Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[NH:7][C:8]1[CH:13]=[C:12](Cl)[C:11]([C:15]#[N:16])=[CH:10][N:9]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:18][O:19][CH2:20][CH2:21][NH2:22].CCN(C(C)C)C(C)C>CS(C)=O>[C:1]([O:5][C:6](=[O:17])[NH:7][C:8]1[CH:13]=[C:12]([NH:22][CH2:21][CH2:20][O:19][CH3:18])[C:11]([C:15]#[N:16])=[CH:10][N:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COCCN
Reactant: CC(C)(C)OC(=O)Nc1cc(Cl)c(C#N)cn1
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: COCCNc1cc(NC(=O)OC(C)(C)C)ncc1C#N
Temperature: 67.5 °C
Reaction time: 1 h

Procedure:
A mixture of tert-butyl(4-chloro-5-cyanopyridin-2-yl)carbamate (intermediate 288, 9.8 g, 38.6 mmol), 2-methoxyethylamine (5.8 g, 77.3 mmol) and DIPEA (6 g, 46.4 mmol) in DMSO (80 ml) was heated at 65-70° C. for 24 h and monitored by chromatography until complete conversion. The solution was then cooled to room temperature and a white solid precipitated gradually. Water (20 ml) was then added slowly within 1 h. The suspension was stirred for a further 1 h, filtered and dried to give the title compound as a white solid. 1H NMR (DMSO-d6, 400 MHz): δ 9.87 (s, 1H), 8.18 (s, 1H), 7.20 (s, 1H), 6.86 (s, 9H), 3.51 (t, 2H), 3.36 (t, 2H), 3.28 (s, 3H), 1.47 (s, 9H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[C:7]([O:11][CH3:12])[CH:6]=[C:5]([CH3:13])[C:4]=1[CH:14]([C:16]1[C:21]([Cl:22])=[CH:20][N:19]=[C:18]([Cl:23])[C:17]=1[Cl:24])[OH:15]>[O-2].[O-2].[Mn+4].C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[C:7]([O:11][CH3:12])[CH:6]=[C:5]([CH3:13])[C:4]=1[C:14]([C:16]1[C:21]([Cl:22])=[CH:20][N:19]=[C:18]([Cl:23])[C:17]=1[Cl:24])=[O:15]
Reactant: COc1cc(C)c(C(O)c2c(Cl)cnc(Cl)c2Cl)c(OC)c1OC
Agent: [Mn+4]
Agent: [O-2]
Solvent: Cc1ccccc1
Product: COc1cc(C)c(C(=O)c2c(Cl)cnc(Cl)c2Cl)c(OC)c1OC
Yield: 84.4 %

Procedure:
16.2 g of manganese dioxide was added to a toluene (180 ml) solution of 5.6 g of (2,3,4-trimethoxy-6-methylphenyl)(2,3,5-trichloro-4-pyridyl)methanol obtained in step (a), followed by stirring under reflux by heating for 3 hours. After the mixture was cooled, it was subjected to filtration, and the solvent was distilled off under reduced pressure to obtain 4.7 g (yield 87%) of 4-(2,3,4-trimethoxy-6-methylbenzoyl)-2,3,5-trichloropyridine (compound No. 186; m.p. 60-61° C.).
Reaction SMILES: [CH3:1][N:2]1[C:6]([N+:7]([O-:9])=[O:8])=[CH:5][N:4]=[C:3]1[C:10]([NH:12][NH:13][C:14]([NH2:16])=[S:15])=N.NNC(N)=S.Cl>CO>[NH2:16][C:14]1[S:15][C:10]([C:3]2[N:2]([CH3:1])[C:6]([N+:7]([O-:9])=[O:8])=[CH:5][N:4]=2)=[N:12][N:13]=1
Reactant: Cn1c([N+](=O)[O-])cnc1C(=N)NNC(N)=S
Agent: Cl
Agent: NNC(N)=S
Solvent: CO
Product: Cn1c([N+](=O)[O-])cnc1-c1nnc(N)s1
Yield: 78 %

