Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].[ClH:11].[N:12]#[C:13][NH2:14]>C(O)C>[ClH:11].[NH:1]([C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6])[C:13]([NH2:14])=[NH:12]
Reactant: Nc1cccc(C(=O)O)c1
Reactant: N#CN
Agent: Cl
Solvent: CCO
Product: N=C(N)Nc1cccc(C(=O)O)c1
Yield: 24.3 %

Procedure:
A mixture of 3-aminobenzoic acid (Aldrich, 2.74 g, 0.02 mol), hydrochloric acid (12N, 1.66 g, 0.02 mol), and cyanamide (1.64 g, 0.04 mol) in absolute ethanol (50 mL) was heated at reflux for 16 h. The mixture was cooled and the precipitate separated by filtration. The cake was washed several times with ether and dried under vacuum to give 1.05 g (26.6%) of the title compound as an off-white amorphous powder, mp 278° C.
Reaction SMILES: [C:1]([C:4]1[C:9]([F:10])=[CH:8][N:7]=[CH:6][C:5]=1[C:11]1[O:12][C:13]2[CH:19]=[CH:18][C:17]([C:20]#[N:21])=[CH:16][C:14]=2[CH:15]=1)(=[O:3])[CH3:2].[CH3:22][Mg]Br>C1COCC1>[F:10][C:9]1[C:4]([C:1]([OH:3])([CH3:22])[CH3:2])=[C:5]([C:11]2[O:12][C:13]3[CH:19]=[CH:18][C:17]([C:20]#[N:21])=[CH:16][C:14]=3[CH:15]=2)[CH:6]=[N:7][CH:8]=1
Reactant: C[Mg]Br
Reactant: CC(=O)c1c(F)cncc1-c1cc2cc(C#N)ccc2o1
Solvent: C1CCOC1
Product: CC(C)(O)c1c(F)cncc1-c1cc2cc(C#N)ccc2o1
Temperature: -78 °C
Reaction time: 1 h
Yield: 28.4 %

Procedure:
To 2-(4-acetyl-5-fluoropyridin-3-yl)benzofuran-5-carbonitrile 11b (200 mg, 0.714 mmol) in THF (3.57 mL) at −78° C. was added methylmagnesium bromide (3M in Et2O, 0.714 mL, 2.142 mmol). The mixture was stirred for 1 hr at −78° C., and then for 1 hr at 0° C. The mixture was quenched with saturated NH4Cl and extracted with EtOAc two times, dried over magnesium sulfate, filtered and concentrated. The residue was purified via Biotage (10-40% EtOAc/heptane; SNAP25 column), and then purified on Waters mass directed preparative-HPLC (ACN—H2O—NR4OH, Xbridge Preparation C18 column, 30×100 mm) giving the title compound 11 (60 mg, 28%). 1H NMR (400 MHz, MeOD) δ ppm 1.70 (d, J=1.96 Hz, 6H) 6.94 (s, 1H) 7.55-7.71 (m, 2H) 8.00-8.11 (m, 1H) 8.39 (s, 1H) 8.53 (d, J=3.73 Hz, 1H). LC-MS (M+1) 297.1, t=1.50 min.
Reaction SMILES: [CH3:1][CH:2]1[CH2:10][C:9]2[C:4](=[CH:5][C:6]([CH3:12])=[CH:7][C:8]=2[CH3:11])[C:3]1=[O:13].[BH4-].[Na+].CC(C)=O.O>CCO>[CH3:1][CH:2]1[CH2:10][C:9]2[C:4](=[CH:5][C:6]([CH3:12])=[CH:7][C:8]=2[CH3:11])[CH:3]1[OH:13]
Reactant: Cc1cc(C)c2c(c1)C(=O)C(C)C2
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: CC(C)=O
Product: Cc1cc(C)c2c(c1)C(O)C(C)C2
Temperature: 25 °C
Reaction time: 18 h
Yield: 93.9 %

