Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[S:3]1[C:7]([CH2:8][C:9]2[C:10]([O:38][CH3:39])=[N:11][C:12]3[C:17]([C:18]=2[Cl:19])=[CH:16][C:15]([C:20]([C:32]2[N:36]([CH3:37])[CH:35]=[N:34][CH:33]=2)([C:22]2[CH:23]=[N:24][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:26][CH:27]=2)[OH:21])=[CH:14][CH:13]=3)=[CH:6][C:5]2[CH:40]=[CH:41][CH:42]=[CH:43][C:4]1=2.[C:44](OC(=O)C)(=[O:46])[CH3:45].C([O-])(O)=O.[Na+]>CN(C=O)C>[C:44]([O:21][C:20]([C:15]1[CH:16]=[C:17]2[C:12](=[CH:13][CH:14]=1)[N:11]=[C:10]([O:38][CH3:39])[C:9]([CH2:8][C:7]1[S:3][C:4]3[CH:43]=[CH:42][CH:41]=[CH:40][C:5]=3[CH:6]=1)=[C:18]2[Cl:19])([C:32]1[N:36]([CH3:37])[CH:35]=[N:34][CH:33]=1)[C:22]1[CH:23]=[N:24][C:25]([C:28]([F:30])([F:31])[F:29])=[CH:26][CH:27]=1)(=[O:46])[CH3:45]
Reactant: CC(=O)OC(C)=O
Reactant: COc1nc2ccc(C(O)(c3ccc(C(F)(F)F)nc3)c3cncn3C)cc2c(Cl)c1Cc1cc2ccccc2s1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1nc2ccc(C(OC(C)=O)(c3ccc(C(F)(F)F)nc3)c3cncn3C)cc2c(Cl)c1Cc1cc2ccccc2s1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
Sodium hydride (0.12 g, 2.98 mmol) was added to a yellow solution of (3-(benzo[b]thiophen-2-ylmethyl)-4-chloro-2-methoxyquinolin-6-yl)(1-methyl-1H-imidazol-5-yl)(6-(trifluoromethyl)pyridin-3-yl)methanol (0.88 g, 1.49 mmol, Intermediate 51: step c) in dry DMF (25 mL) at room temperature. The mixture was stirred at room temperature for 45 minutes and then acetic anhydride (0.28 mL, 2.98 mmol) was added. The resulting dark mixture was stirred at room temperature overnight. Ice was added followed by NaHCO3 (saturated aqueous solution). The aqueous mixture was extracted with EtOAc (2×). The combined organic extracts were washed with brine, dried over Na2SO4, filtered and evaporated in vacuo to provide the title compound which was carried on to the next step without further purification.
Reaction SMILES: Cl.N(OCCC(C)C)=O.[NH:10]1[C:14](=[O:15])[CH2:13][CH2:12][C@H:11]1[C:16]([NH:18][C@H:19]([C:26]([NH:28][C@H:29]([C:40]([N:42]=[N+]=[N-])=[O:41])[CH2:30][C:31]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[NH:33][CH:32]=1)=[O:27])[CH2:20][C:21]1[N:25]=[CH:24][NH:23][CH:22]=1)=[O:17].Cl.[CH2:46]([O:48][C:49](=[O:70])[CH2:50][NH:51][C:52](=[O:69])[C@H:53]([CH2:61][C:62]1[CH:67]=[CH:66][C:65]([OH:68])=[CH:64][CH:63]=1)[NH:54][C:55](=[O:60])[C@H:56]([CH2:58][OH:59])N)[CH3:47]>O1CCCC1.C(N(CC)CC)C.CN(C)C=O>[CH2:46]([O:48][C:49](=[O:70])[CH2:50][NH:51][C:52](=[O:69])[C@H:53]([CH2:61][C:62]1[CH:67]=[CH:66][C:65]([OH:68])=[CH:64][CH:63]=1)[NH:54][C:55](=[O:60])[C@H:56]([CH2:58][OH:59])[NH:42][C:40](=[O:41])[C@H:29]([CH2:30][C:31]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[NH:33][CH:32]=1)[NH:28][C:26](=[O:27])[C@H:19]([CH2:20][C:21]1[N:25]=[CH:24][NH:23][CH:22]=1)[NH:18][C:16](=[O:17])[C@@H:11]1[CH2:12][CH2:13][C:14](=[O:15])[NH:10]1)[CH3:47]
Reactant: CCOC(=O)CNC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](N)CO
Reactant: [N-]=[N+]=NC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@@H]1CCC(=O)N1
Agent: CC(C)CCON=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCOC(=O)CNC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@H](CO)NC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@@H]1CCC(=O)N1
Temperature: -50 °C
Reaction time: 21 h

