Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[N:8]([C:9]([C:11]2[N:12]=[C:13]([CH3:23])[S:14][C:15]=2[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=2)=[O:10])[CH2:7][C@H:6]2[C@@H:4]1[CH2:5]2.[CH3:24][C:25]1([CH3:37])[CH2:29][C:28]2[CH:30]=[CH:31][CH:32]=[C:33]([C:34](O)=[O:35])[C:27]=2[O:26]1>>[Cl:22][C:18]1[CH:17]=[C:16]([C:15]2[S:14][C:13]([CH3:23])=[N:12][C:11]=2[C:9]([N:8]2[CH2:7][C@H:6]3[C@H:4]([CH2:5]3)[C@H:3]2[CH2:2][NH:1][C:34]([C:33]2[C:27]3[O:26][C:25]([CH3:37])([CH3:24])[CH2:29][C:28]=3[CH:30]=[CH:31][CH:32]=2)=[O:35])=[O:10])[CH:21]=[CH:20][CH:19]=1
Reactant: CC1(C)Cc2cccc(C(=O)O)c2O1
Reactant: Cc1nc(C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CN)c(-c2cccc(Cl)c2)s1
Product: Cc1nc(C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CNC(=O)c2cccc3c2OC(C)(C)C3)c(-c2cccc(Cl)c2)s1

Procedure:
prepared by reaction of ((1S,2S,5R)-2-Aminomethyl-3-aza-bicyclo[3.1.0]hex-3-yl)-[5-(3-chloro-phenyl)-2-methyl-thiazol-4-yl]-methanone with 2,2-Dimethyl-2,3-dihydro-benzofuran-7-carboxylic acid.
Reaction SMILES: [CH2:1]([C:3]1[NH:4][C:5]2[C:10]([C:11]=1[C:12]1[CH2:13][CH2:14][NH:15][CH2:16][CH:17]=1)=[CH:9][C:8]([F:18])=[CH:7][CH:6]=2)[CH3:2]>CO.[Pd]>[CH2:1]([C:3]1[NH:4][C:5]2[C:10]([C:11]=1[CH:12]1[CH2:13][CH2:14][NH:15][CH2:16][CH2:17]1)=[CH:9][C:8]([F:18])=[CH:7][CH:6]=2)[CH3:2]
Reactant: CCc1[nH]c2ccc(F)cc2c1C1=CCNCC1
Agent: [Pd]
Solvent: CO
Product: CCc1[nH]c2ccc(F)cc2c1C1CCNCC1

Procedure:
2.83 g 2-ethyl-5-fluoro-3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole are suspended in 50 ml of methanol and hydrogenated with 0.3 g Pd/C 10% at normal pressure and ambient temperature. The catalyst is suction filtered and the filtrate is evaporated to dryness. 2.3 g (V-1) are obtained as a solid. 1H NMR (400 MHz, DMSO): 2.70 (2H, q); 1.19 (3H, t).
Reaction SMILES: I[C:2]1[N:3]=[CH:4][N:5]2[C:11]3[S:12](=[O:15])[CH:13]=[CH:14][C:10]=3[CH2:9][N:8]([CH3:16])[CH2:7][C:6]=12.[CH3:17][C:18]([OH:22])([C:20]#[CH:21])[CH3:19]>C(NCC)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[OH:22][C:18]([CH3:19])([CH3:17])[C:20]#[C:21][C:2]1[N:3]=[CH:4][N:5]2[C:11]3[S:12](=[O:15])[CH:13]=[CH:14][C:10]=3[CH2:9][N:8]([CH3:16])[CH2:7][C:6]=12
Reactant: C#CC(C)(C)O
Reactant: CN1CC2=C(n3cnc(I)c3C1)S(=O)C=C2
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCNCC
Product: CN1CC2=C(n3cnc(C#CC(C)(C)O)c3C1)S(=O)C=C2