Procedure:
37.48 g of 2,4,6-trimethyl-indan-1-one (0.215 mol) were dissolved in 200 mL of EtOH in a 500 mL, 3-neck rounded bottom flask equipped with a magnetic stirring bar, a thermometer and a reflux condenser. NaBH4 (15.01 g, 0.397 mol) was then slowly added keeping the temperature below 20° C. during the addition. The light yellow suspension was stirred at r.t. for 18 h. Then 100 mL of acetone were cautiously added (careful: exothermic reaction!) and subsequently the solvents removed giving a white solid. The latter was treated with 100 mL of water and extracted with toluene (2×150 mL). The water phase was further extracted with toluene, the organic phases were combined and washed with a 10% aqueous solution of NH4Cl. After washing, the organic phase was dried over Na2SO4, filtered and evaporated to give 35.57 g of a yellow sticky solid: its 1H-NMR analysis showed the target product as 1.4/1 mixture of two diastereoisomers, contaminated by 5% wt. of starting indanone (yield 89.2%). The product was used as such in the next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:17]([NH2:19])=[O:18])=[CH:4][C:5]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[N:7]([CH2:14][CH3:15])[C:6]=2[N:16]=1.ClS([N:24]=[C:25]=[O:26])(=O)=O>C(Cl)Cl>[NH2:24][C:25]([NH:1][C:2]1[C:3]([C:17]([NH2:19])=[O:18])=[CH:4][C:5]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[N:7]([CH2:14][CH3:15])[C:6]=2[N:16]=1)=[O:26]
Reactant: CCn1c2ccccc2c2cc(C(N)=O)c(N)nc21
Reactant: O=C=NS(=O)(=O)Cl
Solvent: ClCCl
Product: CCn1c2ccccc2c2cc(C(N)=O)c(NC(N)=O)nc21
Temperature: 0 °C
Reaction time: 2 h
Yield: 18 %

Procedure:
A solution of 2-amino-9-ethyl-9H-pyrido[2,3-b]indole-3-carboxamide (1, 71 mg, 0.28 mmol) in DCM (1 mL) was cooled to 0° C. and chlorosulfonyl isocyanate (27 Au, 0.31 mmol) was added. The mixture was stirred at 0° C. under an atmosphere of argon. After 2 h, the reaction was quenched with a few drops of water and concentrated under reduced pressure. The crude product was purified by HPLC (Phenomenex Luna 15 μm C18, aqueous NH4OAc/CH3CN) to yield 2-[(aminocarbonyl)amino]-9-ethyl-9H-pyrido[2,3-b]indole-3-carboxamide (21, 15 mg, 18%). NH4OAc standard conditions. DAD Retention time =6.40 min. M+H=298. 1H NMR (300 MHz, DMSO-d6): δ 11.44 (s, 1H), 9.04 (s, 1H), 8.70 (br s, 1H), 8.30 (br s, 1H), 7.99 (d, J=7.6 Hz, 1H), 7.69 (d, J=8.1 Hz, 2H), 7.49 (t, J=8.1 Hz, 1H), 7.32 (t, J=7.6 Hz, 1H), 7.24 (br s, 1H), 4.42 (q, J=7.1 Hz, 2H), 1.35 (t, J=7.1 Hz, 3H).
Reaction SMILES: [N:1]([C@:4]12[CH2:39][CH2:38][C@@H:37]([C:40]([CH3:42])=[CH2:41])[C@@H:5]1[C@@H:6]1[C@@:19]([CH3:22])([CH2:20][CH2:21]2)[C@@:18]2([CH3:23])[C@@H:9]([C@:10]3([CH3:36])[C@@H:15]([CH2:16][CH2:17]2)[C:14]([CH3:25])([CH3:24])[C:13]([C:26]2[CH:35]=[CH:34][C:29]([C:30]([O:32]C)=[O:31])=[CH:28][CH:27]=2)=[CH:12][CH2:11]3)[CH2:8][CH2:7]1)=[C:2]=[O:3].CN(C)CCNC(=O)N[C@]12CC[C@@H](C(C)=C)[C@@H]1[C@@H]1[C@@](C)(CC2)[C@@]2(C)[C@@H]([C@]3(C)[C@@H](CC2)C(C)(C)C(C2C=CC(C(O)=O)=CC=2)=CC3)CC1.[CH3:90][N:91]([CH3:103])[C@H:92]1[C@H:96]([N:97]2[CH2:102][CH2:101][NH:100][CH2:99][CH2:98]2)[CH2:95][O:94][CH2:93]1>>[CH3:90][N:91]([CH3:103])[C@@H:92]1[CH2:93][O:94][CH2:95][C@H:96]1[N:97]1[CH2:102][CH2:101][N:100]([C:2]([NH:1][C@:4]23[CH2:39][CH2:38][C@@H:37]([C:40]([CH3:42])=[CH2:41])[C@@H:5]2[C@@H:6]2[C@@:19]([CH3:22])([CH2:20][CH2:21]3)[C@@:18]3([CH3:23])[C@@H:9]([C@:10]4([CH3:36])[C@@H:15]([CH2:16][CH2:17]3)[C:14]([CH3:24])([CH3:25])[C:13]([C:26]3[CH:27]=[CH:28][C:29]([C:30]([OH:32])=[O:31])=[CH:34][CH:35]=3)=[CH:12][CH2:11]4)[CH2:8][CH2:7]2)=[O:3])[CH2:99][CH2:98]1
Reactant: CN(C)[C@@H]1COC[C@H]1N1CCNCC1
Reactant: C=C(C)[C@@H]1CC[C@]2(N=C=O)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: C=C(C)[C@@H]1CC[C@]2(NC(=O)NCCN(C)C)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Product: C=C(C)[C@@H]1CC[C@]2(NC(=O)N3CCN([C@@H]4COC[C@H]4N(C)C)CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Yield: 20 %