Procedure:
To a stirred suspension of 1.165 g. of L-pyroglutamyl-L-histidyl-L-tryptophanyl hydrazide (prepared as described in Example 1(b) above) in 30 ml. of N,N-dimethylformamide, cooled to -20° C., is added 6.13 ml. of 2.45 N hydrogen chloride in tetrahydrofuran and 0.5 ml. of isoamyl nitrite, and the resulting mixture is stirred at -10° to -20° C. for one hour. The mixture, which contains L-pyroglutamyl-L-histidyl-L-tryptophanyl azide, is next cooled to -50° C. and to it are added first 2.1 ml. of triethylamine, then 975 mg. of L-seryl-L-tyrosylglycine ethyl ester hydrochloride (prepared as described in (b) above), and finally 0.35 ml. more of triethylamine. The stirred mixture is allowed to warm to 0° C. during one hour and is kept at -5° C. for 21 hours. It is then filtered, and the filtrate is evaporated under reduced pressure to give a residue of L-pyroglutamyl-L-histidyl-L-tryptophanyl-L-seryl-L-tyrosylglycine ethyl ester, which is dissolved in 50 ml. of methanol. To the solution is added 2 ml. of 99% hydrazine hydrate, and the resulting mixture is kept at room temperature for 16 hours. The solid that forms is isolated by filtration and stirred well with 20 ml. of water. The aqueous mixture is heated on the steam bath for 20 minutes, filtered, and the isolated solid is mixed with 15 ml. of methanol. The methanolic mixture is heated on the steam bath for 15 minutes, and the solid product is again isolated by filtration and dried. It is L-pyroglutamyl-L-histidyl-L-tryptophanyl-L-seryl-L-tyrosylglycyl hydrazide monohydrate; m.p. 218°-220° C.; [α]D25 -22.7° (1% in 1 N hydrochloric acid).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH:12]=O)[CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.Cl.[CH3:15][NH:16][CH3:17].[C-:18]#[N:19].[Na+].O>CS(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH:12]([N:16]([CH3:17])[CH3:15])[C:18]#[N:19])[CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: [C-]#N
Reactant: CNC
Reactant: O=CC1(c2ccc(Cl)cc2)CCC1
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CN(C)C(C#N)C1(c2ccc(Cl)cc2)CCC1
Temperature: 25 °C
Reaction time: 66 h

Procedure:
A mixture of 1-(4-chlorophenyl)cyclobutanecarbaldehyde (13.7 g), dry dimethylamine hydrochloride (6.6 g) and dry dimethylsulphoxide (50 ml) was added dropwise to a stirred mixture of sodium cyanide (3.9 g) in dry dimethylsulphoxide (100 ml). The mixture was stirred for 66 hours at ambient temperature and the reaction mixture was poured into water. The mixture was extracted with ether and the ether solution was then extracted with dilute hydrochloric acid. The aqueous phase was basified and extracted with ether. Removal of the ether gave 2-[1-(4-chlorophenyl)cyclobutyl]-2-dimethylaminoacetonitrile (m.p. 90°-91° C.).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH2:13]([N:15]([CH2:19][CH3:20])[CH2:16][CH2:17][NH2:18])[CH3:14].Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1>CN(C=O)C.ClCCl>[CH2:13]([N:15]([CH2:19][CH3:20])[CH2:16][CH2:17][NH:18][C:8](=[O:10])[C:7]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:12][CH:11]=1)[CH3:14]
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Reactant: CCN(CC)CCN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: ClCCl
Product: CCN(CC)CCNC(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of 4-nitrobenzoic acid (2.00 g, 11.9 mmol), N,N-diethylethylene diamine (1.53 g, 13.16 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (2.74 g, 14.35 mmol), and 1-hydroxybenzotriazole hydrate (2.19 g, 14.35 mmol) in 15 mL DMF was stirred at room temperature for 4 hours. The mixture was diluted with dichloromethane (100 mL) and washed with aqueous saturated sodium bicarbonate solution (50 mL). The aqueous layer was re-extracted with dichloromethane (2×50 mL) and the combined organic solutions were dried (Na2SO4), filtered and evaporated under reduced pressure. The crude mixture was purified on silica gel column to provide N-(2-(diethylamino)-ethyl)-4-nitrobenzamide as an amber colored oil (2.2 g 69%).
Reaction SMILES: [F:1][C:2]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([F:13])=[C:9]([NH2:14])[CH:8]=1)=[O:5].[CH3:20][N:21]1[CH2:26][CH2:25][C:24](=O)[CH2:23][CH2:22]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[Cl:46]CCCl>>[ClH:46].[F:1][C:2]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([F:13])=[C:9]([NH:14][CH:24]2[CH2:25][CH2:26][N:21]([CH3:20])[CH2:22][CH2:23]2)[CH:8]=1)=[O:5]
Reactant: ClCCCl
Reactant: Nc1cc(NC(=O)c2ccc(F)cc2F)ccc1F
Reactant: CN1CCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Product: CN1CCC(Nc2cc(NC(=O)c3ccc(F)cc3F)ccc2F)CC1
Product: Cl
Yield: 70 %

