-2-thienyl]methyl]-4-methyl-phenyl]-6-methoxy-tetrahydropyran-2-carbaldehyde 9h (1.8 g, yellow grease), which was used directly in the next step without purification.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][N:7]=[C:6]([Cl:10])[CH:5]=1)(=[O:3])[CH3:2].C(O[CH:14](OCC)[N:15]([CH3:17])[CH3:16])C>>[CH3:14][N:15]([CH3:17])[CH:16]=[CH:2][C:1]([C:4]1[CH:9]=[CH:8][N:7]=[C:6]([Cl:10])[CH:5]=1)=[O:3]
Reactant: CC(=O)c1ccnc(Cl)c1
Reactant: CCOC(OCC)N(C)C
Product: CN(C)C=CC(=O)c1ccnc(Cl)c1

Procedure:
16.2 g (104.2 mmol) of 4-acetyl-2-chloro-pyridine are stirred for 1 hour at 110° with 116 ml of dimethylformamide diethylacetal. After cooling to 0°, filtering and drying at 60° under HV, 3-dimethylamino-1-(2-chloro-4-pyridyl)-2-propen-1-one is obtained; 1 H-NMR (dimethyl sulfoxide): 2.98 (3H,s), 3.2 (3H,s), 5.9 (1H,d), 7.8 (3H,m), 8.5 (1H,d).