Procedure:
The title compound was prepared in 20% yield from methyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-isocyanato-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate following the same procedure as described for the preparation of 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(3-(2-(dimethylamino)ethyl)ureido)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoic acid, except (3S,4S)—N,N-dimethyl-4-(piperazin-1-yl)tetrahydrofuran-3-amine was used instead of N,N-dimethylethylenediamine in Step 1. LCMS: m/e 755.6 (M+H)+, 1.85 min (method 6). 1H NMR (500 MHz, METHANOL-d4) δ=7.93 (d, J=8.2 Hz, 2H), 7.23 (d, J=8.2 Hz, 2H), 5.31 (d, J=6.1 Hz, 1H), 4.78 (s, 1H), 4.64 (br. s., 1H), 4.09 (d, J=3.4 Hz, 1H), 4.05 (d, J=4.9 Hz, 2H), 4.02 (td, J=3.5, 6.8 Hz, 1H), 3.96 (td, J=5.1, 10.1 Hz, 1H), 3.73 (d, J=5.2 Hz, 1H), 3.56-3.41 (m, 4H), 2.96 (s, 6H), 2.87-2.66 (m, 5H), 2.59 (d, J=13.1 Hz, 1H), 2.45 (dd, J=8.7, 11.7 Hz, 1H), 2.16 (dd, J=6.4, 17.1 Hz, 1H), 1.97-1.90 (m, 1H), 1.90-1.82 (m, 1H), 1.82-1.74 (m, 2H), 1.73 (s, 3H), 1.66-1.54 (m, 3H), 1.51 (d, J=12.5 Hz, 4H), 1.45-1.26 (m, 6H), 1.23-1.15 (m, 2H), 1.13 (s, 3H), 1.10 (d, J=13.4 Hz, 2H), 1.06 (s, 3H), 1.04 (s, 3H), 0.97 (s, 3H), 0.95 (s, 3H).
Reaction SMILES: [CH3:1][S:2]([CH2:5][CH2:6][OH:7])(=[O:4])=[O:3].C(N(C(C)C)CC)(C)C.[CH3:17][S:18](Cl)(=[O:20])=[O:19]>C(Cl)Cl>[CH3:17][S:18]([O:7][CH2:6][CH2:5][S:2]([CH3:1])(=[O:4])=[O:3])(=[O:20])=[O:19]
Reactant: CS(=O)(=O)Cl
Reactant: CS(=O)(=O)CCO
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)CCOS(C)(=O)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 50 %