Procedure:
1-(1-Methyl-5-nitro-2-imidazolecarboximidoyl)-3-thiosemicarbazide is cyclized as in Example 10 with the exception that the 0.3 g. of the thiosemicarbazide in 7 ml. of 6N hydrochloric acid is replaced by 0.49 g. of the thiosemicarbazide in 5 ml. of methanol plus 0.5 ml. of concentrated hydrochloric acid. The cyclization is also effected by the use of 0.49 g. of the thiosemicarbazide in 5 ml. of methanol plus 0.5 ml. of 6N ethanolic hydrogen chloride. In each of these variations, a 78% yield of the title compound is realized. The cyclization is likewise accomplished by the use of dilute aqueous sulfuric acid, phosphoric, nitric, p-toluenesulfonic, benzene sulfonic, methylsulfonic or hydrobromic acid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[CH:8][C:9]2[N:10]([CH:12]=[C:13]([C:15]([NH:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[O:16])[N:14]=2)[CH:11]=1)=[CH2:5])[CH3:2].C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=[O:38])=CC=1>C(O)CO>[CH3:5][C:4]1([C:6]2[CH:7]=[CH:8][C:9]3[N:10]([CH:12]=[C:13]([C:15]([NH:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[O:16])[N:14]=3)[CH:11]=2)[O:38][CH2:2][CH2:1][O:3]1
Reactant: C=C(OCC)c1ccc2nc(C(=O)Nc3ccccc3)cn2c1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: OCCO
Product: CC1(c2ccc3nc(C(=O)Nc4ccccc4)cn3c2)OCCO1
Yield: 20.2 %

Procedure:
A mixture of 80 mg of 6-(1-ethoxyvinyl)-N-phenylimidazo[1,2-a]pyridine-2-carboxamide, 2.5 mL of toluene, 280 μL of ethylene glycol and 170 mg of para-toluenesulfonic acid is placed over molecular sieves. The mixture is refluxed for 2 hours and then cooled, filtered and diluted with 20 mL of dichloromethane and 20 mL of water, and neutralized with 2N sodium hydroxide solution. The aqueous phase is washed with dichloromethane and the combined organic phases are dried and concentrated to dryness. The residue is chromatographed on a silica cartridge, eluting with a gradient of dichloromethane and ethyl acetate of from 0/30 to 70/30 to give 17 mg of 6-(2-methyl-1,3-dioxolan-2-yl)-N-phenylimidazo[1,2-a]pyridine-2-carboxamide in the form of a white solid.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[O:8][CH2:7][CH2:6][N:5]([C:9]2[S:10][C:11]3[C:17](=[O:18])[CH2:16][C:15]([CH3:20])([CH3:19])[CH2:14][C:12]=3[N:13]=2)[CH2:4]1.N1C=CC=CC=1.[C:27]1([S:33](Cl)(=[O:35])=[O:34])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C(Cl)Cl>[CH3:19][C:15]1([CH3:20])[CH2:14][C:12]2[N:13]=[C:9]([N:5]3[CH2:6][CH2:7][O:8][CH:3]([CH2:2][NH:1][S:33]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)(=[O:35])=[O:34])[CH2:4]3)[S:10][C:11]=2[C:17](=[O:18])[CH2:16]1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CC1(C)CC(=O)c2sc(N3CCOC(CN)C3)nc2C1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC1(C)CC(=O)c2sc(N3CCOC(CNS(=O)(=O)c4ccccc4)C3)nc2C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 20.3 %

Procedure:
To a stirred solution of Example 154 (0.10 g, 0.34 mmol) and pyridine (0.04 g, 0.51 mmol) in DCM (10 mL) was added benzenesulphonyl chloride (0.06 g, 0.34 mmol) and the reaction mixture was stirred at room temperature for 4 h. The solvent was then removed in vacuo and purification by preparative HPLC gave the title compound (0.03 g, 20%) as a white solid. δH (CDCl3) 7.90 (2H, dd, J 6.9 and 1.5 Hz), 7.60 (3H, m), 4.87 (1H, t, J 6.0 Hz), 4.00 (2H, m), 3.75 (1H, m), 3.60 (2H, m), 3.20 (2H, m), 3.00 (2H, m), 2.70 (2H, s), 2.40 (2H, s), 1.10 (6H, s). LCMS (ES+) 436.0 (M+H)+.
Reaction SMILES: [Br:1][CH2:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]2[C:17]3[CH:16]=[C:15]4[CH2:18][CH2:19][CH2:20][C:21](=[O:22])[C:14]4=[CH:13][C:12]=3[O:11][CH2:10][C:9]=2[CH:23]=1)=[O:4].[Br-:24].[Br-].[Br-].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.ClCCl>CO>[Br:24][CH:20]1[CH2:19][CH2:18][C:15]2=[CH:16][C:17]3[C:8]4[CH:7]=[CH:6][C:5]([C:3](=[O:4])[CH2:2][Br:1])=[CH:23][C:9]=4[CH2:10][O:11][C:12]=3[CH:13]=[C:14]2[C:21]1=[O:22]
Reactant: [Br-]
Reactant: O=C(CBr)c1ccc2c(c1)COc1cc3c(cc1-2)CCCC3=O
Agent: c1cc[nH+]cc1
Solvent: CO
Solvent: ClCCl
Product: O=C(CBr)c1ccc2c(c1)COc1cc3c(cc1-2)CCC(Br)C3=O
Temperature: 20 °C
Reaction time: 3 h
Yield: 83.8 %