Procedure:
5.52 g of 5,6-dihydro-7-iodo-5-methyl-4H-imidazo[1,5-a]thieno[3,2-f][1,4]diazepine-one in 30 ml of diethylamine was treated with 1.92 ml of 2-methyl-3-butyn-2-ol, 75 mg of bis-(triphenylphosphine)-palladium(II) chloride and 13 mg of copper(I) iodide. The mixture was stirred at reflux temperature for 2 hours. The reaction mixture was then evaporated in a vacuum. The residue was dissolved in dichloromethane and this solution was washed twice with water. After drying over sodium sulphate this solution was chromatographed through 300 g of silica gel. Unreacted starting material was first recovered with dichloromethane/ethanol mixtures 99:1, 98:2 and 97:3. There was then eluted with dichloromethane/ethanol mixtures 96:4 and 95:5 an oily substance which crystallized from ethyl acelate/diethyl ether. There was obtained 5,6-dihydro-7-(3-hydroxy-3-methyl-1-butynyl)-5-methyl-4H-imidazo[1,5-a]-thieno[3,2-f][1,4]diazepine-one of melting point 180°-181°.
Reaction SMILES: [SH:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[C:11]1([CH3:23])[CH:16]=[CH:15][C:14]([S:17]([CH2:20][CH2:21]O)(=[O:19])=[O:18])=[CH:13][CH:12]=1.OS(O)(=O)=O>CN(C=O)C>[S:17]([CH2:20][CH2:21][S:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5])([C:14]1[CH:15]=[CH:16][C:11]([CH3:23])=[CH:12][CH:13]=1)(=[O:19])=[O:18]
Reactant: Cc1ccc(S(=O)(=O)CCO)cc1
Reactant: O=C(O)c1cccnc1S
Agent: O=S(=O)(O)O
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)CCSc2ncccc2C(=O)O)cc1
Reaction time: 8 h
Yield: 14.9 %

Procedure:
A solution of 7.3 g (47 mmol) of 2-mercaptonicotinic acid and 9.6 g (48 mmol) of 2-(p-toluenesulfonyl)-ethanol was dissolved in DMF (80 ml). 0.5 ml of conc. H2SO4 was then carefully added dropwise, and stirring was carried out overnight under reflux. The reaction mixture was concentrated using a Genevac (EZ2). The residue was dissolved in acetonitrile and the solid was separated off. The mother liquor was concentrated, and MeOH was added. The resulting solid was filtered off and dried. 2.35 g (7 mmol, 14.8%) of 2-(2-tosylethylthio)nicotinic acid were obtained as solid.
Reaction SMILES: [C:1]1([C:7]2[CH2:11][CH:10]([CH2:12][CH2:13][CH:14]=O)[O:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[Cl:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C(N(C(C)C)CC)(C)C>C(Cl)Cl>[Cl:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[N:24]1[CH2:29][CH2:28][N:27]([CH2:14][CH2:13][CH2:12][CH:10]2[O:9][N:8]=[C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH2:11]2)[CH2:26][CH2:25]1
Reactant: O=CCCC1CC(c2ccccc2)=NO1
Reactant: Clc1ccccc1N1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Clc1ccccc1N1CCN(CCCC2CC(c3ccccc3)=NO2)CC1
Yield: 78.1 %