Procedure:
In a 50 mL round-bottomed flask, 2-(methylsulfonyl)ethanol (1.24 g, 9.99 mmol, Eq: 1.00) was combined with DCM (5 mL). To the resulting solution was added diisopropylethylamine (2.1 mL, 12.0 mmol, Eq: 1.2) and methanesulfonyl chloride (1.37 g, 931 μL, 12.0 mmol, Eq: 1.2). The ice bath was removed and the reaction was stirred at rt overnight. The crude reaction mixture was concentrated in vacuo and the residue was partitioned between EtOAc and water. The organic layer was dried over Na2SO4 and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 80 g, 10% to 80% EtOAc in hexanes) to give 2-(methylsulfonyl)ethyl methanesulfonate (1.01 g).
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:22])([F:21])[CH2:17]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][CH3:15])[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(N2CCC(F)(F)C2)C2N=NNC=2N=1)(C)(C)C.BrCC1[CH:50]=[CH:49][C:48]([F:51])=[CH:47][C:46]=1[Cl:52]>>[C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:21])([F:22])[CH2:17]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[CH:50]=[CH:49][C:48]([F:51])=[CH:47][C:46]=3[Cl:52])[C:9]=2[N:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: Fc1ccc(CBr)c(Cl)c1
Reactant: CCn1nnc2c(N3CCC(F)(F)C3)nc(C(C)(C)C)nc21
Agent: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn[nH]c2n1
Product: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nnn(Cc3ccc(F)cc3Cl)c2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoro-pyrrolidin-1-yl)-3-ethyl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 61), the title compound was prepared from 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 1-(bromomethyl)-2-chloro-4-fluorobenzene and isolated as colorless gum (5.8 mg, 33%). MS (m/e): 425.4 (MH+).
Reaction SMILES: [C:1]1(=O)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[NH2:11][OH:12]>>[C:1]1(=[N:11][OH:12])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: O=C1CCc2ccccc21
Reactant: NO
Product: ON=C1CCc2ccccc21

Procedure:
In Step 1 a 1-indanone is treated with a hydroxylamine and a base to produce a 1-indanone oxime. In Step 2 the oxime is hydrogenated to produce a corresponding primary amine, both R and S forms. In Step 3 the primary amine is then added to D-N-acetyl-3,4-dimethoxyphenylalanine in alcohol to produce the (R,R) and (R,S) salts of the primary amine. The (R,S) salt crystallizes first and the (R,R) salt is soluble. These are separated by filtration. The mother liquor, on concentrating and cooling precipitates the desired R,R isomer in high yield and optical purity. In Step 4 a solution of R,R isomer is treated with a base to produce the R form of the primary amine. In Step 5 the R primary amine is reacted with a tertiary amine and 6-chloropurineriboside to produce the adenosine compounds of Formula I of the present invention, for example, N6 -[1-(R)-indanyl]adenosine. ##STR4##
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH2:7].[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([S:16](Cl)(=[O:18])=[O:17])=[CH:12][CH:11]=1>C(Cl)Cl.N1C=CC=CC=1>[NH2:7][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=1[NH:8][S:16]([C:13]1[CH:14]=[CH:15][C:10]([Cl:9])=[CH:11][CH:12]=1)(=[O:18])=[O:17]
Reactant: Nc1ccccc1N
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: Nc1ccccc1NS(=O)(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Yield: 84.9 %