Procedure:
A mixture of 3-(2-bromoacetyl)-10,11-dihydro-5H-dibenzo[c,g]chromen-8(9H)-one (2.58 g, 6.95 mmol), pyridinium tribromide (2.56 g, 8.0 mmol), dichloromethane (22 mL) and methanol (2.5 mL) was stirred at about 20° C. for 3 hours to obtain a slurry. The precipitated product was filtered, washed with dichloromethane (10 mL) and dried in a vacuum oven at 40° C. to give 9-bromo-3-(2-bromoacetyl)-10,11-dihydro-5H-dibenzo[c,g]chromen-8(9H)-one (2.62 g, 84% yield). 400 MHz 1H NMR (CDCl3) δ 8.03-8.01 (m, 1H), 7.85 (d, J=8.2 Hz, 1H), 7.82 (s, 1H), 7.71 (s, 1H), 7.67 (s, 1H), 5.19 (s, 2H), 4.74 (dd, J=4.1, 4.1 Hz, 1H), 4.45 (s, 2H), 3.37-3.29 (m, 1H), 2.99-2.92 (m, 1H), 2.59-2.46 (m, 2H).
Reaction SMILES: [N:1]([C:4]1[C:5]([F:17])=[C:6]([CH:11]2[CH2:15][NH:14][C:13](=[O:16])[CH2:12]2)[CH:7]=[CH:8][C:9]=1[F:10])=[N+:2]=[N-:3].[CH2:18]=[O:19].[OH-].[Na+]>CCO>[N:1]([C:4]1[C:5]([F:17])=[C:6]([CH:11]2[CH2:15][N:14]([CH2:18][OH:19])[C:13](=[O:16])[CH2:12]2)[CH:7]=[CH:8][C:9]=1[F:10])=[N+:2]=[N-:3]
Reactant: C=O
Reactant: [N-]=[N+]=Nc1c(F)ccc(C2CNC(=O)C2)c1F
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: [N-]=[N+]=Nc1c(F)ccc(C2CC(=O)N(CO)C2)c1F

Procedure:
In a 50 ml three necked flask fitted with a magnetic stirrer, under inert atmosphere, a solution of 4-(3-azido-2,4-difluoro-phenyl)-pyrrolidin-2-one a14 (1.84 g, 7.73 mmol), formaldehyde (35% w/w in water, 2.3 g) and NaOH (0.015 g) in EtOH (20 ml) is heated at 60° C. for 3 h. The reaction mixture is evaporated and dried azeotropically with toluene to give the crude alcohol which is purified by chromatography on silicagel (CH2Cl2/MeOH: 98/02 (v/v)) to give 4-(3-azido-2,4-difluoro-phenyl)-1-hydroxymethyl-pyrrolidin-2-one a15 (1.64 g, 79%).
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20](SCCC)=[N:19][C:18]4=[O:26])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:29]([F:32])([F:31])[F:30])[CH:3]=1.[N:33]1([CH:40]2[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]2)[CH2:38][CH2:37][CH2:36][CH:35]([OH:39])[CH2:34]1>>[Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20]([N:43]5[CH2:42][CH2:41][CH:40]([N:33]6[CH2:38][CH2:37][CH2:36][CH:35]([OH:39])[CH2:34]6)[CH2:45][CH2:44]5)=[N:19][C:18]4=[O:26])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:29]([F:32])([F:30])[F:31])[CH:3]=1
Reactant: CCCSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Reactant: OC1CCCN(C2CCNCC2)C1
Product: O=C1N=C(N2CCC(N3CCCC(O)C3)CC2)SC1=Cc1ccc2c(cnn2Cc2ccc(Cl)cc2C(F)(F)F)c1