Procedure:
Using a procedure similar Example 24 using 2,4-difluoro-N-(3-amino-4-fluorophenyl)benzamide (Preparation 16,452 mg, 1.7 mmol), 1-methyl-4-piperidone (384 mg, 0.42 mL, 3.4 mmol), 1,2-dichloroethane (15 mL), powdered molecular sieves 4 Å (1 g), glacial acetic acid (306 mg, 0.3 mL, 5.1 mmol), sodium triacetoxyborohydride (900 mg, 4.25 mmol) to obtain the free base of the title compound (434 mg, 70% yield) and the title compound: mass spectrum (ion spray): m/z=364.1 (M+1); analysis calc'd for C19H20F3N3O.HCl.H2O: C, 54.61; H, 5.55; N, 10.06. Found: C, 54.48; H, 5.36; N, 9.93. 1H NMR δ (methanol-d4) 7.79(m, 1H), 7.63(d, 1H), 7.11(m, 4H), 3.74(m, 1H), 3.62(d, 2H), 3.30(dd, 2H), 2.88(s, 3H), 2.36(d, 2H), 1.93(m, 2H)
Reaction SMILES: C([O:5][C:6](=[O:36])[CH2:7][CH:8]([C:33](=[S:35])[NH2:34])[C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]2[CH:18]=[C:19]([C:23]3[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=3)[CH:20]=[CH:21][CH:22]=2)=[CH:11][CH:10]=1)(C)(C)C.Cl[CH2:38][C:39](=O)[CH3:40].Cl.[CH3:43][CH2:44]O>>[CH3:38][C:39]1[N:34]=[C:33]([CH:8]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]3[CH:18]=[C:19]([C:23]4[CH:24]=[CH:25][C:26]([C:29]([F:32])([F:30])[F:31])=[CH:27][CH:28]=4)[CH:20]=[CH:21][CH:22]=3)=[CH:11][CH:10]=2)[CH2:7][C:6]([O:5][CH2:43][CH3:44])=[O:36])[S:35][CH:40]=1
Reactant: CCO
Reactant: CC(C)(C)OC(=O)CC(C(N)=S)c1ccc(OCc2cccc(-c3ccc(C(F)(F)F)cc3)c2)cc1
Reactant: CC(=O)CCl
Agent: Cl
Product: CCOC(=O)CC(c1ccc(OCc2cccc(-c3ccc(C(F)(F)F)cc3)c2)cc1)c1nc(C)cs1
Temperature: 50 °C

Procedure:
A solution of 51.2 (100 mg, 0.19 mmol) in EtOH (3 mL) was treated with chloroacetone (88 mg, 0.95 mmol). The resulting mixture was refluxed for 5 h. Aqueous HCl (6N, 25 μL) was added into above reaction mixture and the reaction was heated at 50° C. overnight. The solvent was removed under reduced pressure. The product was purified via flash chromatography (50% ethyl acetate in hexanes) to yield 51.3 (50 mg). MS ESI (pos.) m/e: 526 (M+H).
Reaction SMILES: [CH2:1]([N:8]1[C:12]([CH3:13])=[CH:11][C:10]([C:14](OCC)=[O:15])=[C:9]1[C:19]([O:21]CC)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[NH2:25][NH2:26].Cl>COCCOCCOC>[CH2:1]([N:8]1[C:9]2[C:19](=[O:21])[NH:25][NH:26][C:14](=[O:15])[C:10]=2[CH:11]=[C:12]1[CH3:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cc(C)n(Cc2ccccc2)c1C(=O)OCC
Reactant: NN
Agent: Cl
Solvent: COCCOCCOC
Solvent: O
Product: Cc1cc2c(=O)[nH][nH]c(=O)c2n1Cc1ccccc1
Temperature: 110 °C
Reaction time: 2 h