Procedure:
3-(3-Phenyl-4,5-dihydroisoxazol-5-yl)propanal (20.7 mg, 0.094 mmol), 1-(2-chlorophenyl)piperazine hydrochloride (20.0 mg, 0.086 mmol), molecular sieve (5 beads), NaBH(OAc)3 (54.5 mg, 0.257 mmol) and diisopropylethylamine (26.9 L, 0.085 mmol) were reacted in 3 mL of methylene chloride for about 12 hr. With the following processes the same as in Example 1, 25.8 mg (87.2%) of the target compound was obtained.
Reaction SMILES: I[C:2]1[CH:3]=[N:4][N:5]2[C:10]([C:11]([F:14])([F:13])[F:12])=[CH:9][C:8]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=3)=[N:7][C:6]=12.[C:25]1([C:31]#[CH:32])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[C:25]1([C:31]#[C:32][C:2]2[CH:3]=[N:4][N:5]3[C:10]([C:11]([F:14])([F:13])[F:12])=[CH:9][C:8]([C:15]4[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=4)=[N:7][C:6]=23)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: FC(F)(F)c1ccc(-c2cc(C(F)(F)F)n3ncc(I)c3n2)cc1
Reactant: C#Cc1ccccc1
Product: FC(F)(F)c1ccc(-c2cc(C(F)(F)F)n3ncc(C#Cc4ccccc4)c3n2)cc1

Procedure:
The title compound was prepared from 3-Iodo-7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.1, method 2, step 2) (340 mg, 1.0 mmol) and phenylacetylene (267 mg, 1.0 mmol) according to general procedure II. Obtained as an orange solid (250 mg, 58%). MS (ISP) 432.3[(M+H)+]; mp 144-145° C.
Reaction SMILES: C(N(CC)CC)C.Cl.[CH3:9][C:10]1[C:18]([O:19][C@@H:20]2[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]2)=[CH:17][CH:16]=[C:15]2[C:11]=1[CH:12]=[N:13][NH:14]2.[CH3:27][S:28](Cl)(=[O:30])=[O:29].O>O1CCCC1.ClCCl>[CH3:9][C:10]1[C:18]([O:19][C@@H:20]2[CH2:25][CH2:24][C@H:23]([NH:26][S:28]([CH3:27])(=[O:30])=[O:29])[CH2:22][CH2:21]2)=[CH:17][CH:16]=[C:15]2[C:11]=1[CH:12]=[N:13][NH:14]2
Reactant: Cc1c(O[C@H]2CC[C@@H](N)CC2)ccc2[nH]ncc12
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: Cc1c(O[C@H]2CC[C@@H](NS(C)(=O)=O)CC2)ccc2[nH]ncc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Under a nitrogen atmosphere, triethylamine (49.5 μl, 0.355 mmol) was added at 0° C. to a solution of the cis-4-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexanamine hydrochloride (100 mg, 0.355 mmol) obtained in Example 410 in tetrahydrofuran (4 ml), followed by adding dropwise thereto a solution of methanesulfonyl chloride (28 μl, 0.362 mmol) in dichloromethane (2 ml). After 30 minutes, the resulting mixture was heated to room temperature and triethylamine (0.355 mmol) was further added thereto. After 2 hours, triethylamine (0.355 mmol) and methanesulfonyl chloride (0.355 mmol) were further added thereto. After 2 hours, the reaction solution was poured into water and extracted with ethyl acetate. The extract solution was concentrated under reduced pressure and the resulting residue was purified by a silica gel column chromatography (eluent: chloroform/ethyl acetate) to obtain cis-N-{4-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexyl}methanesulfonamide (31.7 mg, 28%).
Reaction SMILES: [CH2:1]([C:3]1[N:13]([CH2:14][C:15]2[CH:16]=[C:17]3[C:22](=[CH:23][CH:24]=2)[N:21]=[C:20]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[C:31]([OH:33])=[O:32])[CH:19]=[C:18]3C(O)=O)[C:6]2=[N:7][C:8]([CH3:12])=[CH:9][C:10]([CH3:11])=[C:5]2[N:4]=1)[CH3:2].S(=O)(=O)(O)O.O.C(=O)([O-])[O-].[Na+].[Na+]>N1C2C(=CC=CC=2)C=CC=1>[CH2:1]([C:3]1[N:13]([CH2:14][C:15]2[CH:16]=[C:17]3[C:22](=[CH:23][CH:24]=2)[N:21]=[C:20]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[C:31]([OH:33])=[O:32])[CH:19]=[CH:18]3)[C:6]2=[N:7][C:8]([CH3:12])=[CH:9][C:10]([CH3:11])=[C:5]2[N:4]=1)[CH3:2]
Reactant: CCc1nc2c(C)cc(C)nc2n1Cc1ccc2nc(-c3ccccc3C(=O)O)cc(C(=O)O)c2c1
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: c1ccc2ncccc2c1
Solvent: O
Product: CCc1nc2c(C)cc(C)nc2n1Cc1ccc2nc(-c3ccccc3C(=O)O)ccc2c1
Temperature: 170 °C
Yield: 73.4 %