Procedure:
5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(3-hydroxy-[1,4′]bipiperidinyl-1′-yl)-thiazol-4-one was prepared from 5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-propylsulfanyl-thiazol-4-one and [1,4′]Bipiperidinyl-3-ol following General Procedure B.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=O.[CH2:8]([O:10][CH:11]([O:14][CH2:15][CH3:16])[CH2:12][NH2:13])[CH3:9].O>C1(C)C=CC=CC=1>[CH2:8]([O:10][CH:11]([O:14][CH2:15][CH3:16])[CH2:12][N:13]=[CH:6][C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)[CH3:9]
Reactant: CCOC(CN)OCC
Reactant: O=Cc1cccs1
Solvent: O
Solvent: Cc1ccccc1
Product: CCOC(CN=Cc1cccs1)OCC
Yield: 93.5 %

Procedure:
2-Thiophene aldehyde (62.8 g) and 74.6 g of aminoacetaldehyde diethylacetal were dissolved in 200 mL of toluene and heated to reflux for 6 hours together with dehydration using a Dean-Stark trap. After confirming that a theoretical amount of water was separated, the solvent was evaporated therefrom in vacuo. The concentrated liquid was purified by a vacuum distillation to give 119 g of the objective compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5](Br)=[CH:4][N:3]=1.[CH3:9][O-:10].[Na+]>CO.[Cu]>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:10][CH3:9])=[CH:4][N:3]=1
Reactant: Nc1ccc(Br)cn1
Reactant: C[O-]
Agent: [Cu]
Agent: [Na+]
Solvent: CO
Product: COc1ccc(N)nc1
Temperature: 160 °C
Reaction time: 72 h
Yield: 41.7 %

Procedure:
Add 2-amino-5-bromopyridine (5.0 g, 29 mmol) to a freshly prepared solution of sodium methoxide (1.3 g, 58 mmol) in methanol (50 mL) and then add copper powder (1.8 g, 2.9 mmol). Heat and stir the mixture in a sealed tube at 160° C. for 3 days. Cool, filter through celite and concentrate under reduced pressure. Dissolve the residue in dichloromethane, then wash with water and saturated aqueous sodium chloride. Dry over magnesium sulfate, concentrate under reduced pressure, and subject the residue to silica gel chromatography, eluting with hexane/ethyl acetate; 3:1 to 0:1 to provide the title compound (1.5 g).
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.C([O-])([O-])=O.[K+].[K+].S(O[CH2:28][CH2:29][CH:30]1[O:35][C:34]2[CH:36]=[CH:37][CH:38]=[CH:39][C:33]=2[O:32][CH2:31]1)(C)(=O)=O.C(O)C>C(#N)C>[F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:10][CH2:11][N:12]([CH2:28][CH2:29][CH:30]4[O:35][C:34]5[CH:36]=[CH:37][CH:38]=[CH:39][C:33]=5[O:32][CH2:31]4)[CH2:13][CH2:14]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: CS(=O)(=O)OCCC1COc2ccccc2O1
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCO
Product: Fc1ccc2c(C3CCN(CCC4COc5ccccc5O4)CC3)noc2c1

Procedure:
A mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (4.7 g, 21 mmol), K2CO3 (3.5 g, 25.4 mmol) and 2-mesyloxyethyl-1,4-benzodioxan (5.5 g, 21.3 mmol) in acetonitrile (250 ml) was heated at reflux for 3.5 hours. At the end of the reaction, insolubles were filtered. The solid was washed with dichloromethane (200 ml). The solutions were combined and evaporated to an oil. This crude oil was purified by flash chromatography on a silica gel column. The material thus obtained was crystal- lized from ethanol. The 2-[4(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]- ethyl]-1,Sbenzodioxan crystals were collected and weighed 3.8 g, 48%, m.p.=112°-113° C.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([S:13]([N:16]1[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][CH:24]3[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)[C:18](=[O:30])[CH2:17]1)(=[O:15])=[O:14])[CH:7]=[CH:6]2.S(O)(O)(=O)=O.CS[C:38](=[NH:40])[NH2:39].CSC(=N)N.C[O-].[Na+]>CO>[C:38]([N:27]1[CH2:28][CH2:29][CH:24]([CH2:23][CH2:22][N:19]2[CH2:20][CH2:21][N:16]([S:13]([C:8]3[CH:7]=[CH:6][C:5]4[C:10](=[CH:11][CH:12]=[C:3]([Cl:2])[CH:4]=4)[CH:9]=3)(=[O:15])=[O:14])[CH2:17][C:18]2=[O:30])[CH2:25][CH2:26]1)(=[NH:39])[NH2:40]
Reactant: CSC(=N)N
Reactant: O=C1CN(S(=O)(=O)c2ccc3cc(Cl)ccc3c2)CCN1CCC1CCNCC1
Agent: C[O-]
Agent: Cl
Agent: O=S(=O)(O)O
Solvent: CO
Product: N=C(N)N1CCC(CCN2CCN(S(=O)(=O)c3ccc4cc(Cl)ccc4c3)CC2=O)CC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 55.3 %