Procedure:
A solution of 175.3 g (0.56 mol) of diethyl 1-benzyl-5-methylpyrrole-2,3-dicarboxylate and 540 ml (11.1 mol) of hydrazine hydrate in 880 ml of diglyme is heated to 110° C. After 2 h, a further 270 ml (5.5 mol) of hydrazine hydrate are added dropwise in the course of 90 min. The mixture is subsequently stirred at 110° C. for a further 16 h. After cooling and addition of 2 1 of ice-water, the mixture is adjusted to pH 5 with conc. hydrochloric acid. The precipitate is filtered with suction and washed with 5 1 of water. After drying over potassium hydroxide in a high vacuum and precipitating from diisopropyl ether/ethyl acetate, 127.3 g (89%) of the title compound are isolated. M.p.: 322°-324° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[NH:7][CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:16]=[CH:17][N:18]3[C:23]=2[C:22](SC)=[N:21][CH:20]=[N:19]3)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[Cl:27][C:28]1[CH:29]=[C:30]([NH2:42])[CH:31]=[CH:32][C:33]=1[O:34][CH2:35][C:36]1[CH:37]=[N:38][CH:39]=[CH:40][CH:41]=1>>[C:1]([O:5][C:6](=[O:26])[NH:7][CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:16]=[CH:17][N:18]3[C:23]=2[C:22]([NH:42][C:30]2[CH:31]=[CH:32][C:33]([O:34][CH2:35][C:36]4[CH:37]=[N:38][CH:39]=[CH:40][CH:41]=4)=[C:28]([Cl:27])[CH:29]=2)=[N:21][CH:20]=[N:19]3)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Nc1ccc(OCc2cccnc2)c(Cl)c1
Reactant: CSc1ncnn2ccc(CN3CCC(NC(=O)OC(C)(C)C)CC3)c12
Product: CC(C)(C)OC(=O)NC1CCN(Cc2ccn3ncnc(Nc4ccc(OCc5cccnc5)c(Cl)c4)c23)CC1
Yield: 60.1 %

Procedure:
Compound 2B (78 mg, 61%) was prepared from 1B (86 mg, 0.23 mmol) and 2A (86 mg, 0.37 mmol) by a route analogous to that used for the preparation of 1F (method one).
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N+:9]([O-])=O.[Cl-].[NH4+].O>C(O)(C)C>[CH3:1][NH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH2:9]
Reactant: CNc1ccccc1[N+](=O)[O-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CC(C)O
Product: CNc1ccccc1N

Procedure:
A mixture composed of 15.2 g (0.1 mol) of N-methyl-2-nitroaniline, 24 g of reduced iron, 0.8 g of ammonium chloride, 20 ml of water and 200 ml of isopropanol was stirred with heating at about 100° C. for 30 minutes in a 1 liter 3 necked flask. The reaction solution was filtered and the filtrate was concentrated under reduced pressure to obtain the crude product of N-methylphenylenediamine. The compound was dissolved in 100 ml of tetrahydrofuran, to which was added 8.7 g (0.11 mol) of pyridine and to which was added dropwise 36 g (0.1 mol) of tribromoacetyl bromide under cooling with ice. After the completion of the dropwise addition, the mixture was stirred at room temperature for 1 hour and then under heating on a steam bath for about 2 hours. The reaction solution was poured into about 500 ml of ice water and the crystals thus-deposited were collected by filtration to obtain 10.6 g of Compound (II-15). A melting point was 108° to 112° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH:8]([F:10])[F:9])[CH:5]=[C:4]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)[N:3]=1.[Br:21][C:22]1[N:23]=[CH:24][NH:25][CH:26]=1>>[Br:21][C:22]1[N:23]=[CH:24][N:25]([C:2]2[N:7]=[C:6]([CH:8]([F:10])[F:9])[CH:5]=[C:4]([C:11]3[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=3)[N:3]=2)[CH:26]=1
Reactant: FC(F)c1cc(-c2ccc(C(F)(F)F)cc2)nc(Cl)n1
Reactant: Brc1c[nH]cn1
Product: FC(F)c1cc(-c2ccc(C(F)(F)F)cc2)nc(-n2cnc(Br)c2)n1