Procedure:
To a solution of o-phenylenediamine (4 mmol) in DCM (20 mL) and pyridine (4 mL) at 0° C., 4-chlorobenzenesulfonyl chloride (4.4 mmol) was added in small portions. The reaction mixture was then gradually warmed to RT with stirring continued until the reaction was complete as determined by TLC or LC-MS. The reaction mixture was then diluted with DCM (20 mL). The organic phase was washed with water (2×20 mL) and 20 mL of brine. The organic phase was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue obtained was purified by flash column chromatography eluting with DCM/EtOAc to give 960 mg of N-(2-aminophenyl)-4-chlorobenzenesulfonamide. LC: Tr 0.92 min, MS: 284.0 (M+1)+.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([O:11][C:12]3[CH:13]=[C:14]([NH:18][C:19](=[O:31])[C:20]4[CH:25]=[CH:24][CH:23]=[C:22]([C:26]5([C:29]#[N:30])[CH2:28][CH2:27]5)[CH:21]=4)[CH:15]=[CH:16][CH:17]=3)[CH:8]=[CH:7][C:5]=2[N:6]=1.Cl.Cl.[CH3:34][N:35]1[CH2:40][CH2:39][N:38]([CH2:41][C:42](O)=[O:43])[CH2:37][CH2:36]1.Cl.C(N=C=NCCCN(C)C)C.C(N(CC)CC)C>N1C=CC=CC=1.CN(C)C1C=CN=CC=1.CO>[C:29]([C:26]1([C:22]2[CH:21]=[C:20]([CH:25]=[CH:24][CH:23]=2)[C:19]([NH:18][C:14]2[CH:15]=[CH:16][CH:17]=[C:12]([O:11][C:9]3[CH:8]=[CH:7][C:5]4[N:6]=[C:2]([NH:1][C:42](=[O:43])[CH2:41][N:38]5[CH2:39][CH2:40][N:35]([CH3:34])[CH2:36][CH2:37]5)[S:3][C:4]=4[CH:10]=3)[CH:13]=2)=[O:31])[CH2:27][CH2:28]1)#[N:30]
Reactant: N#CC1(c2cccc(C(=O)Nc3cccc(Oc4ccc5nc(N)sc5c4)c3)c2)CC1
Reactant: CN1CCN(CC(=O)O)CC1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: c1ccncc1
Solvent: CO
Solvent: CCN(CC)CC
Product: CN1CCN(CC(=O)Nc2nc3ccc(Oc4cccc(NC(=O)c5cccc(C6(C#N)CC6)c5)c4)cc3s2)CC1
Temperature: 25 °C
Reaction time: 14 h
Yield: 23.5 %

Procedure:
To a solution of N-{3-[(2-amino-1,3-benzothiazol-6-yl)oxy]phenyl}-3-(1-cyanocyclopropyl)benzamide (436 mg, 1.02 mmol) produced in Example A15(iii) in pyridine (10 mL) were added (4-methylpiperazin-1-yl)acetic acid dihydrochloride (278 mg, 1.20 mmol), N,N-dimethylpyridine-4-amine (79.3 mg, 649 μmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (470 mg, 2.45 mmol) at room temperature, and the mixture was stirred at room temperature for 14 hr. To the reaction mixture were added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (454 mg, 2.37 mmol), (4-methylpiperazin-1-yl)acetic acid dihydrochloride (281 mg, 1.22 mmol), and triethylamine (10 mL) and the mixture was further stirred for 4 hr. To the reaction mixture was added methanol (10 mL) and the mixture was stirred at room temperature for 30 min and concentrated under reduced pressure. The residue was diluted with ethyl acetate (100 mL), washed with saturated aqueous ammonium chloride solution (80 mL×2) and saturated aqueous sodium hydrogencarbonate solution (50 mL), successively, and dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/methanol=100/0→90/10) and crystallized from ethyl acetate and hexane to give the title compound (136 mg, 24%) as colorless crystals.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C:6]([C:8]1[CH:9]=[C:10]([C:22]2[CH:27]=[CH:26][C:25]([O:28][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:24][CH:23]=2)[C:11](=[O:21])[N:12]2[C:17]=1[C:16]1[S:18][CH:19]=[CH:20][C:15]=1[CH:14]=[CH:13]2)=[O:7].[I:42]I>>[CH3:1][O:2][CH2:3][CH2:4][N:5]([C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1)[C:6]([C:8]1[CH:9]=[C:10]([C:22]2[CH:27]=[CH:26][C:25]([O:28][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:24][CH:23]=2)[C:11](=[O:21])[N:12]2[C:17]=1[C:16]1[S:18][C:19]([I:42])=[CH:20][C:15]=1[CH:14]=[CH:13]2)=[O:7]
Reactant: COCCN(C(=O)c1cc(-c2ccc(OCc3ccccc3)cc2)c(=O)n2ccc3ccsc3c12)c1ccccc1
Reactant: II
Product: COCCN(C(=O)c1cc(-c2ccc(OCc3ccccc3)cc2)c(=O)n2ccc3cc(I)sc3c12)c1ccccc1