Procedure:
To a solution of 4-(6-chloronaphthalene-2-sulfonyl)-1-[2-(4-piperidyl)ethyl]-2-piperazinone Hydrochloride (118 mg) in methanol (10 ml) was added a solution of S-methylisothiourea hemisulfate (315 mg) and 28% sodium methoxide in methanol (482 mg), and the mixture was stirred at room temperature for 3 days. The solvent was concentrated and purified with CHP20 column chromatography (water:acetonitrile:1 N hydrochloric acid=70:30:1), and then purified with LH20 (methanol) to give colorless amorphous of the title compound (66 mg).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.[OH-].[Na+].[Cl:12][CH2:13][CH2:14][CH2:15]Br>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.ClCCl>[Cl:12][CH2:13][CH2:14][CH2:15][N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: c1ccc2[nH]cnc2c1
Reactant: ClCCCBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: ClCCl
Product: ClCCCn1cnc2ccccc21
Temperature: 60 °C
Yield: 61.6 %

Procedure:
1H-benzimidazole (11.8 g, 0.10 mol) was dissolved into 200 ml of 20% wt. sodium hydroxide, 3-chlorobromopropane (31.4 g, 0.20 mol) and tetrabutyl ammonium bromide (1.0 g) were added, and mixed for 5 min. The mixture was heated to 60° C., stirred to react for 2 hours. Then the reaction solution was cooled down to ambient temperature, 100 ml of dichloromethane was added for extraction and liquid separation. To the aqueous phase, 100 of dichloromethane was added for extraction. Organic phases were mixed, washed with 100 ml of saturated saline. Liquid was separated, and organic phase was evaporated to dryness to produce oily product. Oily products were separated and purified by chromatography with neutral Al2O3 to produce 12.0 g of 1-(3-chloropropyl)-1H-benzimidazole, with a yield of 62.0%.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1.[C:21]([NH:24][CH:25]1[CH2:30][CH2:29][CH2:28][NH:27][CH2:26]1)(=[O:23])[CH3:22].C(N(CC)CC)C>CS(C)=O>[C:21]([NH:24][CH:25]1[CH2:30][CH2:29][CH2:28][N:27]([C:11]2[C:12]([F:14])=[C:13]3[C:8]([C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5][N:4]3[CH:1]3[CH2:2][CH2:3]3)=[CH:9][C:10]=2[F:16])[CH2:26]1)(=[O:23])[CH3:22]
Reactant: O=C(O)c1cn(C2CC2)c2c(F)c(F)c(F)cc2c1=O
Reactant: CC(=O)NC1CCCNC1
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CC(=O)NC1CCCN(c2c(F)cc3c(=O)c(C(=O)O)cn(C4CC4)c3c2F)C1
Temperature: 100 °C
Yield: 66.6 %