Procedure:
The title compound was prepared from 2-chloro-4-difluoromethyl-6-(4-trifluoromethyl-phenyl)-pyrimidine (example A.5) (1.0 g, 3.24 mmol) and commercially available 4-bromo-imidazole (0.71 g, 4.86 mmol) according to the general procedure IVa. Obtained as a light brown solid (0.98 g, 72%). MS (ISP) 420.9 [(M+H)+]; mp 147° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([CH3:42])[C:10]([NH:12][CH:13]([CH:39]([CH3:41])[CH3:40])[C:14]([N:16]1[CH2:20][CH2:19][CH2:18][CH:17]1[CH2:21][C:22]1[C:26]2[CH:27]=[C:28](OS(C(F)(F)F)(=O)=O)[CH:29]=[CH:30][C:25]=2[O:24][CH:23]=1)=[O:15])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].[N:49]1[CH:54]=[CH:53][CH:52]=[C:51](B(O)O)[CH:50]=1>C1(C)C=CC=CC=1.CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([O:5][C:6](=[O:7])[NH:8][CH:9]([C:10](=[O:11])[NH:12][CH:13]([C:14]([N:16]1[CH2:20][CH2:19][CH2:18][CH:17]1[CH2:21][C:22]1[C:26]2[CH:27]=[C:28]([C:51]3[CH:50]=[N:49][CH:54]=[CH:53][CH:52]=3)[CH:29]=[CH:30][C:25]=2[O:24][CH:23]=1)=[O:15])[CH:39]([CH3:40])[CH3:41])[CH3:42])([CH3:4])([CH3:3])[CH3:2]
Reactant: OB(O)c1cccnc1
Reactant: CC(NC(=O)OC(C)(C)C)C(=O)NC(C(=O)N1CCCC1Cc1coc2ccc(OS(=O)(=O)C(F)(F)F)cc12)C(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CC(NC(=O)OC(C)(C)C)C(=O)NC(C(=O)N1CCCC1Cc1coc2ccc(-c3cccnc3)cc12)C(C)C
Temperature: 100 °C
Yield: 72.9 %

Procedure:
A mixture of 35 (0.063 g, 0.10 mmol), K2CO3 (70 mg, 0.50 mmol), 3-pyridineboronic acid (0.015 g, 0.12 mmol), and (Ph3P)4Pd (5 mg, 3 mol %) in anhydrous toluene (5 mL) was heated at 100° C. in a sealed tube for 1 h. The reaction mixture was cooled to room temperature, diluted with EtOAc, washed with saturated aqueous NaHCO3, brine, dried over anhydrous Na2SO4, filtered and concentrated. The crude product was purified by flash silica gel chromatography (EtOAc) to afford 40 mg (72%) of 36 as an oil. 1H NMR (CDCl3, 300 MHz) δ8.94 (d, 1H); 8.59 (d, 1H); 8.01-7.95 (m, 1H); 7.74-7.64 (m, 1H); 7.58-7.37 (m, 4H); 6.94 (d, 1H); 4.61 (t, 1H); 4.50-4.47 (m, 1H); 4.30 (t, 1H0; 4.21 (br, 1H); 3.79-3.71 (m, 1H); 3.66-3.59 (m, 1H); 2.42-3.36 (m, 1H); 2.58-2.50 (m, 1H); 2.13-2.09 (m, 1H); 2.01-1.71 (m, 4H); 1.45 (m, 9H); 1.37 (d, 3H); 1.03-0.94 (m, 6H) ppm.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Cl)=[CH:4][CH:3]=1.C(O)C.[NH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1>CCOCC>[F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][N:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)=[CH:4][CH:3]=1
Reactant: C1CNCCN1
Reactant: Fc1ccc(CCl)cc1
Solvent: CCO
Solvent: CCOCC
Product: Fc1ccc(CN2CCNCC2)cc1
Temperature: 20 °C
Reaction time: 2 h
Yield: 55.7 %