Procedure:
Eighteen mg of the 6-(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl-2-(2-carboxyphenyl)-4-quinolinecarboxylic acid obtained in Example 17 were dissolved in 5 ml of quinoline. After adding 0.5 ml of conc. sulfuric acid, the mixture was heated at 170° C. for 1 hour. Then the reaction mixture was poured into water, made alkaline by adding sodium carbonate and washed with toluene. The aqueous layer was neutralized with 3M hydrochloric acid until a precipitate was formed. Then the precipitate was collected by filtration and purified by flash chromatography on silica gel with the use of chloroform/methanol. Thus 12 mg of 2-{6-[(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl]quinolin-2-yl}benzoic acid were obtained. NMR (270 MHz, CDCl3): δ 7.5-8.2 (m,8H); 7.4 (s,1H); 7.0 (s,1H); 5.7 (s,2H); 2.8 (q,J=8Hz,2H); 2.7 (s,3H); 2.6 (s,3H); 1.7 (t,J=8Hz,3H).
Reaction SMILES: [Cl:1][C:2]1[N:11]=[CH:10][C:9]2[NH:8][CH2:7][C@@H:6]3[CH2:12][O:13][CH2:14][CH2:15][N:5]3[C:4]=2[N:3]=1.CC(C)([O-])C.[Na+].Cl[CH2:23][C:24]1[O:28][CH:27]=[N:26][CH:25]=1>CS(C)=O>[Cl:1][C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH2:23][C:24]3[O:28][CH:27]=[N:26][CH:25]=3)[CH2:7][C@@H:6]3[CH2:12][O:13][CH2:14][CH2:15][N:5]3[C:4]=2[N:3]=1
Reactant: Clc1ncc2c(n1)N1CCOC[C@H]1CN2
Reactant: ClCc1cnco1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: CS(C)=O
Product: Clc1ncc2c(n1)N1CCOC[C@H]1CN2Cc1cnco1

Procedure:
The title compound was prepared in a manner similar to PREPARATION x5 using (R)-2-chloro-5,6,6a,7,9,10-hexahydro-[1,4]oxazino[3,4-h]pteridine (PREPARATION x2, 351 mg, 1.547 mmol) in DMSO (10 mL), sodium tert-butoxide (178 mg, 1.856 mmol) and 5-(chloromethyl)oxazole (200 mg, 1.702 mmol) (171 mg, 36%). ESI-MS m/z [M+H]+ calc'd for C13H14ClN5O2, 308.09; found 308.1.
Reaction SMILES: CC([O-])(C)C.[K+].[Cl:7][C:8]1[CH:9]=[C:10]([OH:15])[CH:11]=[CH:12][C:13]=1[Cl:14].Cl[C:17]1[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][N:18]=1>CS(C)=O>[Cl:7][C:8]1[CH:9]=[C:10]([CH:11]=[CH:12][C:13]=1[Cl:14])[O:15][C:17]1[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][N:18]=1
Reactant: Oc1ccc(Cl)c(Cl)c1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: O=[N+]([O-])c1ccc(Oc2ccc(Cl)c(Cl)c2)nc1
Temperature: 90 °C
Reaction time: 8 h