Procedure:
By lithiation of 8-(4-benzyloxy-phenyl)-7-oxo-7H-thieno[2,3-a]quinolizine-10-carboxylic acid (2-methoxy-ethyl)-phenyl-amide and reaction with iodine.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][C:8]([O:10]CC)=O.[CH3:13][NH:14][CH3:15]>CO>[CH3:13][N:14]([CH3:15])[C:8](=[O:10])[CH2:7][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1
Reactant: CNC
Reactant: CCOC(=O)Cc1ccccn1
Solvent: CO
Product: CN(C)C(=O)Cc1ccccn1

Procedure:
To 5.0 g of ethyl 2-pyridylacetate dissolved in 25 ml of MeOH was added 20 ml of dimethyl amine. The mixture was heated at 90° in a steel autoclave for 96 hrs. The solvent/amine mixture was allowed to evaporate until a residual oil was obtained. The residual oill was distilled to afford 4.5 g of the desired N,N-dimethyl-(2-pyridyl)acetamide as a free-flowing yellow oil, bp 105°-110°/0.5 mm.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:9]([Cl:13])[C:3]=1[C:4]([N:6]=[C:7]=[O:8])=[O:5].[Cl:14][C:15]1[CH:16]=[C:17]([CH:19]=[CH:20][C:21]=1[Cl:22])[NH2:18]>C1C=CC=CC=1>[Cl:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:9]([Cl:13])[C:3]=1[C:4]([NH:6][C:7]([NH:18][C:17]1[CH:19]=[CH:20][C:21]([Cl:22])=[C:15]([Cl:14])[CH:16]=1)=[O:8])=[O:5]
Reactant: O=C=NC(=O)c1c(Cl)cccc1Cl
Reactant: Nc1ccc(Cl)c(Cl)c1
Solvent: c1ccccc1
Product: O=C(NC(=O)c1c(Cl)cccc1Cl)Nc1ccc(Cl)c(Cl)c1

Procedure:
35 g of 2,6-dichlorobenzoylisocyanate in 100 ml of dry benzene are added drop by drop, with stirring and cooling, to a solution of 24.3 g of 3,4-dichloroaniline in 200 ml of dry benzene. Much heat is evolved and a precipitate is formed which is drawn off while hot and then is washed with hot benzene. The resulting N-(2,6-dichlorobenzoyl)-N'-(3,4-dichlorophenyl)-urea is pure, as is shown by thin layer chromatography (with ethylacetate as the solvent). If desired, the product may be recristallized from acetonitrile. Melting point 238° K.
Reaction SMILES: C([O:8][C:9](=[O:23])[C:10]1[CH:15]=[CH:14][C:13]([CH:16]=[CH:17][C:18]([O:20][CH3:21])=[O:19])=[C:12]([CH3:22])[CH:11]=1)C1C=CC=CC=1.[H][H]>C1COCC1.CO.[Pd]>[CH3:21][O:20][C:18]([CH2:17][CH2:16][C:13]1[CH:14]=[CH:15][C:10]([C:9]([OH:23])=[O:8])=[CH:11][C:12]=1[CH3:22])=[O:19]
Reactant: COC(=O)C=Cc1ccc(C(=O)OCc2ccccc2)cc1C
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)CCc1ccc(C(=O)O)cc1C
Yield: 99.9 %