Procedure:
A solution of 29 g of p-fluorobenzyl chloride in 50 g of reagent ethanol was added dropwise to a stirred solution of 34.5 g of piperazine in 150 g of reagent ethanol. A cold water bath was used to maintain the reaction temperature at 20° C. during the addition. The reaction mixture was stirred for an additional 11/2 hours and then added to 2 liters of ether. Precipitated piperazine hydrochloride was filtered off. The filtrate was concentrated to an oil, which was chromatographed on a silica column, the eluant being a mixture of CH2Cl2 /methanol/ammonium hydroxide in the ratio of 45:5:1. After concentration of appropriate fractions, 21.7 g of 1-(4-fluorobenzyl)piperazine were isolated as a colorless liquid (56% of theory).
Reaction SMILES: [NH2:1][C:2]1[N:3]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:4]=[C:5]2[C:14]3[CH:13]=[CH:12][C:11]([NH2:15])=[CH:10][C:9]=3[NH:8][C:7](=[O:16])[C:6]=12.Cl[CH2:24][C:25](Cl)=[O:26].C(N(CC)CC)C.[CH3:35][N:36]1[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1>O.O1CCCC1>[NH2:1][C:2]1[N:3]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:4]=[C:5]2[C:14]3[CH:13]=[CH:12][C:11]([NH:15][C:25](=[O:26])[CH2:24][N:39]4[CH2:40][CH2:41][N:36]([CH3:35])[CH2:37][CH2:38]4)=[CH:10][C:9]=3[NH:8][C:7](=[O:16])[C:6]=12
Reactant: CN1CCNCC1
Reactant: Nc1ccc2c(c1)[nH]c(=O)c1c(N)n(-c3ccccc3)nc12
Reactant: O=C(Cl)CCl
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CN1CCN(CC(=O)Nc2ccc3c(c2)[nH]c(=O)c2c(N)n(-c4ccccc4)nc23)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 3,7-diamino-2-phenyl-2,5-dihydro-4H-pyrazolo[4,3-c]quinolin-4-one (100 mg), chloroacetyl chloride (28.6 μl), triethylamine (71.7 μl ) and tetrahydrofuran (6 ml) was stirred at room temperature for 30 minutes, and 1-methylpiperazine (76.1 μl) was added thereto. The reaction mixture was stirred at room temperature for additional 30 minutes and with heating under reflux for 6 hours. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The extract was washed with water and brine, dried over anhydrous magnesium sulfate and then the solvent was distilled off under reduced pressure. Ethyl acetate was added to the residue. The precipitated solid was collected by filtration, and washed with ethyl acetate to obtain the target compound (64 mg).
Reaction SMILES: C1C(=O)N([Br:8])C(=O)C1.[C:9]([C:13]1[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=1[NH2:15])([CH3:12])([CH3:11])[CH3:10].O>CN(C=O)C>[Br:8][C:18]1[CH:17]=[CH:16][C:14]([NH2:15])=[C:13]([C:9]([CH3:12])([CH3:10])[CH3:11])[CH:19]=1
Reactant: CC(C)(C)c1ccccc1N
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)c1cc(Br)ccc1N
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of NBS (218 mg, 1 mmol) in DMF was added a solution of 2-tert-butylaniline (149 mg, 1 mmol) in DMF at rt. The reaction mixture was stirred for 4 h at rt, then water (30 mL) was added and the mixture was extracted with EA (150 mL). The organic layer was washed with brine and dried over Na2SO4, concentrated and purified by CC (hexane/EA=3/1) to give compound P19a (180 mg, 79%).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]([OH:12])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[CH2:13](Br)[CH:14]=[CH2:15].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:7][O:6][C:4](=[O:5])[C:3]1[CH:8]=[CH:9][C:10]([O:12][CH2:15][CH:14]=[CH2:13])=[CH:11][C:2]=1[OH:1]
Reactant: C=CCBr
Reactant: COC(=O)c1ccc(O)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CCOc1ccc(C(=O)OC)c(O)c1
Yield: 67 %