Procedure:
To 44.9 g of t-BuOK in 250 ml of DMSO was added 65.2 g of 3,4-dichlorophenol in 50 ml of DMSO causing a temperature rise to between 65°-70° C. To this warm solution was added 2-chloro-5-nitropyridine (63.4 g) which raised the temperature to 90° C. The mixture was stirred without heating until the temperature dropped to 40° C. (~1 hr). The reaction mixture was poured into 1 kilogram (kg) of ice-water and the solid collected by filtration. The solid was dissolved in CH2Cl2, dried over Na2CO3, treated with charcoal, redried over MgSO4 and then filtered. The CH2Cl2 solution was concentrated to 250 ml, then diluted to 700 ml with hexane and allowed to stand overnight. From this solution, a crystalline material was collected by filtration and 94.8 g of 2-(3,4-dichlorophenoxy)-5-nitropyridine obtained, m.p. 101°-102.5° C.
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[CH2:8][CH2:7][CH2:6][C@@H:5]([OH:9])[CH2:4]1.[Si:10](Cl)([C:23]([CH3:26])([CH3:25])[CH3:24])([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.N1C=CN=C1.CN(C1C=CC=CN=1)C>CN(C)C=O>[Si:10]([O:1][CH2:2][C@H:3]1[CH2:8][CH2:7][CH2:6][C@@H:5]([OH:9])[CH2:4]1)([C:23]([CH3:26])([CH3:25])[CH3:24])([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: OC[C@H]1CCC[C@@H](O)C1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: CN(C)c1ccccn1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](OC[C@H]1CCC[C@@H](O)C1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
10.5 g of (1S,3R)/(1R,3S)-3-hydroxymethylcyclohexanol are dissolved in 300 ml of dimethylformamide, and 23 ml of tert-butyldiphenylsilanyl chloride, 8.0 g of imidazole and 200 mg of dimethylaminopyridine are added. The mixture is stirred at room temperature for 12 hours. The dimethylformamide is removed under reduced pressure and the residue is dissolved in 300 ml of ethyl acetate and washed five times with in each case 100 ml of water. The organic phase is dried over MgSO4 and the solvent is then removed under reduced pressure. This gives 27.0 g of (1S,3R)/(1R,3S)-3-(tert-butyldiphenylsilanyloxymethyl)cyclohexanol as an oil. C23H32O2Si (368.6), Rf(n-heptane:ethyl acetate=1:1)=0.42.
Reaction SMILES: O[CH2:2][C:3]1[S:4][C:5]([N+:8]([O-:10])=[O:9])=[CH:6][CH:7]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:31]>ClCCl.[Cl-].[Na+].O>[Br:31][CH2:2][C:3]1[S:4][C:5]([N+:8]([O-:10])=[O:9])=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1ccc(CO)s1
Reactant: BrC(Br)(Br)Br
Agent: [Cl-]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc(CBr)s1
Reaction time: 2 h
Yield: 72.5 %

Procedure:
To a stirred solution of 2-hydroxymethyl-5-nitro-thiophene (18.8 g, 118 mmol) in dichloromethane (500 ml) at 0° C. was added triphenylphosphine (3 1.5 g, 120 mmol) followed by carbon tetrabromide (39 g, 118 mmol). The mixture was stirred for 2 hours, poured into half saturated brine and extracted with dichloromethane. The organic layer was dried over magnesium sulphate and the solvent removed at reduced pressure. The crude product was purified by silica gel chromatography using 15% ethyl acetate/hexane as the eluant to give 2-bromomethyl-5-nitrothiophene (19 g, 61%) as a brown oil.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][NH:12][C:11](=[O:15])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].CN(C=O)C.[Cl:23][C:24]1[CH:31]=[CH:30][CH:29]=[CH:28][C:25]=1[CH2:26]Cl>ClCCl.O>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([CH2:26][C:25]2[CH:28]=[CH:29][CH:30]=[CH:31][C:24]=2[Cl:23])[C:11](=[O:15])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=c1cc(OCc2ccccc2)cc[nH]1
Reactant: ClCc1ccccc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: ClCCl
Product: O=c1cc(OCc2ccccc2)ccn1Cc1ccccc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 65.9 %