Procedure:
A mixture of 4-(2-methoxycarbonyl-vinyl)-3-methyl-benzoic acid benzyl ester (11.6 g, 37.4 mmol) and Pd/C (5%, 1.5 g) in THF (300 mL) and methanol (100 mL) is stirred under 60 psi of hydrogen overnight. Catalyst is filtered off, filtrate is concentrated giving the title compound (8.3 g, 100%).
Reaction SMILES: [CH:1](=O)[CH2:2][CH2:3][CH3:4].[C:6]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])#[N:7].N1CCCCC1.[H][H]>C(O)(=O)C.[Pd]>[CH2:1]([CH:8]([C:6]#[N:7])[C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:2][CH2:3][CH3:4]
Reactant: CCOC(=O)CC#N
Reactant: [H][H]
Reactant: CCCC=O
Agent: [Pd]
Solvent: CC(=O)O
Solvent: C1CCNCC1
Product: CCCCC(C#N)C(=O)OCC
Temperature: 25 °C

Procedure:
323 g of butyraldehyde and 422 g of ethyl cyanoacetate are dissolved in 750 ml of glacial acetic acid, 15 g of piperidine are added, and the reaction mixture is stirred, during which it warms to about 55° C. After the reaction mixture has been cooled to room temperature, 20 g of 5% Pd-C catalyst are added, and the mixture is then hydrogenated at 30° and an H2 pressure of 2 bar until the calculated amount of hydrogen has been taken up (about 7 hours). After the catalyst has been separated off, the hydrogenation solution is evaporated on a rotary evaporator, the residue is taken up in..methyl tertiary-butyl ether (MTB ether), and the solution is washed by shaking twice with water and subsequently with 5% NaHCO3 solution. The organic phase is dried and evaporated. The residue is distilled in vacuo (2×10-2 mbar) (62° C. to 78°), to give ethyl 2-butylcyanoacetate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][CH:9]=[C:8]([CH2:11][CH2:12]I)[C:7]=2[CH:14]=1.[F:15][C:16]1[CH:17]=[C:18]2[C:23](=[C:24]([N:26]3[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)[CH:25]=1)[N:22]=[CH:21][CH:20]=[CH:19]2>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][CH:9]=[C:8]([CH2:11][CH2:12][N:29]3[CH2:30][CH2:31][N:26]([C:24]4[CH:25]=[C:16]([F:15])[CH:17]=[C:18]5[C:23]=4[N:22]=[CH:21][CH:20]=[CH:19]5)[CH2:27][CH2:28]3)[C:7]=2[CH:14]=1
Reactant: Fc1cc(N2CCNCC2)c2ncccc2c1
Reactant: COc1ccc2occ(CCI)c2c1
Product: COc1ccc2occ(CCN3CCN(c4cc(F)cc5cccnc45)CC3)c2c1

Procedure:
8-{4-[2-(5-methoxy-1-benzofuran-3-yl)ethyl]-1-piperazinyl}-6-fluoro-quinoline was prepared by following the procedure outlined in example 21, step 6, starting from 2-(5-methoxy-1-benzofuran-3-yl)ethyl iodide (301 mg, 1 mmol) and 6-fluoro-8-piperazino quinoline (231 mg, 1 mmol). The product was purified by silica-gel column chromatography by eluting it initially with 80% ethyl acetate:hexane and then with 5% methanol:ethyl acetate, yielding a brown low melting solid. Yield: 130 mg (32%); (M+H): 406; 1HNMR (400 MHz, CDCl3); δ 8.83˜8.82 (dd, J1=1.6 Hz, J2=1.6 Hz, 1H); 8.06˜8.05 (dd, J1=1.7 Hz, J2=1.7 Hz, 1H); 7.60˜6.88 (m, 7H); 3.86 (s, 3H); 3.66˜3.56 (broad s, 4H); 2.93˜2.82 (m, 8H).
Reaction SMILES: C1COCC1.[CH3:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([Mg]Br)=[CH:10][CH:9]=1.Cl[C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=1.C1(C)C=CC=CC=1>CCCCCC>[F:23][C:20]1[CH:21]=[CH:22][C:17]([C:11]2[CH:12]=[CH:13][C:8]([O:7][CH3:6])=[CH:9][CH:10]=2)=[CH:18][CH:19]=1
Reactant: Fc1ccc(Cl)cc1
Reactant: COc1ccc([Mg]Br)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COc1ccc(-c2ccc(F)cc2)cc1
Reaction time: 24 h
Yield: 91 %