Procedure:
A mixture of 102 g (0.607 mol) of methyl 2,4-dihydroxybenzoate, 54 mL (0.619 mol) of allyl bromide and 126 g (0.91 mol) of anhydrous potassium carbonate in 300 mL of anhydrous acetone was stirred at reflux for 3 hours. The reaction mixture was filtered and the solid was washed with acetone. After removal of the acetone from the filtrate under reduced pressure, the residue was distilled to give 85 g (67% yield), bp 106°-108°/0.3 mm of 2-hydroxy-4-(2-propenyloxy)benzoic acid methyl ester.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][CH:5]([C:8]([OH:10])=[O:9])[CH2:4][CH2:3]1.S(=O)(=O)(O)O.C([O-])([O-])=O.[Na+].[Na+].[CH2:22](O)[CH3:23]>>[CH2:22]([O:9][C:8]([CH:5]1[CH2:6][CH2:7][CH:2]([OH:1])[CH2:3][CH2:4]1)=[O:10])[CH3:23]
Reactant: O=C(O)C1CCC(O)CC1
Reactant: CCO
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CCOC(=O)C1CCC(O)CC1
Yield: 100 %

Procedure:
4-Hydroxycyclohexane carboxylic acid (5 g, 34.5 mmol) was heated to reflux for 16 hours in the presence of 50 mL of ethyl alcohol and 2 mL of sulfuric acid. Reaction volume was reduce by half at reduced pressure and mixture was poured into sat. Na2CO3. Mixture was extracted 3×50 mL of ethyl acetate and combined organics were washed with brine and dried over MgSO4. Title compound was obtained as a colorless crude oil. (5.9 g; 100% yield).
Reaction SMILES: [S:1]1[C:13]2[C:12]3[C:11](=[O:14])[NH:10][CH2:9][CH2:8][C:7]=3[CH:6]=[CH:5][C:4]=2[N:3]=[CH:2]1.I[C:16]1[CH:17]=[N:18][CH:19]=[CH:20][C:21]=1[CH3:22].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.[Cu](I)I>[CH3:22][C:21]1[CH:20]=[CH:19][N:18]=[CH:17][C:16]=1[N:10]1[CH2:9][CH2:8][C:7]2[CH:6]=[CH:5][C:4]3[N:3]=[CH:2][S:1][C:13]=3[C:12]=2[C:11]1=[O:14]
Reactant: O=C1NCCc2ccc3ncsc3c21
Reactant: Cc1ccncc1I
Agent: I[Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: Cc1ccncc1N1CCc2ccc3ncsc3c2C1=O
Yield: 20.3 %

Procedure:
7,8-Dihydrothiazolo[4,5-h]isoquinolin-9(6H)-one (I-66c: 0.13 g, 0.0006 mol) was reacted with 3-iodo-4-methylpyridine (0.15 g, 0.0007 mol), copper iodide (0.036 g, 0.00019 mol), trans-N,N′-dimethyl-cyclohexyl-1,2-diamine (0.027 g, 0.00019 mol) and potassium phosphate (0.45 g, 0.0015 mol) in 1,4-dioxane (10 mL) to afford the crude product. Purification by column chromatography on silica gel (2% methanol in DCM) afforded 36 mg of the product (20.2% yield).
Reaction SMILES: Cl.Cl.[CH3:3][C:4]1[CH:17]=[C:7]2[C:8]([C@@H:12]3[CH2:14][C@H:13]3[CH2:15][NH2:16])=[CH:9][CH:10]=[CH:11][N:6]2[N:5]=1.C(N(CC)CC)C.[CH:25]1([C:28](Cl)=[O:29])[CH2:27][CH2:26]1.C(O)C>O1CCCC1>[CH3:3][C:4]1[CH:17]=[C:7]2[C:8]([C@@H:12]3[CH2:14][C@H:13]3[CH2:15][NH:16][C:28]([CH:25]3[CH2:27][CH2:26]3)=[O:29])=[CH:9][CH:10]=[CH:11][N:6]2[N:5]=1
Reactant: O=C(Cl)C1CC1
Reactant: Cc1cc2c([C@@H]3C[C@H]3CN)cccn2n1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1cc2c([C@@H]3C[C@H]3CNC(=O)C3CC3)cccn2n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 87.7 %

Procedure:
To a suspension of 1-[(1R,2R)-2-(2-methylpyrazolo[1,5-a]pyridin-4-yl)cyclopropyl]methanamine dihydrochloride (750 mg, 2.74 mmol) and triethylamine (1.52 mL, 10.9 mmol) in tetrahydrofuran (27 mL) was added cyclopropanecarbonyl chloride (372 μL, 4.10 mmol) under ice-cooling, and the mixture was stirred at room temperature for 3 hr. Ethanol was added to the reaction solution. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (methanol/ethyl acetate=0/100→5/95) to give the title compound (647 mg, yield 88%).