Procedure:
A solution of 4-benzyloxy-1H-pyridone (300 mg, 1.49 mmol) and NaH (60 mg, 1.49 mmol) in solvent of DMF was stirred for 30 min followed by adding 2-chlorobenzyl chloride (240 mg, 1.49 mmol) further stirring for 30 min at room temperature. The resulting solution was worked up with Water and dichloromethane and purified by column chromatography (ethyl acetate/hexane, 1:1) to obtain the titled compound (320 mg, 67%).
Reaction SMILES: CC1(C)COB([C:8]2[C:9]([F:28])=[CH:10][C:11]([F:27])=[C:12]([C@:14]3([CH3:26])[C:20]([F:22])([F:21])[C:19]([CH3:24])([CH3:23])[O:18][CH2:17][C:16](=[O:25])[NH:15]3)[CH:13]=2)OC1.Cl[C:31]1[O:32][C:33]2[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][C:34]=2[N:35]=1>[Pd]>[Cl:40][C:37]1[CH:38]=[CH:39][C:33]2[O:32][C:31]([C:8]3[C:9]([F:28])=[CH:10][C:11]([F:27])=[C:12]([C@:14]4([CH3:26])[C:20]([F:21])([F:22])[C:19]([CH3:23])([CH3:24])[O:18][CH2:17][C:16](=[O:25])[NH:15]4)[CH:13]=3)=[N:35][C:34]=2[CH:36]=1
Reactant: CC1(C)COB(c2cc([C@@]3(C)NC(=O)COC(C)(C)C3(F)F)c(F)cc2F)OC1
Reactant: Clc1ccc2oc(Cl)nc2c1
Agent: [Pd]
Product: CC1(C)OCC(=O)N[C@](C)(c2cc(-c3nc4cc(Cl)ccc4o3)c(F)cc2F)C1(F)F
Yield: 42 %

Procedure:
In a manner analogous to that described in Example 19a), the palladium-catalyzed coupling of (R)-5-[5-(5,5-dimethyl-[1,3,2]dioxaborinan-2-yl)-2,4-difluoro-phenyl]-6,6-difluoro-5,7,7-trimethyl-[1,4]oxazepan-3-one (intermediate D1.1) and 2,5-dichlorobenzo[d]oxazole yielded the title compound (42% yield) as a white solid. MS (ISP): m/z=457.2 [M+H]+.
Reaction SMILES: CO[C:3](=[O:11])[C:4]1[CH:9]=[CH:8][CH:7]=[N:6][C:5]=1[NH2:10].[O-]CC.[Na+].C([O:18][C:19](=O)[CH2:20][C:21]1[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=1)C>CN(C)C=O>[OH:11][C:3]1[C:4]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[NH:10][C:19](=[O:18])[C:20]=1[C:21]1[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=1
Reactant: CCOC(=O)Cc1cccnc1
Reactant: COC(=O)c1cccnc1N
Agent: CC[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=c1[nH]c2ncccc2c(O)c1-c1cccnc1
Temperature: 150 °C