Procedure:
Using a THF solution of p-methoxyphenylmagnesium bromide (1.88 mL, 0.64 M, 1.2 mmol) and 1-chloro-4-fluorobenzene (130.6 mg, 1.0 mmol) as starting materials, the reaction was performed at a scale of 1.0 mmol at 60° C. for 24 hours in the same manner as in Example 2. After performing silica gel column chromatography (toluene=15, 30 and 50% in hexane), the above compound (0.184 g, yield=91%, purity=>99% (GC analysis)) was obtained as a white solid.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[C:4]=1[F:25])#[N:2].[NH:26]1[CH2:29][CH:28]([N:30]2[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]2)[CH2:27]1>>[F:25][C:4]1[C:5]([CH3:24])=[C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([N:26]4[CH2:29][CH:28]([N:30]5[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]5)[CH2:27]4)=[O:21])=[CH:17][N:16]=3)[C:13]=2[OH:14])[CH:7]=[CH:8][C:3]=1[C:1]#[N:2]
Reactant: C1CCN(C2CNC2)CC1
Reactant: Cc1c(-c2cnn(-c3ccc(C(=O)O)cn3)c2O)ccc(C#N)c1F
Product: Cc1c(-c2cnn(-c3ccc(C(=O)N4CC(N5CCCCC5)C4)cn3)c2O)ccc(C#N)c1F

Procedure:
The title compound was prepared in a manner similar to Example 303 using 6-(4-(4-cyano-3-fluoro-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid and 1-(azetidin-3-yl)piperidine. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.22-2.00 (m, 6H) 2.33 (d, J=2.27 Hz, 3H) 2.84 (br. s., 2H) 3.23-3.70 (m, 2H) 4.06-4.19 (m, 1H) 4.33 (br. s., 2H) 4.61 (br. s., 1H) 4.66-4.77 (m, 1H) 7.63 (d, J=7.07 Hz, 1H) 7.75 (t, J=7.45 Hz, 1H) 7.98-8.89 (m, 4H). ESI-MS m/z [M+H]+ 461.3.
Reaction SMILES: [I:1][C:2]1[CH:14]=[N:13][C:5]2[N:6]([CH3:12])[C:7](=[O:11])O[C:9](=[O:10])[C:4]=2[CH:3]=1.IC1C=NC(NC)=[C:20](C=1)[C:21]([O:23][CH3:24])=[O:22].IC1C=NC(NC)=C(C=1)C(OCC)=O.ClC(OC(Cl)(Cl)Cl)=O>ClCCCl.O1CCOCC1>[OH:10][C:9]1[C:4]2[C:5](=[N:13][CH:14]=[C:2]([I:1])[CH:3]=2)[N:6]([CH3:12])[C:7](=[O:11])[C:20]=1[C:21]([O:23][CH3:24])=[O:22]
Reactant: CNc1ncc(I)cc1C(=O)OC
Reactant: Cn1c(=O)oc(=O)c2cc(I)cnc21
Agent: CCOC(=O)c1cc(I)cnc1NC
Agent: O=C(Cl)OC(Cl)(Cl)Cl
Solvent: ClCCCl
Solvent: C1COCCO1
Product: COC(=O)c1c(O)c2cc(I)cnc2n(C)c1=O
Temperature: 80 °C

Procedure:
6-Iodo-1-methyl-1H-pyrido[2,3-d][1,3]oxazine-2,4-dione. To a mixture of methyl 5-iodo-2-(methylamino)nicotinate and ethyl 5-iodo-2-(methylamino)nicotinate (10.5 g) and 1,4-dioxane (10 mL) in anhydrous 1,2-dichloroethane (1000 mL) was added trichloromethyl chloroformate (15.43 mL, 128.45 mmol) dropwise over 1 hour, with stirring and heating at 80° C. After addition, the reaction mixture was stirred at 80° C. for 4 hours, and was allowed to reach room temperature. The solvent was evaporated, and the residue was washed with a 1:1 mixture of EtOAc/hexanes (100 mL) and dried in vacuo to give the title compound.