Procedure:
A mixture of 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid(566 mg), 3-acetamidopiperidine (300 mg), triethylamine (220 mg) and dimethylsulfoxide (10 ml) was heated at 100° C. for 2 hours with stirring. Thereafter the mixture was cooled to room temperature and ice water was added thereto. The precipitated crystalline was filtered off andwashed with methanol-ether to give 7-(3-acetamidopiperidin-1-yl)-1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (540 mg) (m.p. 280°-282° C., recrystallized from methanol). The product (405 mg) obtained in the above manner was suspended in 6N hydrochloric acid (5 ml) and heated at 100° C. for 2.5 hours with stirring. The reaction mixture was further processed in a similar manner to step (b) of Example 1 to afford hydrochloride of 7-(3-aminopiperidinly-1)-1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid. The physical properties of this product were identical with those of the compound provided in Example 1.
Reaction SMILES: [CH3:1][N:2]([CH3:28])[C:3]([C:5]1[N:22]([CH:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)[C:8]2[N:9]=[C:10]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([CH:20]=O)=[CH:16][N:15]=3)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4].[C:29]([O:33][C:34]([N:36]1[CH2:41][CH2:40][NH:39][CH2:38][CH:37]1[CH3:42])=[O:35])([CH3:32])([CH3:31])[CH3:30]>>[C:29]([O:33][C:34]([N:36]1[CH2:41][CH2:40][N:39]([CH2:20][C:17]2[CH:16]=[N:15][C:14]([NH:13][C:10]3[N:11]=[CH:12][C:7]4[CH:6]=[C:5]([C:3](=[O:4])[N:2]([CH3:28])[CH3:1])[N:22]([CH:23]5[CH2:24][CH2:25][CH2:26][CH2:27]5)[C:8]=4[N:9]=3)=[CH:19][CH:18]=2)[CH2:38][CH:37]1[CH3:42])=[O:35])([CH3:32])([CH3:30])[CH3:31]
Reactant: CN(C)C(=O)c1cc2cnc(Nc3ccc(C=O)cn3)nc2n1C1CCCC1
Reactant: CC1CNCCN1C(=O)OC(C)(C)C
Product: CC1CN(Cc2ccc(Nc3ncc4cc(C(=O)N(C)C)n(C5CCCC5)c4n3)nc2)CCN1C(=O)OC(C)(C)C

Procedure:
Following General Procedure C, 7-Cyclopentyl-2-(5-formyl-pyridin-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (0.298 g, 0.788 mmol) and 2-methyl-piperazine-1-carboxylic acid tert-butyl ester (0.316 g, 1.58 mmol) gave 4-[6-(7-cyclopentyl-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-pyridin-3-ylmethyl]-2-methyl-piperazine-1-carboxylic acid tert-butyl ester a yellowish oil (0.341 g, 77%) [following purification by SiO2 chromatography eluting with 2-6% MeOH/DCM].
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[NH:7][CH2:8][CH2:9][CH2:10][NH:11][C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:15]=[CH:14][C:13]=1[N+:22]([O-])=O)([CH3:4])([CH3:3])[CH3:2]>C1COCC1.[Pt]>[C:1]([O:5][C:6](=[O:25])[NH:7][CH2:8][CH2:9][CH2:10][NH:11][C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:15]=[CH:14][C:13]=1[NH2:22])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCCCNc1c([N+](=O)[O-])cnc2ccccc12
Agent: [Pt]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCCCNc1c(N)cnc2ccccc12
Reaction time: 72 h

Procedure:
The product from step (ii) (12 g) was dissolved in dry THF (250 mL), 1% Pt/C catalyst (3 g) was added and the reaction mixture hydrogenated (H2 pressure: 3 bar) for 72 h at rt. The product was filtered through a glass fibre filter paper and purified via neutral Aluminum oxide column eluting with 4% MeOH in DCM and further purified via RPHPLC to give subtitle compound, yield 1.3 g.
Reaction SMILES: CN1CCCC1=O.F[C:9]1[C:14]([F:15])=[CH:13][C:12]([F:16])=[C:11]([NH:17][CH:18]([CH3:20])[CH3:19])[N:10]=1.[CH3:21][O:22][C:23]1[CH:30]=[CH:29][C:26]([CH2:27][NH2:28])=[CH:25][CH:24]=1.C1C=CC=CC=1>CCCCCC>[F:16][C:12]1[C:11]([NH:17][CH:18]([CH3:20])[CH3:19])=[N:10][C:9]([NH:28][CH2:27][C:26]2[CH:29]=[CH:30][C:23]([O:22][CH3:21])=[CH:24][CH:25]=2)=[C:14]([F:15])[CH:13]=1
Reactant: COc1ccc(CN)cc1
Reactant: CC(C)Nc1nc(F)c(F)cc1F
Solvent: CN1CCCC1=O
Solvent: CCCCCC
Solvent: c1ccccc1
Product: COc1ccc(CNc2nc(NC(C)C)c(F)cc2F)cc1
Temperature: 150 °C
Reaction time: 15 h