Procedure:
To a solution of 2-amino-nicotinic acid methyl ester (200 mg) (Example 1.1) in N,N-dimethylformamide (“DMF”) (2 ml) was added sodium ethoxide (21 μl) (21% by weight in ethanol) followed by ethyl-3-pyridyl-acetate (200 μl). The reaction mixture was heated in the microwave at 150° C. for 15 minutes. The mixture was quenched by addition of aqueous hydrochloric acid (2M) (0.72 ml) and then diluted with water. The precipitate was isolated by filtration and washed with water and finally triturated with diethyl ether to give 4-hydroxy-3-pyridin-3-yl-1H-[1,8]naphthyridin-2-one as a beige solid (109 mg). 1H-NMR (400 MHz, d6-DMSO): 11.75 (bs, 1H), 8.70 (m, 1H), 8.52-8.53 (dd, 1H), 8.48-8.49 (dd, 1H), 8.35-8.37 (dd, 1H), 7.98 (d, 1H), 7.45-7.49 (dd, 1H), 7.23-7.26 (dd, 1H) ppm.
Reaction SMILES: [Na].N.[CH3:3][CH:4]([CH2:17][CH2:18][CH:19]=[C:20]([CH3:22])[CH3:21])[CH2:5][CH:6]=[CH:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]([CH3:16])[CH3:15])=[CH:10][CH:9]=1>O1CCCC1>[CH3:3][CH:4]([CH2:17][CH2:18][CH2:19][CH:20]([CH3:22])[CH3:21])[CH2:5][CH:6]=[CH:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]([CH3:15])[CH3:16])=[CH:10][CH:9]=1
Reactant: CC(C)=CCCC(C)CC=Cc1ccc(C(C)C)cc1
Agent: N
Agent: [Na]
Solvent: C1CCOC1
Product: CC(C)CCCC(C)CC=Cc1ccc(C(C)C)cc1
Reaction time: 1 h

Procedure:
To a stirred solution of 16 g (0.7 g at) of sodium in 600 ml of liquid ammonia was added dropwise a solution of 93 g (0.34 mol.) of 4,8-dimethyl-1-(p-isopropylphenyl)nona-1,7-diene in 125 ml of anhydrous tetrahydrofuran. Total addition time was one hour. The excess sodium was destroyed by the cautious addition of methanol. Then 200 ml of hexane were added and the ammonia was allowed to evaporate. To the residue a saturated solution of NH4Cl was added cautiously. The organic layer was separated, and the aqueous layer was diluted with water and extracted twice with hexane. The combined hexane layers were washed with water, dilute HCl, brine and then dried. Evaporation of the hexane and distillation of the residue yielded the title product. Yield was 88 g (94%), bp 130°-135° C/0.1 mm. nD25 =1.4938.
Reaction SMILES: [CH3:1][N:2]([CH3:24])[CH2:3][CH2:4][NH:5][C:6]([C:8]1[C:13]2=[N:14][C:15]3[C:20]([C:21](=[O:22])[N:12]2[CH:11]=[CH:10][CH:9]=1)=[CH:19][C:18](I)=[CH:17][CH:16]=3)=[O:7].[N:25]1[CH:30]=[CH:29][CH:28]=[C:27](B(O)O)[CH:26]=1.C(=O)([O-])[O-].[Na+].[Na+]>O>[CH3:1][N:2]([CH3:24])[CH2:3][CH2:4][NH:5][C:6]([C:8]1[C:13]2=[N:14][C:15]3[CH:16]=[CH:17][CH:18]([C:27]4[CH:26]=[N:25][CH:30]=[CH:29][CH:28]=4)[CH2:19][C:20]=3[C:21](=[O:22])[N:12]2[CH:11]=[CH:10][CH:9]=1)=[O:7]
Reactant: OB(O)c1cccnc1
Reactant: CN(C)CCNC(=O)c1cccn2c(=O)c3cc(I)ccc3nc12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: CN(C)CCNC(=O)c1cccn2c(=O)c3c(nc12)C=CC(c1cccnc1)C3
Temperature: 25 °C
Yield: 73.9 %

Procedure:
A mixture of N-[2-(dimethylamino)ethyl]-2-iodo-11-oxo-11H-pyrido[2,1-b]quinazoline-6-carboxamide (100 mg), 3-pyridinyl-boronic acid (225.41 mg), tetrakis(tri-phenylphosphine)palladium(0) (66.22 mg) and sodium carbonate (0.57 ml of 2 M (1.15 mmol)) was heated in an oil bath at 120° C.-125° C. for 45 minutes. The reaction mixture was cooled to room temperature, diluted with water (30 ml), and extracted with CH2Cl2 (3×30 ml). Combined organic phases were washed with brine (50 ml), dried with MgSO4, filtered and concentrated in vacuo. The residue was purified on SiO2 (50 g; gradient elution with 10-30% MeOH/CHCl3) to give the desired product (66 mg).
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][CH:7]=[N:6][C:5]=1[N:10]([C:12](=[O:25])[CH2:13][C:14]1[C:19]([CH2:20][CH3:21])=[CH:18][C:17]([CH3:22])=[CH:16][C:15]=1[CH2:23][CH3:24])[CH3:11].CC(C)([O-])C.[K+]>CN(C)C=O>[CH2:20]([C:19]1[CH:18]=[C:17]([CH3:22])[CH:16]=[C:15]([CH2:23][CH3:24])[C:14]=1[C:13]1[C:12](=[O:25])[N:10]([CH3:11])[C:5]2[C:4]([C:3]=1[OH:2])=[CH:9][CH:8]=[CH:7][N:6]=2)[CH3:21]
Reactant: CCc1cc(C)cc(CC)c1CC(=O)N(C)c1ncccc1C(=O)OC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCc1cc(C)cc(CC)c1-c1c(O)c2cccnc2n(C)c1=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 2-{[2-(2,6-diethyl-4-methyl-phenyl)-acetyl]-methyl-amino}-nicotinic acid methyl ester (300 mg) in N,N-dimethylformamide (5 ml) was added potassium tert-butoxide (250 mg). The reaction mixture was stirred at ambient temperature for 18 hours, and then at 50° C. for 2 hours. The reaction mixture was partitioned the reaction between water and dichloromethane. The phases were separated and the aqueous phase was extracted with further dichloromethane and ethyl acetate. The aqueous phase was acidified by addition of aqueous hydrochloric acid (2M) and extracted three times with ethyl acetate. The combined organic extracts were dried over magnesium sulfate and concentrated. The residue was passed through a plug of silica eluting with ethyl acetate to give Compound No. D20 of Table D as an off-white solid (320 mg).
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH:10]1[CH2:19][CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[C:15]([O:20]C)[CH:16]=2)[CH2:11]1)[CH3:2].Cl.[N:23]1([CH2:30][CH2:31][O:32][C:33]2[CH:41]=[CH:40][C:36]([C:37](O)=O)=[CH:35][CH:34]=2)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1.N1(CCOC2C=CC(CN(CC)C3C=CC=CC=3C3CCC4C(=CC=C(OC)C=4)C3)=CC=2)CCCCCC1>>[N:23]1([CH2:30][CH2:31][O:32][C:33]2[CH:41]=[CH:40][C:36]([CH2:37][CH2:2][CH2:1][NH:3][C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[CH:10]3[CH2:19][CH2:18][C:17]4[CH:16]=[C:15]([OH:20])[CH:14]=[CH:13][C:12]=4[CH2:11]3)=[CH:35][CH:34]=2)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: CCNc1ccccc1C1CCc2cc(OC)ccc2C1
Reactant: O=C(O)c1ccc(OCCN2CCCCCC2)cc1
Agent: CCN(Cc1ccc(OCCN2CCCCCC2)cc1)c1ccccc1C1CCc2cc(OC)ccc2C1
Agent: Cl
Product: Oc1ccc2c(c1)CCC(c1ccccc1NCCCc1ccc(OCCN3CCCCCC3)cc1)C2

Procedure:
Synthesized from ethyl[2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)phenyl]amine and 4-(2-azepan-1-ylethoxy)benzoic acid hydrochloride according to an analogous synthetic method to Example 152, [4-(2-azepan-1-ylethoxy)benzyl]ethyl[2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)phenyl]amine (504 mg) was used according to an analogous synthetic method to Example 111 to provide the title compound (394 mg).