Procedure:
To 4.1 g of N-methylpyrrolidone were added all amount of the 2,3,5-trifluoro-6-isopropylaminopyridine as described above together with 3.1 g of p-methoxybenzylamine, and the mixture was stirred at 150° C. for 15 hours and allowed to cool. After adding 50 ml of the mixed solution of benzene and n-hexane (1:1, v/v), the solution was washed twice with 400 ml of distilled water. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain 3.9 g of the title compound as a brown crude oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][O:12]1)[N:6]=[C:5]2I.[CH3:18][S:19][C:20]1[N:25]=[C:24]([Sn](CCCC)(CCCC)CCCC)[CH:23]=[CH:22][N:21]=1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I.CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][O:12]1)[N:6]=[C:5]2[C:22]1[CH:23]=[CH:24][N:25]=[C:20]([S:19][CH3:18])[N:21]=1
Reactant: Brc1ccc2c(c1)c(I)nn2C1CCCCO1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccnc(SC)n1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: CSc1nccc(-c2nn(C3CCCCO3)c3ccc(Br)cc23)n1
Temperature: 100 °C
Yield: 42.1 %

Procedure:
A glass microwave reaction vessel was charged with 5-bromo-3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (2.04 g, 5.01 mmol), Pd(PPh3)4 (0.555 g, 0.480 mmol), CuI (0.130 g, 0.683 mmol) and 2-(methylthio)-4-(tributylstannyl)pyrimidine (2.23 g, 5.37 mmol, Frontier Scientific). DMF (6 mL) was added and the reaction mixture was sealed under argon and heated thermally at 100° C. for 6.5 h. The solvent was removed in vacuo and the residue was dissolved in MeOH, evaporated onto silica gel and purified by flash chromatography (Isco, (80 gram)) eluting with 2M NH3 in MeOH:DCM (0:1→1:19) to give 855 mg of a tan amorphous solid. m/z: 405.0 [M+1].
Reaction SMILES: [CH:1]1[C:14]2[C:13]3([CH2:16][CH2:17][C:18]([OH:20])=O)[CH2:15][CH:6]([C:7]4[C:12]3=[CH:11][CH:10]=[CH:9][CH:8]=4)[C:5]=2[CH:4]=[CH:3][CH:2]=1.S(Cl)([Cl:23])=O>C1C=CC=CC=1>[CH:1]1[C:14]2[C:13]3([CH2:16][CH2:17][C:18]([Cl:23])=[O:20])[CH2:15][CH:6]([C:7]4[C:12]3=[CH:11][CH:10]=[CH:9][CH:8]=4)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)CCC12CC(c3ccccc31)c1ccccc12
Reactant: O=S(Cl)Cl
Solvent: c1ccccc1
Product: O=C(Cl)CCC12CC(c3ccccc31)c1ccccc12

Procedure:
A solution of β-(9,10-dihydro-9,10-methano-9-anthryl)propionic acid and thionyl chloride in benzene was refluxed for 4 hours. Evaporation of excess thionyl chloride and benzene gave β-(9,10-dihydro-9,10-methano-9-anthryl)propionic acid chloride, which was dissolved in dry tetrahydrofuran. The solution was added to a 30% aqueous monomethylamine solution at 0°-5° C. The reaction mixture was stirred at 0°-15° C., diluted with water and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried over anhydrous sodium sulfate and evaporated to dryness to give β-(9,10-dihydro-9,10-methano-9-anthryl)-propionic acid monomethylamide. M.P. 200°-201° C.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][C:7]([C:8]([NH:10][NH2:11])=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:14]([C:17]1[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=1)(=O)[CH3:15].C(O)C>CN(C)C=O>[N:20]1[CH:21]=[CH:22][C:17]([C:14](=[N:11][NH:10][C:8](=[O:9])[C:7]2[CH:12]=[CH:13][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)[CH3:15])=[CH:18][CH:19]=1
Reactant: NNC(=O)c1ccc([N+](=O)[O-])cc1
Reactant: CC(=O)c1ccncc1
Solvent: CN(C)C=O
Solvent: CCO
Product: CC(=NNC(=O)c1ccc([N+](=O)[O-])cc1)c1ccncc1
Yield: 78.4 %

Procedure:
A mixture of 3.62 gm (0.02 mole) of p-nitrobenzhydrazide, 2.42 gm (0.02 mole) of 4-acetylpyridine and 100 ml of absolute ethanol is refluxed 3 hours. Sufficient dimethylformamide is added to the mixture at boiling to give a solution. The hot solution is filtered. The filtrate is diluted with water to the cloud point. The mixture is chilled in the refrigerator. The product is collected, washed with ether and dried to yield 4.46 gm (79%) of the title compound; mp 251.2°.